This case was originally published in 2017. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.
A 58-year-old woman presented with headache, photophobia, and confusion. She reported recent treatment for sinusitis. CT imaging demonstrated a hypodense lesion in the right parieto-occipital lobe with mass effect. MRI showed an enhancing T2-hyperintensity in the right posterior temporal, occipital, and parietal lobes (Image A). Cerebral infarct was diagnosed, and the patient was discharged after clinical management. Two weeks later, she developed headache, altered mental status, and ataxia. MRI showed new lesions in the left frontal lobe and right basal ganglia and interval increase of the right parieto-occipital lesion (Image B and Image C). Within one week, the patient developed seizures with increasing intracranial pressure. She became unresponsive, and imaging confirmed subfalcine and transtentorial herniation. The patient expired shortly thereafter, and a full autopsy was performed.
Right parietal lobe and right basal ganglia
Whole Slide Image
The whole slide image provided is an H&E stain from a brain autopsy.
What is the BEST diagnosis?
Granulomatous amoebic encephalitis
Primary CNS lymphoma
Which of the following is a common etiology of this disease?
What is the proposed mode of transmission for the responsible organism?
Bite from infected mosquito
Contact lenses cleaned with contaminated solutions
Contaminated blood transfusions
Ingestion of contaminated food
Inhalation of contaminated dust or contact with infected skin wounds
What is the MOST RELIABLE method to confirm the diagnosis of Balamuthia mandrillaris infection?
Culture with bacteria-coated agar plates
Multiplex real-time PCR assay
Serologic tests for IgM and IgG titers
Wet mount of CSF
Discussion and Diagnosis
The diagnosis is granulomatous amoebic encephalitis (GAE) caused by Balamuthia mandrillaris infection. Autopsy examination showed an edematous brain with multiple hemorrhagic and necrotic areas in the cerebrum, basal ganglia, cerebellum, and brainstem. Microscopic examination revealed a mixed inflammatory infiltrate, extensive necrosis, and hemorrhage in the brain parenchyma (Image D), as well as chronic inflammation in the leptomeninges. The histomorphologic appearance in GAE can range from acute inflammation with neutrophils to a chronic granulomatous response with lymphocytes, macrophages, and plasma cells. Despite its name, true granulomas are often not seen. Encysted organisms and trophozoites are typically present in a perivascular pattern and are associated with angiitis and hemorrhagic necrosis of the meninges and underlying brain tissue. Trophozoites are pleomorphic (measuring 12–60 µm) and have a vesicular nucleus with one or more dense central nucleoli. Spherical cyst forms (not seen in this case) range in size from 12–30 µm and have a wavy, irregular outer wall composed of three layers. On H&E, the trophic and cyst stages of Acanthamoeba spp. and B. mandrillaris look similar and cannot be accurately differentiated by histomorphology. In this case, necrotic areas harbored prominent perivascular clusters of large cells. As is typical for GAE, these cells resembled macrophages with vesicular nuclei and central nucleoli (Image E) but were negative for macrophage markers CD68 (Image F) and CD163 (Image G). Grocott methenamine silver stain - which can highlight the amoebic cyst wall in more protracted cases - was negative in this example (Image H). Paraffin-embedded tissue sections were subjected to multiplex polymerase chain reaction (PCR) assay, which revealed the causative agent to be Balamuthia mandrillaris.
GAE is a subacute to chronic disease - caused by B. mandrillaris and several species of Acanthamoeba - that most often occurs in immunosuppressed patients. B. mandrillaris is distinct from Acanthamoeba species, however, in that it can also cause infection in immunocompetent hosts. GAE has an insidious onset and protracted clinical course with development of symptoms over a period of two weeks to two years. Clinical signs and symptoms are nonspecific and include headache, meningismus, nausea, and vomiting. There is progression to lethargy, diplopia, hemiparesis, seizures, and coma. Increased intracranial pressure from mass effect and edema can lead to cerebral herniation and death. Due to nonspecific symptoms and difficulty in early diagnosis, there are few documented survivors of GAE. An optimal therapeutic regimen has yet to be established.
Neuroimaging in GAE typically reveals single or multiple space-occupying lesions of low density with peripheral ring enhancement and mass effect. With time, lesions increase in size and number to involve the cerebral hemispheres, cerebellum, brainstem, thalamus, and basal ganglia. These imaging characteristics suggest a wide differential diagnosis including abscess, infarction, vasculitis, and malignant neoplasm. If a lumbar puncture is performed, CSF analysis reveals a profile of aseptic meningitis with moderate lymphocytic pleocytosis, slightly elevated protein, and low to normal glucose levels. Although B. mandrillaris has rarely been isolated from a CSF sample, a wet mount to look for organisms should nonetheless be performed.
