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. 2025 Mar 13;13:60. doi: 10.1186/s40478-025-01963-8

The role of plasma metagenomic sequencing in identification of Balamuthia mandrillaris encephalitis

Sarah Y Edminster 1,2, Ryan W Rebbe 1,2, Christopher Khatchadourian 1,2, Kyle M Hurth 1,2, Anna J Mathew 1,2, Julie Huss-Bawab 1,2, Mark S Shiroishi 3, Devin Clark 4, Andrew P Norgan 5, Susan M Butler-Wu 1,2, Annie Hiniker 1,2,✉
PMCID: PMC11908043  PMID: 40082992

Abstract

Balamuthia mandrillaris is a rare, free-living amoeba (FLA) that causes granulomatous amoebic encephalitis, a disease with close to 90% mortality. The geographical ranges of many FLA are expanding, potentially increasing human exposure to B. mandrillaris. Here, we report a case of a 58-year-old woman with progressive neurological symptoms, ultimately diagnosed postmortem with B. mandrillaris encephalitis through plasma metagenomic next-generation sequencing (mNGS) despite negative results on both cerebrospinal fluid (CSF) mNGS and CSF PCR testing. Histologic analysis and real-time PCR (qPCR) studies on postmortem brain tissue confirmed B. mandrillaris infection with significant vascular clustering of trophozoites. Retrospective analysis of CSF mNGS data demonstrated subthreshold reads for B. mandrillaris, emphasizing the challenges of interpreting low-level pathogen signals. A systematic review of 159 published B. mandrillaris cases revealed only two reports of B. mandrillaris diagnosed using plasma mNGS, both of which also had diagnostic CSF studies. This case demonstrates the diagnostic challenges of B. mandrillaris infections, highlights its vascular tropism, and suggests that plasma mNGS may warrant evaluation as a diagnostic tool for B. mandrillaris.

Keywords: Balamuthia, Balamuthia mandrillaris, Amoeba, Amoebic encephalitis, Plasma metagenomic sequencing, Free living amoeba, Granulomatous amoebic encephalitis

Introduction

Balamuthia mandrillaris is a free-living amoeba (FLA) that causes granulomatous amoebic encephalitis (GAE), a rare and highly fatal condition characterized pathologically by variable degrees of inflammation, granuloma formation, and tissue necrosis. Found in soil and water, B. mandrillaris infections typically arise from direct inoculation through skin wounds or inhalation [11]. GAE often presents with nonspecific neurological symptoms, including headache, fever, and focal deficits, which complicates diagnosis and can delay treatment [11]. Accurate diagnosis requires differentiation from Acanthamoeba spp., another cause of GAE.

The increasing prevalence of amoebic infections over recent decades has been associated with climate change [27], suggesting that the need for diagnostic tools for B. mandrillaris may increase. Traditional diagnostic methods such as cerebrospinal fluid (CSF) analysis and neuroimaging frequently fail to identify B. mandrillaris [92]. Recent advances in metagenomic next-generation sequencing (mNGS) have augmented diagnosis of many central nervous system infections [25, 29, 36, 104]. mNGS sequences all nucleic acids present in a sample at very high depth, allowing unbiased pathogen detection from diverse tissue samples [25, 29, 36, 104]. While mNGS has been applied successfully to CSF and brain tissue in many GAE cases, the diagnostic utility of plasma mNGS in GAE has not been comprehensively evaluated.

Here, we report a fatal case of B. mandrillaris GAE diagnosed via plasma mNGS, despite negative CSF mNGS results. Retrospective analysis of CSF mNGS revealed subthreshold reads for B. mandrillaris, emphasizing the challenges of interpreting low-level pathogen signals. This case and our review of the literature highlight the organism’s pronounced vascular tropism, which we hypothesize could underlie a potential utility for plasma mNGS as a diagnostic tool for GAE.

