A 76‐year‐old male with multiple enhancing brain lesions

The patient is a 78yearold male with a history of multiple cutaneous and soft tissue squamous cell carcinomas of the face and ear statuspost resection and a right parotid gland tumor statuspost parotidectomy (diagnosis unknown). He works on a ranch with horses and cows on a property with freshwater ponds. He originally presented with flank pain and weakness. Computed tomography of the chest demonstrated soft tissue disease and lymphadenopathy involving the left axilla and anterior mediastinum, bilateral adrenal masses, and a large pleuralbased mass. To evaluate for malignancy, biopsies of a right adrenal nodule and right pleuralbased mass were performed and demonstrated granulomatous inflammation. He was stabilized clinically and discharged. Five months later, he was admitted because of a multiple month history of subacute mental status changes and inability to ambulate. Magnetic resonance imaging of the head demonstrated numerous enhancing intracranial lesions involving both cerebral hemispheres with prominent adjacent edema, the largest measuring 3.6 cm in the right occipital lobe (Figure 1A– C). He was treated with wholebrain radiation for presumed metastases. Histoplasma PCR and serology, tuberculosis PCR, and evaluation for lymphoma were negative. He continued to decline clinically and underwent an open biopsy of a left frontal brain lesion (Box 1). Received: 12 October 2021 | Accepted: 21 February 2022


| C L I N ICA L PR E SE N TAT ION
The patient is a 78-year-old male with a history of multiple cutaneous and soft tissue squamous cell carcinomas of the face and ear status-post resection and a right parotid gland tumor status-post parotidectomy (diagnosis unknown). He works on a ranch with horses and cows on a property with fresh-water ponds. He originally presented with flank pain and weakness. Computed tomography of the chest demonstrated soft tissue disease and lymphadenopathy involving the left axilla and anterior mediastinum, bilateral adrenal masses, and a large pleural-based mass. To evaluate for malignancy, biopsies of a right adrenal nodule and right pleural-based mass were performed and demonstrated granulomatous inflammation. He was stabilized clinically and discharged. Five months later, he was admitted because of a multiple month history of subacute mental status changes and inability to ambulate. Magnetic resonance imaging of the head demonstrated numerous enhancing intracranial lesions involving both cerebral hemispheres with prominent adjacent edema, the largest measuring 3.6 cm in the right occipital lobe ( Figure 1A-C). He was treated with whole-brain radiation for presumed metastases. Histoplasma PCR and serology, tuberculosis PCR, and evaluation for lymphoma were negative.
He continued to decline clinically and underwent an open biopsy of a left frontal brain lesion (Box 1).

BOX 1 Slide scan
Access the whole slide scan at http://image.upmc. edu:8080/Neuro Patho logy/BPA/BPA-21-10-253. svs/view.apml? . These structures were present throughout the brain parenchyma and clustered around blood vessels, which were variably necrotic ( Figure 2C). No encysted forms were identified. There was a mixture of associated acute and chronic inflammation and regions of collagen deposition, reminiscent of early granulation tissue formation. A diagnostic study was obtained. Shortly following this diagnosis because of continued patient decline, he was transitioned to comfort care measures and died.
The diagnosis was confirmed by multiplex real-time polymerase chain reaction (PCR) for the detection of free-living amebae, performed on formalin-fixed paraffin-embedded tissue.

| DI SC US SION
Various free-living amebae (FLAs) can cause central nervous system infection in humans, including B. mandrillaris, Naegleria fowleri, and multiple species of Acanthamoeba [1][2][3]. N. fowleri leads to a rapidly fatal infection, primary amoebic meningoencephalitis (PAM), which typically affects children and young adults who have recently swam in freshwater [1][2][3]. Granulomatous amoebic encephalitis (GAE) is caused by B. mandrillaris and multiple species of Acanthamoeba. Although patients who develop GAE because of Acanthamoeba spp. are typically immunocompromised, B. mandrillaris can infect immunocompetent individuals, particularly children and older adults [1,2]. Systemic infection with B. mandrillaris can have a subacute to chronic clinical course, developing over 2 weeks to 2 years [1,3].
As a soil-borne pathogen, B. mandrillaris is found ubiquitously in the environment, and infection rates have no relation to seasonal changes [2]. Possible routes of infection include inhalation of B. mandrillaris present in the soil or inoculation through a wound [3]. The exact pathogenic mechanisms of B. mandrillaris that allow it to gain access to the central nervous system are unclear, although studies have demonstrated that it possesses enzymes such as metalloprotease, which may lead to degradation of extracellular matrix (ECM) proteins once it has reached the blood-brain barrier [2]. By electron microscopy, B. mandrillaris has been demonstrated to show cup-like structures which bind to ECM proteins [2]. Additionally, it has been shown that B. mandrillaris induces the production of cytokine interleukin-6 by brain endothelial cells, which may initiate an inflammatory response [3].
Histologically, two stages within the life cycle of B. mandrillaris can be identified: the trophozoite and the cyst form. The trophozoites are typically uninucleate and have a nucleus with a centrally placed, dense karyosome, and abundant bubbly cytoplasm [1][2][3]. Although not identified in this case, double-walled cysts are also often seen and can be a histologic feature that distinguishes it from N. fowleri [1][2][3]. Trophozoites and cysts may be seen within and surrounding blood vessel walls with an associated mixed acute and chronic inflammation, in addition to hemorrhage and necrosis. Given that patients with GAE may be immunocompromised, the presence of granulomatous inflammation is variable [1].
GAE caused by B. mandrillaris may be preceded by painless, plaque-like skin lesions up to 2 years prior to the encephalitic presentation [1][2][3]. However, once GAE has developed, the clinical course is often fatal [2]. Common presenting neurologic symptoms include headache, nausea and vomiting, seizures, meningismus, and myalgia [2,3]. Imaging findings are variable in patients with GAE, ranging from an isolated to multiple low-density, "spaceoccupying" lesions, which may mimic other disease processes such as abscess, metastatic tumor, or hemorrhage [3].