Balamuthia mandrillaris Meningoencephalitis in an Immunocompetent Patient: An Unusual Clinical Course and a Favorable Outcome Open Access

A previously healthy 72-year-old woman in upstate New York presented with recent-onset (2 weeks) multiple episodes of focal motor seizure involving the left side of the face and the left hand, and accompanied by transient visual loss and aphasia. There were no preceding respiratory symptoms or skin infections.

The patient travels frequently to El Paso, Tex, and had been in Arizona recently. She does not swim, but often works in a garden with compost soil and was doing so just prior to her illness. She also works frequently in the soil in Texas.

Findings from the physical examination on admission were relatively unremarkable; the patient had no complaints of fever, chills, headache, skin lesions, or gastrointestinal symptoms. Her cranial nerves were intact. Meningeal signs and papilledema were absent. Motor examination revealed good strength and normal muscle tone. Sensory examination showed grossly intact functioning.

Magnetic resonance imaging with contrast revealed 2 ring-enhancing lesions, one in the right precentral region (1.5 cm) and the other in the left posterotemporal region (0.5 cm) (Figure, A). Suspecting possible metastatic disease, an excisional biopsy of the right frontal lesion was performed. Intraoperative frozen sections and smears showed brain tissue with necrosis, acute inflammation, and reactive changes suggestive of acute infarct. Paraffin sections (Figure, B and C) of formalin-fixed tissue revealed focally necrotic brain tissue with acute and chronic inflammatory infiltrate with a few eosinophils. Some, but not all, tissue fragments showed numerous spherical microorganisms (approximately 30 μm in diameter) with round eosinophilic nuclei and ample pale eosinophilic granular cytoplasm, consistent with amebic trophozoites. No granulomas were seen. Careful retrospective review of the frozen section slides revealed profiles that were suggestive of but not diagnostic for amoeba.

In view of her history of recent travel to Texas, Acanthamoeba and Naegleria infections were considered as possible diagnoses, and empirical antibiotic treatment was initiated. The specimens were also immediately sent to the Division of Parasitic Disease, Centers for Disease Control and Prevention, where Balamuthia mandrillaris was diagnosed by indirect immunofluorescence study. The medication was then switched to pentamidine (300 mg intravenously once a day [qd]), sulfadiazine (1.5 g 4 times a day), fluconazole (400 mg qd), and clarithromycin (500 mg 3 times a day [tid]).

Ten days after the excisional biopsy of the right frontal lesion, a follow-up magnetic resonance image revealed slightly further evolution of the left posterotemporal lesion. However, the patient has been doing well without any neurological symptoms and was discharged home with the prescribed antibiotics on the 13th hospital day. As of the time this article was written, no new lesions or further symptoms had developed and the patient had remained asymptomatic.

Amebic meningoencephalitis classically demonstrates 2 distinct clinical entities: primary amebic meningoencephalitis and granulomatous amebic encephalitis.1 Primary amebic meningoencephalitis is produced by thermophilic Naegleria fowleri. It is an acute, fulminant, hemorrhagic necrotizing meningoencephalitis, resulting in death 3 to 7 days after exposure. Primary amebic meningoencephalitis usually affects children and young healthy adults with a recent history of swimming in freshwater lakes, ponds, or heated swimming pools or contact with dust or mud. In contrast, granulomatous amebic encephalitis is caused by “opportunistic” amebas of Acanthamoeba species or Balamuthia mandrillaris and has a much more prolonged clinical course, often seen in debilitated or malnourished individuals, chronic alcoholics, patients with acquired immunodeficiency syndrome (AIDS), or patients undergoing immunosuppressive therapy for organ transplants.1,2 However, Balamuthia is also capable of infecting healthy hosts, including children.3,4 It has a much more prolonged clinical course than primary amebic meningoencephalitis.

Balamuthia mandrillaris (previously known as Leptomyxid ameba) was first identified as a pathogen when it was isolated from the brain of a mandrill baboon at the San Diego Zoo.2 More than 85 cases of human encephalitis due to B mandrillaris have been reported worldwide; 40 of these occurred in the United States, including 10 patients with human immunodeficiency virus/AIDS.2 Epidemiologically, most cases in the United States have been reported from the warmer southern or southwestern states, but 1 adult case has been reported from New York.5 It is unlikely that the disease has a seasonal pattern, since symptom onsets have been reported in both summer and winter.4 

The life cycle of Balamuthia includes a vegetative trophic stage and a dormant cyst stage. Trophozoites, 12 to 60 μm (mean, 30 μm), are primarily uninucleate with a 5-μm nucleus and a centrally located large nucleolus, occasionally with 2 or 3 nucleoli.2 The cysts, 6 to 30 μm (mean, 15 μm), are usually spherical and have 1 nucleus and a layer of refractile granules underneath the inner cyst wall.2,6 

The pathogenesis of Balamuthia infection remains unclear. The route of infection is thought to be transmission from soil via the skin or respiratory tract, reaching the brain by hematogenous spread. The recent isolation of B mandrillaris from a soil sample7 suggests that our patient probably acquired the infection while working with soil. Diagnosis of B mandrillaris granulomatous amebic encephalitis has been extremely rare antemortem and requires a high degree of suspicion. Neuroimaging usually shows single or multiple, heterogeneous, enhancing lesions with no obvious anatomical predilection.8 ,Balamuthia has not been found in the cerebrospinal fluid.9 The cerebrospinal fluid findings may show mononuclear pleocytosis with elevated protein and normal to low glucose levels. No characteristic clinical presentation, laboratory results, or radiologic findings have been found to be particularly associated with Balamuthia encephalitis.2 Biopsy is necessary for diagnosis and demonstrates patchy chronic or subacute granulomatous encephalitis with trophozoites and cysts present in the brain tissue. As Balamuthia is virtually indistinguishable histologically from Acanthamoeba, further differentiation via immunofluorescence studies or ultrastructural studies is required. Indirect immunofluorescence using antisera against different Acanthamoeba species and B mandrillaris has been available for tissue sections.1,9 A serum antibody test that may be helpful in the diagnosis of B mandrillaris infection also has been developed.10,11 Cultures of B mandrillaris from brain tissue and the environment have been established recently, allowing for assessment of the efficacy of drugs against B mandrillaris in vitro.7,12 

Recent sequencing of mitochondrial small-subunit rRNA genes, unique to B mandrillaris, has resulted in the development of primers that amplify a Balamuthia-specific polymerase chain reaction product.13,14 These primers may be useful for retrospective analysis of fixed tissues and possible identification of Balamuthia in vivo.13 

No known effective treatment for encephalitis due to B mandrillaris has been established to date. However, 2 patients (a 64-year-old man and a 5-year-old girl) with biopsy-confirmed B mandrillaris encephalitis have survived after treatment with the following regimen: clarithromycin, 500 mg qd; fluconazole, 400 mg qd; sulfadiazine, 1.5 g every 6 hours; and 5-fluorocytosine, 1.5 g every 6 hours.15 The 64-year-old man suffered severe neurological defects. Our patient, although 72 years old, is apparently doing well under a similar regimen, 6 months after the brain biopsy.