Case presentation

A 58-year-old woman, with no significant past medical history, presented with 10 days of progressive neurological symptoms, including right facial numbness, left-sided hemiparesis, imbalance, and tinnitus. She presented with no visible skin lesions; however, she reported having sustained superficial scratches on her arms from gardening several weeks prior, which had resolved. Upon examination, no skin lesions were observed. Brain MRI revealed a 2.1 cm rim-enhancing lesion in the right pons with surrounding edema and mass effect (Fig. 1a). CSF analysis showed lymphocytic pleocytosis (132–203 cells/µL), increased opening pressure (27 cm H2O), elevated protein (64 mg/dL), and normal glucose levels. Comprehensive testing for bacterial, fungal, mycobacterial, viral, and autoimmune etiologies yielded negative results (see Table 1). Flow cytometry indicated reactive T-cells without aberrancy.

Fig. 1.

Fig. 1

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Initial MRI and surgical biopsy. a Initial axial post-contrast T1-weighted MRI, performed the day after admission, showed a right pontine rim-enhancing lesion (arrow). Right middle cerebellar peduncle biopsy demonstrated b macrophage-rich chronic inflammation (H&E, 20x) with c CD68 stain highlighting numerous macrophages (CD68, 20x). d Rare possible granulomas were identified (H&E, 40x). Scale bars: b, c = 50 µm, d = 20 µm

Table 1.

Laboratory test results

Test type Test name Result
Culture Aerobic & Anaerobic No growth
AFB No growth
Serology Interferon-gamma Release Assay Non-reactive
HIV Ab/Ag screen Non-reactive
RPR Qualitative Non-reactive
Toxoplasmosis Ab IgG/IgM Not Detected
Aspergillus Ab Not Detected
CNS Demyelination Ab Panel No Informative Antibodies Identified
ANCA Ab Not Detected
Sjogren Ab Not Detected
PCR E. coli KI Not Detected
H. influenzae Not Detected
L. monocytogenes Not Detected
N. meningitidis Not Detected
S. agalactiae Not Detected
S. pneumoniae Not Detected
CMV Not Detected
HSV-1 Not Detected
HSV-2 Not Detected
VZV Not Detected
EBV Not Detected
HSV-6 Not Detected
HPeV Not Detected
C. neoformans/gattii Not Detected
Coccidioides Ab Not Detected
Other CSF Cytology & Chemistry Colorless & Clear, > 200 cells/mm3, PMN 11%, Plasma 2%, Nucleated cell count 2%, Lymph 85%, Mono 60 mg/dL, Protein 64 mg/dL
Flow Cytometry No Abnormal T-cell Population
Oligoclonal Bands Absent
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A biopsy of the right middle cerebellar peduncle showed chronic inflammation with macrophage infiltration (CD68-positive) and necrosis, without identifiable organisms and with rare possible granulomas (Fig. 1b–d). Stains for acid-fast bacilli (AFB), fungal organisms (GMS), Gram-positive/negative bacteria, and other pathogens were negative. Cultures of blood, CSF, and biopsy tissue—including anaerobic, fungal, and mycobacterial screens—were negative. Despite broad-spectrum antimicrobials and methylprednisolone for suspected demyelination, the patient’s condition deteriorated.

Follow up MRI, performed 28 days after the initial scan, demonstrated expansion of the initial lesion with new brainstem, cerebellar, cerebral, and leptomeningeal lesions (Fig. 2a–c), and multifocal vessel wall enhancement of the bilateral middle cerebral, internal carotid, and vertebral arteries (Fig. 4a–d). Cyclophosphamide was initiated for suspected primary CNS angiitis. Biopsies of the dura and cerebellum showed only chronic inflammation. mNGS of CSF was not reported to be positive for any organisms. The patient’s disease progressed to status epilepticus, obstructive hydrocephalus, brainstem herniation, and death. Plasma mNGS, ordered prior to the patient’s death, identified B. mandrillaris postmortem.