The environmental niche for B. mandrillaris is not well understood, but it has mainly been isolated from soil. There are no known insect vectors or human carrier states. The most likely portal of entry for infection is inhalation of contaminated dust or contact with infected skin wounds. The initial site of infection is thought to be the lower respiratory tract, skin, or sinuses. The angiotrophic nature of this organism suggests that B. mandrillaris spreads hematogenously. It has also been isolated from skin, adrenal glands, kidneys, and liver - further supporting the idea of hematogenous dissemination. These amoebic organisms produce metalloproteinases that destroy extracellular matrix and facilitate invasion into human tissue. B. mandrillaris also stimulates microvascular endothelial cells to release interleukin-6 and alter the permeability of the blood-brain barrier.
B. mandrillaris elicits a humoral response in the host with an IgM response in the early stages, followed by an IgG response. The production of serum antibodies results in elevated titers seen in patients. However, both IgM and IgG antibodies have been detected in healthy individuals with titers ranging from 1:64 to 1:256, making the serologic test less helpful for diagnosis. B. mandrillaris cannot be easily cultured because it will not grow on bacteria-coated agar plates. The organism can be isolated with cell-free growth medium and mammalian cell culture, but it has a long doubling time. Definitive identification involves the use of immunohistochemical stains with Balamuthia-specific antibodies, electron microscopy, or Balamuthia-specific PCR from tissue. Multiplex real-time PCR, which can be applied to CSF or brain tissue, is particularly helpful as it can simultaneously detect the free-living amoebae Naegleria fowleri, Acanthamoeba spp., and B. mandrillaris.
Take Home Points
- Granulomatous amoebic encephalitis (GAE), caused by Balamuthia mandrillaris and several species of Acanthamoeba, has a subacute to chronic clinical course.
- Unlike the acanthamoebic form, GAE caused by B. mandrillaris can occur in both immunocompromised and immunocompetent individuals.
- GAE should be considered when neuroimaging shows multiple space-occupying lesions with low density and mass effect.
- Classic histopathology of GAE consists of chronic granulomatous inflammation with angiitis and hemorrhagic necrosis, but true granulomas are frequently not identified. Cysts and trophozoites are found in a perivascular distribution.
- Definitive identification can be made with Balamuthia-specific immunohistochemical stains, Balamuthia-specific PCR, and multiplex real-time PCR assay.
- Baig AM, Khan NA. A proposed cascade of vascular events leading to granulomatous amoebic encephalitis. Microbial Pathogenesis. 2015;88:48-51.
- Ellison D, et al. Parasitic Infections. In: Ellison D, et al., eds. Neuropathology: A reference text of CNS pathology. 3rd ed. New York, NY: Mosby, an imprint of Elsevier; 2013: 403-407.
- Koshy AA, Blackburn BG, Singh U. Free-Living Amebae. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA: Saunders, an imprint of Elsevier; 2015: 3059-3068.
- Vivesvara GS. Pathogenic and opportunistic free-living amoebae: agents of human and animal disease. In: Farrar J, Hotez PJ, Junghanss T, et al, eds. Manson’s Tropical Diseases. 23rd ed. Philadelphia, PA: Saunders, an imprint of Elsevier; 2014: 683-691.
- Yachnis AT, Rivera-Zengotita ML. Parasitic infections. In: Neuropathology: A Volume in the High-Yield Pathology Series. 1st ed. Philadelphia, PA: Saunders, an imprint of Elsevier; 2014: 216-224.
- What is the BEST diagnosis?
- A. Bacterial leptomeningitis
- B. Cerebral infarction
- C. Granulomatous amoebic encephalitis
- D. Primary CNS lymphoma
- E. Vasculitis
- Which of the following is a common etiology of this disease?
- A. Balamuthia mandrillaris
- B. Entamoeba histolytica
- C. Mycobacterium tuberculosis
- D. Naegleria fowleri
- E. Trypanosoma cruzi
- What is the proposed mode of transmission for the responsible organism?
- A. Bite from infected mosquito
- B. Contact lenses cleaned with contaminated solutions
- C. Contaminated blood transfusions
- D. Ingestion of contaminated food
- E. Inhalation of contaminated dust or contact with infected skin wounds
- What is the MOST RELIABLE method to confirm the diagnosis of Balamuthia mandrillaris infection?
- A. Culture with bacteria-coated agar plates
- B. H&E-stained sections
- C. Multiplex real-time PCR assay
- D. Serologic tests for IgM and IgG titers
- E. Wet mount of CSF