Acanthamoeba encephalitis: A Case Report and Review of Therapy

Abstract

Background:

Acanthamoeba is a rare cause of encephalitis yet is associated with high mortality. Treatment protocols vary greatly and generally include combination therapy across a wide spectrum of antiinfective classes.

Case Description:

A 63-year-old male who underwent renal transplantation presented 6 months after transplantation with depressed level of consciousness. Imaging of the head with computerized tomography showed an enhancing lesion suspicious for brain abscess. Biopsy of the lesion showed Acanthamoeba cysts. The patient was treated with sulfadiazine, fluconazole, flucytosine, azithromycin, and miltefosine but without success. We review recently published cases of Acanthamoeba encephalitis with an emphasis on treatment protocols and outcomes.

Conclusion:

Free-living protozoans such as Acanthamoeba are ubiquitous in the environment and should be suspected in immunosuppressed persons who present with central nervous system findings and brain abscess. Biopsy is critical to establish the etiology so that appropriate combination therapy can be deployed.

INTRODUCTION

Acanthamoeba was discovered in 1930 and since then at least 24 species have been described.[19,22] It is ubiquitous in nature and has been isolated from soil, fresh and brackish water, bottled mineral water, cooling towers of power plants, heating, ventilating and air conditioning units, and just about any surface that comes in contact with water, including medical and laboratory devices.[22] Here we report a case of cerebral Acanthamoeba infection in an immunocompromised host, which was unsuccessfully treated with combination therapy including miltefosine.

CASE REPORT

A 63-year-old male with a history of kidney transplantation presented to the Emergency Department for altered mental status. His wife observed the patient to have intermittent confusion for the previous 2 weeks and also noted that he was sleeping more than usual. She denied fever, nausea, vomiting, neck rigidity, photophobia, or any gross motor or sensory deficits in the patient. The patient had not traveled outside Mississippi since his transplant 6 months prior to the onset of symptoms. He was taking mycophenolate and tacrolimus for his renal allograft. On the night of admission the patient was found unresponsive in his bed. Emergency responders found the patient with marked bradycardia and a temporary pacemaker was placed en route to the hospital.

Upon arrival to the hospital the patient was arousable but unable to answer questions or follow commands. Laboratory results included the following: white blood cell count – 9000/μL (90% neutrophils, 5% lymphocytes, 4% monocytes, 1% eosinophils), hemoglobin–10.3 g/dL, hematocrit–32.4%, platelets – 177,000/mL, sodium – 136 mmol/L, potassium – 6.8 mmol/L, chloride – 105 mmol/L, HCO₃^-2- 20 mmol/L, BUN – 42 mg/dL, creatinine – 3.4 mg/dL, lactic acid 3.7 mmol/L, troponin – undetectable. Chest radiograph demonstrated mild cardiomegaly with clear lungs. Computerized tomography (CT) of the head showed low density areas in the left parietal, occipital and frontal lobe thought to potentially be watershed infarcts. He was admitted to the hospital with a diagnosis of ischemic stroke.

Magnetic resonance imaging (MRI) of the brain showed intracranial masses in the left frontal lobe [Figure 1] as well as the left posterior temporal–occipital interface with edema. Dexamethasone was initiated to reduce edema and antiseizure medications were begun as well. Six days after admission, the patient underwent biopsy of the left frontal lobe lesion. This initial biopsy revealed numerous granulomata with extensive abscess formation and necrosis but no pathogens identified with special staining. Three days following the initial biopsy, another biopsy was performed in an effort to make a specific microbiological diagnosis. This second biopsy, of the left temporal region, showed multiple necrosis, gliosis, and protozoans highly suggestive of Acanthamoeba trophozoites [Figure 2]. The patient was started on combination therapy with sulfadiazine, fluconazole, flucytosine, azithromycin, and miltefosine. His hospital course was complicated by declining kidney function, which ultimately required hemodialysis. The patient became pancytopenic and developed intractable fever despite broad-spectrum antibacterial therapy. He expired during his fifth week of hospitalization.

Figure 1.

Magnetic resonance image of the brain showing an enhancing lesion in the left frontal lobe consistent with an abscess

Figure 2.