Fig. 2.

Fig. 2

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Follow-up MRI findings and gross brain at postmortem examination. Axial post-contrast T1-weighted MRI performed on day 29 of hospitalization showed a expansion of the initial pontine lesion (arrow) with b new brainstem (arrow) and cerebellar lesions (arrows) as well as c cerebral (white arrow) and leptomeningeal (red arrows) lesions. d Brain at autopsy with cerebral edema, cerebellar herniation, hemorrhage, and brainstem necrosis (arrow)

Fig. 4.

Fig. 4

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Vessel wall enhancement on antemortem MRI and H&E stain of postmortem brain. Axial post-contrast T1-weighted MRI performed on day 29 of hospitalization showed vessel abnormalities, including a bilateral middle cerebral artery (MCA) and b bilateral internal carotid artery (ICA) wall enhancement (arrows). c and d provide closer views of vessel wall enhancement (arrows; brightness/contrast of image adjusted for visualization). e Fibrinoid necrosis of the vasculature (arrow, H&E, 20x). f Perivascular trophozoites in the cerebellum (arrow, H&E, 40x). Scale bars: e = 50 µm, f = 20 µm

Autopsy revealed severe cerebral edema, cerebellar herniation, hemorrhage, and necrosis of the occipital lobes, brainstem, and cerebellum (Fig. 2d). Histopathological evaluation demonstrated trophozoites and cysts in necrotic brain tissue and perivascular spaces (Fig. 3a–c). There was marked perivascular inflammation with fibrinoid necrosis of vasculature (Fig. 4e). The trophozoites, many of which were necrotic, were round to ovoid with foamy cytoplasm; most had a single, round nucleus (Fig. 3b). The cyst forms appeared to show varying stages of development, with mature cysts characterized by thick, multilayered capsules enclosing vacuolated cytoplasm, and a nucleus (Fig. 3c). Prominent perivascular clustering of trophozoites and vascular invasion were observed, primarily by cyst forms (Figs. 4f and 5). Giemsa (Figs. 3a, 5d) and PAS (Fig. 5a and b) stains highlighted amoebae. Targeted qPCR on formalin-fixed paraffin-embedded (FFPE) brain tissue confirmed B. mandrillaris DNA in the brainstem and cerebellum (Fig. 3d). Retrospective analysis of CSF mNGS revealed subthreshold reads for B. mandrillaris. PCR for B. mandrillaris on this CSF sample was negative.

Fig. 3.

Fig. 3

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B. mandarallis trophozoites and cysts, and free-living amoeba PCR. a Trophozoites adjacent to cerebellar granule cells (Giemsa, 40x). High-power views of b trophozoites (H&E, 100x) and c cysts (H&E, 100x). d PCR amplification curves of B. mandrillaris specific nucleic acid in: (A) B. mandrillaris positive control (Cp = 28.3) and (B) patient’s cerebellar FFPE tissue (Cp = 31). (C) negative controls (Naegleria fowleri and Vero cell line controls). Scale bars: a = 200 µm; b, c = 10 µm

Fig. 5.

Fig. 5

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Vascular tropism of B. mandrillaris observed at postmortem brain examination. a–b Perivascular trophozoites in the cerebellum (arrows) (PAS; a: 20x, b: 40x). c–e Invasion of the arterial wall, predominantly by cysts (c: H&E, 10x; d: Giemsa, 40x; e: H&E, 100x). Scale bars: a = 50 µm, b, d = 20 µm, c = 100 µm, e 10 µm

Discussion and conclusions

GAE is a rare but often fatal infection caused by free-living amoebae (FLA) such as Acanthamoeba spp. and B. mandrillaris (previously known as “leptomyxid ameba”) [8]. Our autopsy findings included striking perivascular clustering of amoebae and vascular invasion (Figs. 4, 5). The organism’s ability to cross the blood–brain barrier involves interactions with human brain microvascular endothelial cells (HBMECs) via carbohydrate moieties, facilitating CNS invasion [53]. This vascular affinity likely contributed to the multifocal vessel wall enhancement observed on imaging (Fig. 4a–d). We hypothesized that these characteristics facilitated the detectability of circulating trophozoites or DNA fragments in plasma, leading to the positive plasma mNGS result in this case.

To further investigate diagnostic testing regimens and vascular association of B. mandrillaris, we performed a PubMed review with key words “Balamuthia mandrillaris” or “leptomyxid ameba” and identified 159 unique published cases of B. mandrillaris infection that had clear CNS or skin involvement and also reported patient demographics, outcome, and diagnostic methods (Table 2). This revealed 120 cases of B. mandrillaris diagnosed in brain tissue, 18 in skin, and 30 in CSF, with some cases diagnosed at more than one site. There was a high mortality rate of approximately 89%. The average patient age was 36 years, with cases spanning all age groups: children (< 18 years, 59 cases), adults (18–64 years, 72 cases), and older adults (65 + years, 28 cases). Gender distribution included 100 males and 58 females. One case lacked gender information. Within the United States, cases were geographically widespread, with the highest concentrations reported in Texas and California. Notably, the vascular tropism of B. mandrillaris observed in our case aligned with many prior studies. We identified both in vitro evidence for a predilection for perivascular invasion and vascular inflammation [53] as well as at least 10 cases with explicit mention of perivascular or vascular involvement on neuropathologic tissue analysis [24, 32, 33, 50, 56, 79, 81, 120–122].

Table 2.

A systematic review of 159 reported cases of B. mandrillaris infection: demographics, initial presentation, outcome, and diagnostic methods