Giemsa stain of brain tissue showing Acanthamoeba cysts (×400)

DISCUSSION

Granulomatous amoebic encephalitis (GAE) is an infection of the central nervous system with a mortality rate over 50% and is increasingly recognized as an opportunistic infection of immunocompromised hosts. Reported cases of amoebic encephalitis are increasing as awareness of these pathogens and the population of immunosuppressed patients grows. GAE is caused primarily by free-living amoebae species of Acanthamoeba, Sappinia, or Balamuthia. Most cases are diagnosed postmortem and a limited number of cases have reported successful treatment using various combinations of antimicrobial agents.[3,7,14] Mortality from central nervous system (CNS) amoebic infections remains extremely high and may exceed 90%.[5] Currently, there is no recommended standard therapeutic regimen for CNS infections with these amoebae.

The life cycle of Acanthamoeba consist of two stages, a vegetative trophozoite stage and a dormant cyst stage. Under optimal conditions of nutrients, pH and temperature, trophozoitespredominate, however, under stressful conditions, a double-walled cyst is formed. The route of entry into the human body is postulated to be primarily through the lungs or breaks in the skin. The organism then disperses via blood to the brain. The most common manifestations of Acanthamoeba infection are related to CNS involvement. Common signs and symptoms are nonspecific and consist of headache, stiff neck, alterations in mental status or cognitive abilities, nausea, vomiting, low-grade fever, lethargy, gait or coordination disturbances, visual disturbance, focal motor deficits, seizures, or coma.[3,22]

Definitive diagnosis is made by examination of tissue and, rarely, by cerebrospinal fluid (CSF) analysis. CSF may show mild pleocytosis, moderately elevated protein, and low glucose, however, amoebae are frequently seen by any staining or microscopic technique. Serology for amoeba-specific antibodies is available, however, these assays are not widely available and their specificity for active disease is low since most people have been exposed to this organism at one or more times in their life. The most expeditious and common way to make the diagnosis of GAE is to demonstrate trophozoites or cysts in tissue samples.[3] A unique characteristic feature of Acanthamoeba sp. is the presence of fine, tapering, thorn-like acanthopodia protruding from the cell. Trophozoites are 15-50 μm in size with a centrally located nucleus and a densely staining nucleolus. Cysts are 10-25 μm with two cell walls usually discernible and also demonstrate a nucleus with a dense nucleolus. The organism can also be cultivated quite readily in vitro in special media.[3]

Currently, there is no reliably effective drug therapy for Acanthamoeba infection of the CNS. Most published cases have used multiple drug combinations with varying success.[1,2,4,6,8,9,10,11,12,13,15,16,17,18,20,23] A review of the English language literature for cases of CNS infection with Acanthamoeba diagnosed antemortem since 2000 and which described treatment protocols is summarized in Table 1.

Table 1.

Published cases of Acanthamoeba encephalitis since 2000

Of the 18 cases in the literature, 83% (15/18) were males and 61% (11/18) had identifiable underlying immunosuppressive conditions. Mortality was 44% (8/18) and the survivors were evenly divided by the concurrence of an immunosuppressive condition. The number of cases is too small to draw any reliable conclusions about efficacy and there is a large overlap of drugs used between patients who survived and those who succumbed to infection. The Infectious Diseases Society of America (IDSA) guidelines for Acanthamoeba CNS infection have a CIII-level recommendation for either trimethoprim-sulfamethoxazole + rifampin + ketoconazole or fluconazole + sulfadiazine + pyrimethamine.[21] Recently, the Centers for Disease Control and Prevention (CDC) announced the availability of miltefosine as an investigational drug to treat amoebic CNS infection.[5] Two cases included in Table 1 used miltefosine as part of combination therapy and both patients survived. Although the patient presented in this report was also treated with miltefosine, this drug should be strongly considered as part of combination therapy for amoebic infections of the CNS.

CONCLUSION

Because of the rarity of amoebic encephalitis, it is unlikely there will be randomized clinical trials to rigorously test treatment options. Case reports and small series will remain important for identifying trends in epidemiology, natural history, and treatment of amoeba infections of the CNS. As human population demographics shift, and the number of immunosuppressed patients rises, this information will be critical to provide clinicians and laboratory workers with the most effective diagnostic and therapeutic options.