Publication [References #] Demographics (age in years, gender) Clinical presentation Outcome Method of diagnosis Diagnosed by plasma mNGS
Our case 58 F Progressive facial numbness, hemiparesis, imbalance, and tinnitus Deceased mNGS (plasma), qPCR (brain), negative on PCR & mNGS (CSF) Yes
Aboubechara et al. (2024) [120] 4 F Facial droop, dysarthria, hemiparesis, upper respiratory tract symptoms, headache, fever Deceased mNGS (plasma), PCR (CSF) Yes
Xiong et al. (2024) [119] 35 M Fever, limb convulsions, progressive quadriparesis Deceased mNGS (brain) No
Wang et al. (2024) [90] 49 F Headache, dizziness, nausea, emesis, prior skin lesion(s) Deceased mNGS (brain) No
Zheng et al. (2024) [102] 58 M Headache, fever Deceased mNGS (CSF) No
Szymanski et al. (2024) [80] 3 M Fatigue and facial pain, previously healthy with baseline facial palsy with right lip droop Deceased Not specified Not specified
Javed et al. (2024) [33] 33 F Back pain, headache, emesis Deceased PCR & Sanger sequencing (specimen not specified) No
Qin et al. (2024) [66] 47 M Fever following allogenic renal transplant Not specified mNGS (specimen not specified) Not specified
Xu et al. (2024) [94] 66 F Headache Deceased mNGS (CSF) No
Qin et al. (2024) [65] 52 M Headache, difficulty walking, blunted affect Deceased mNGS (CSF), PCR (CSF) No
Li et al. (2024) [46] 77 F Dizziness, unsteady gait Deceased mNGS (CSF) No
Ono et al. (2023) [56] 76 F Headache, nausea Deceased PCR (brain), negative PCR (CSF) No
Gramp et al. (2023) [24] 66 M Skin lesion(s) Deceased PCR (skin & brain) No
Yao et al. (2023) [97] 64 F Headache, abdominal pain, dizziness, unsteady gait, cough, emesis, prior skin lesion(s) Deceased mNGS (CSF), PCR (CSF), qRT-PCR (CSF) No
Spottiswoode et al. (2023) [105] 50s M Seizure Survived mNGS (brain) & Sanger sequencing (brain), negative mNGS (CSF) & PCR(CSF) No
Liu et al. (2023) [47] 61 M Headache Deceased mNGS (CSF) No
Sakusic et al. (2023) [71] 61 F Headache, prior orthotopic heart transplant Deceased Broad-range PCR sequencing (brain) No
Fan et al. (2023) [20] 56 M Transient coma, nausea, emesis Deceased mNGS (CSF) No
Xu et al. (2022) [108] 54 M Headache, dizziness, skin lesion(s) Deceased mNGS (CSF) No
Saffioti et al. (2022) [109] 17 M Headache, weight loss, swollen nose Deceased qPCR (brain) No
Levinson et al. (2022) [106] 80 M Altered mental status, dizziness, vision loss Survived Multiplex RT-qPCR (CSF & brain) No
Tootla et al. (2022) [85] 3(?) Skin lesion(s) Deceased PCR (skin) with bidirectional Sanger sequencing No
Wang et al. (2022) [89] 14 M Skin lesion(s) Survived IHC (skin) No
Wang et al. (2022) [89] 57 F Skin lesion(s) Deceased IHC (skin) No
Wang et al. (2022) [89] 9 M Skin lesion(s) Survived IHC (skin) No
Maehara et al. (2022) [50] 82 M Amnesia, skin lesion(s) Deceased IHC (skin & brain), PCR and sequencing (skin & brain) No
Zhang et al. (2021) [101] 7 M Skin lesion(s) Deceased IHC (skin), PCR (skin), negative NGS (skin) No
Cuoco et al. (2022) [14] 4 M Seizure Survived multiplex RT-qPCR (brain) No
Peng et al. (2022) [59] 54 M Numbness and weakness of extremity Survived mNGS (CSF, brain, & serum) No (serum)
Hu et al. (2022) [30] 37 F Dizziness, skin lesion(s) Deceased mNGS (CSF) No
Ai et al. (2022) [1] 15 M Fever, altered mental status, previous skin lesion(s) Deceased mNGS (CSF), PCR (skin) No
Hirakata et al. (2021) [29] 60 F Homonymous hemianopsia Deceased mNGS (brain), PCR (brain & skin), IHC (brain & skin) No
Kalyatanda (2020) [36] 51 M Seizure, headache, altered mental status, disorientation, left-sided weakness, night sweats, diarrhea Deceased mNGS (plasma), multiplex qPCR (CSF), IHC (brain) Yes
Yi et al. (2020) [98] 9 F Emesis, loss of appetite, fever, headache, difficulty walking, blurred vision, altered mental status Deceased mNGS (CSF) No
Mani et al. (2021) [51] 51 M Blurry vision, headache, imbalance, altered mental status Deceased Multiplex qPCR (CSF) No
Lee et al. (2021) [44] 50 M Headache, dizziness, dysarthria, aphasia Deceased qPCR (brain) No
Zwillman et al. (2021) [103] 65 M Weakness, lethargy, lower extremity cellulitis, fever, encephalopathy Deceased qPCR (brain), IHC (brain) No
Suyo-Prieto et al. (2020) [78] 21 M Seizure, skin lesion(s), nausea, headache Deceased PCR and sequencing (skin) No
Safavi et al. (2021) [70] 3 F Altered mental status, emesis, dizziness, seizure, hemiparesis, ataxia Deceased PCR (brain) No
Wu et al. (2020) [93] 13 F Dizziness, emesis, and blurry vision, prior skin lesion(s) Deceased NGS (CSF), PCR (skin), immunostaining (serum & CSF) No
Aoki et al. (2020) [3] 63 F Dyspnea and left recurrent nerve paralysis Deceased PCR (brain), IHC (brain) No
Pan et al. (2020) [58] 85 F Confusion, weakness, slurred speech Deceased qPCR (brain), PCR (brain) No
Yang et al. (2020) [96] 2 M Fever Deceased NGS (CSF) No
Suzuki et al. (2020) [79] 68 M Seizures, transient right hemiparesis Deceased IHC (brain), PCR (brain) No
Lee et al. (2020) [43] 45 M Seizure Deceased qPCR (brain) No
Kum et al. (2019) [110] 71 M Muscle spasms Deceased Diagnosed based on histomorphology of brain tissue, no confirmatory testing No
Yohannan et al. (2019) [99] 69 F Altered mental status Deceased qPCR (brain), IHC (brain) No
Hara et al. (2019) [116] 56 M Seizure, hemiparalysis, fever, altered level of consciousness Deceased IHC (brain) No
Hara et al. (2019) [116] 72 F Lightheadedness, fever Deceased IHC (brain) No
Hara et al. (2019) [116] 53 M Headache, fever Deceased IHC (brain) No
Hara et al. (2019) [116] 56 F Fever, malaise Deceased IHC (brain) No
Hara et al. (2019) [116] 69 M Altered level of consciousness Deceased IHC (brain) No
Hara et al. (2019) [116] 72 M Loss of appetite, cognitive decline Deceased CSF microscopy, no confirmatory testing No
Hara et al. (2019) [116] 79 M Skin lesion(s) Deceased IHC (brain), PCR (brain) No
Hara et al. (2019) [116] 67 F Diplopia, lightheadedness Deceased Not specified No
Hara et al. (2019) [116] 61 F Homonymous hemianopsia Deceased Whole genome sequencing (brain), PCR (brain), and IHC (brain) No
Hara et al. (2019) [116] 55 M Unknown Deceased IHC (brain), PCR (brain) No
Piper et al. (2018) [62] 69 F Skin lesion(s), seizures, prior chronic sinus infection Deceased qPCR (skin & brain), IFA (serum) No
Tarai et al. (2018) [82] 57 M Altered mental status, seizures Deceased PCR (brain) No
Shehab et al. (2018) [112] 13 F Hemiparesis, slurred speech Deceased Diagnosed based on histomorphology of brain tissue, no confirmatory testing No
Joo et al. (2018) [34] 6 M Headache, fever, emesis Deceased qPCR (CSF) No
Takei et al. (2018) [81] 74 F Somnolence Deceased IHC (brain), negative PCR (CSF, brain) No
Cope et al. (2018) [12] 18 F Headache, fever, lethargy Deceased qPCR (CSF) No
Lehmer et al. (2017) [111] 84 M Skin lesion(s) Survived IFA (brain & skin) No
Mittal et al. (2017) [54] 32 M Seizure Not specified IFA and PCR (specimen not specified) No
Chang et al. (2016) [9] 91 F Skin lesion(s) Survived IHC (skin), PCR (skin) No
Vollmer et al. (2016) [88] 26 M Visual disturbances, lightheadedness, headache, syncope Survived IFA (brain), PCR (brain) No
Kobayashi et al. (2015) [40] 57 F Headache Deceased IHC (brain), PCR (brain) No
Ott et al. (2015) [113] 41 M Encephalitis symptoms Deceased PCR (specimen not specified) No
Roy et al. (2015) [69] 11 M Nausea, emesis, lethargy, clumsiness, and right-sided weakness Deceased IFA (brain, lung), qPCR (brain, CSF), Sanger sequencing (brain, CSF), serology No
Wilson et al. (2015) [92] 74 F Altered mental status, fever Deceased mNGS (CSF), PCR (brain, CSF) Sanger sequencing (brain, CSF), serology, IHC (brain) No
Schafer et al. (2015) [72] 82 M Fever, chills, nausea, emesis, lethargy, altered mental status, prior skin lesion(s) Deceased qPCR (brain), IFA (skin) No
van der Beek et al. (2015) [86] 61 F Fever, headaches, myalgias, prior skin lesions Deceased qPCR (brain, CSF) with sequencing No
Khurana et al. (2015) [39] 18 M Headache, emesis, limb weakness, slurred speech, fever, altered mental status Deceased PCR (brain) No
Khurana et al. (2015) [39] 18 M Headache, diplopia, fever, emesis Deceased PCR (brain) with sequencing No
Greninger et al. (2015) [115] 15 F Limb weakness, headache, emesis, ataxia, confusion Deceased mNGS (CSF, brain), PCR (brain)  No
Itoh et al. (2015) [32] 81 M Somnolence, disoriented, ataxic gait Deceased PCR (brain), IHC (brain) No
Pindyck et al. (2014) [114] 56 M Fever, hyponatremia Deceased IHC (brain), PCR (specimen not specified) No
Lobo et al. (2013) [48] 48 F Headache, neck pain, fever, diplopia, slurred speech, fever Deceased IFA (brain, serum) No
Phillips et al. (2013) [61] 59 M Headache, numbness, tingling Deceased PCR (brain) No
Krasaelap et al. (2013) [42] 4 F Headache, emesis Deceased PCR with sequencing (brain & CSF) No
Moriarty et al. (2013) [117] 4 F Headache, abnormal gait, seizures Survived PCR (brain), serology and IFA (brain) No
Moriarty et al. (2013) [117] 11 F Fever, headache, meningismus Deceased IFA (brain), PCR (brain) No
Kato et al. (2013) [118] 72 M Somnolence, altered level of consciousness, hemiparesis Survived Diagnosed based on CSF morphology, negative PCR (CSF) & IFA (brain) No
Stidd et al. (2012) [77] 2 F Initial fall followed by recurrent falls, ataxia, irritability, lethargy, photophobia, fever Deceased qPCR (brain), IFA (brain) No
Hill et al. (2011) [28] 0 y 8 mo F Lethargy, irritability, seizures, weakness Deceased IFA (brain) No
Doyle et al. (2010) [18] 80 F Skin lesion(s) Survived PCR (brain & skin) No
Yamasaki et al. (2011) [95] 51 F Seizure Deceased IHC (brain), ELISA (brain) No
Silva et al. (2010) [75] 47 F Headache Deceased IHC (brain), PCR (brain) No
Centers for Disease Control and Prevention (CDC) (2010) [7] 27 M Organ donor, presented with presumed stroke, prior skin lesion(s) Deceased Not specified No
Centers for Disease Control and Prevention (CDC) (2010) [7] 56 M Liver transplant recipient, presented with diplopia and difficulty walking Deceased qPCR (brain), IHC (brain & liver) No
Centers for Disease Control and Prevention (CDC) (2010) [7] 24 M Kidney and pancreas transplant recipient, presented with headache, nausea, emesis Deceased qPCR (brain), IHC (brain) No
Centers for Disease Control and Prevention (CDC) (2010) [6] 4 M Organ donor, presented with fever, personality changes, loss of appetite, muscle twitching, headache, seizure Deceased IHC (brain), IFA (brain), PCR (brain) No
Centers for Disease Control and Prevention (CDC) (2010) [6] 31 F Kidney transplant recipient, presented with paresthesias, muscle spasms, headache, nausea, altered mental status, seizure Deceased PCR (brain) No
Centers for Disease Control and Prevention (CDC) (2010) [6] 27 M Kidney transplant recipient, presented with headache, nausea, altered mental status, seizure Survived PCR (CSF) No
Cary et al. (2010) [5] 2 M Vomiting and diarrhea Survived IFA (brain) No
Kansagra et al. (2009) [37] 43 M Fever, headache, and nausea Deceased IFA (brain) No
Prasad et al. (2008) [107] 22 M Numbness, vertigo, difficulty swallowing, weakness, seizure, chronic suppurative otitis media Deceased PCR (brain) No
Silva-Vergara et al. (2007) [76] 32 M Headache, blurred vision, and fever Deceased IFA (brain) No
Perez et al. (2007) [60] 40 M Seizure Deceased IFA (brain) No
Cuevas et al. (2006) [13] 5 F Skin lesion(s) Deceased Diagnosed based on histomorphology of brain tissue, no confirmatory testing No
Tavares et al. (2006) [84] 8 M Headache, medial esotropia, diplopia, signs of intracranial hypertension Deceased IFA (brain), PCR (brain) No
Li et al. (2005) [45] 6 F Headache and stiff neck Deceased IFA (brain) No
White et al. (2004) [91] 32 M Confusion and focal neurological signs, prior skin lesion(s) Deceased IFA (serum) No
Intalapaporn et al. (2004) [31] 23 M Skin lesion(s) Deceased IFA (brain) No
Jung et al. (2004) [35] 72 F Seizure, visual loss, aphasia Survived IFA (brain) No
Pritzker et al. (2004) [64] 89 M Skin lesion(s) Deceased IFA (skin) No
Deetz et al. (2003) [15] 64 M Hemiparesis, speech difficulty, seizure Survived IFA (brain) No
Deetz et al. (2003) [15] 5 F Seizure, fever Survived IFA (brain) No
Bakardjiev et al. (2003) [4] & Schuster et al. (2003) [73] 3 F Fever, fatigue, otitis media, dehydration,seizure, emesis Deceased IFA (serum, brain), PCR (brain) with sequencing  No
Bakardjiev et al. (2003) [4] 2 F Fever, headache, lateral eye deviation, facial palsy, hemiparesis, otitis media Deceased IFA (brain) No
Bakardjiev et al. (2003) [4] 7 M Fever, chills, seizure, wide based gait, cranial nerve palsy (VI), abdominal pain personality change Deceased Elevated serum titers No
Bakardjiev et al. (2003) [4] 2.5 M Fever, emesis, ataxia Deceased IFA (brain), titers (serum, CSF) No
Shirabe et al. (2002) [74] 78 F Fever Deceased IFA (brain) No
Galarza et al. (2002) [21] 12 M Skin lesion(s) Deceased IFA (brain) No
Galarza et al. (2002) [21] 5 M Skin lesion(s), seizure, loss of consciousness Deceased IFA (brain) No
Galarza et al. (2002) [21] 3 F Seizure, loss of consciousness, hemiparesis Deceased IFA (brain) No
Galarza et al. (2002) [21] 6 M Skin lesion(s), hemiparesis, loss of consciousness Deceased IFA (brain) No
Katz et al. (2000) [38] 52 F Seizure, prior skin lesion(s) Deceased IFA (brain) No
Deol et al. (2000) [17] 38 M Skin lesion(s), weight loss, seizures Deceased IFA (brain) No
Recavarren-Arce et al. (1999) [122] 22 M Skin lesion(s), neurological symptoms Deceased IFA (brain) No
Recavarren-Arce et al. (1999) [122] 5 M Skin lesion(s), neurological symptoms Deceased IFA (brain) No
Recavarren-Arce et al. (1999) [122] 9 M Skin lesion(s), neurological symptoms Deceased IFA (brain) No
Recavarren-Arce et al. (1999) [122] 10 M Skin lesion(s), neurological symptoms Deceased IFA (brain) No
Recavarren-Arce et al. (1999) [122] 12 M Skin lesion(s), neurological symptoms Deceased IFA (brain) No
Recavarren-Arce et al. (1999) [122] 50 F Skin lesion(s), neurological symptoms Deceased IFA (brain) No
Recavarren-Arce et al. (1999) [122] 34 M Skin lesion(s), neurological symptoms Deceased IFA (brain) No
Recavarren-Arce et al. (1999) [122] 14 M Skin lesion(s), neurological symptoms Deceased IFA (brain) No
Recavarren-Arce et al. (1999) [122] 28 M Skin lesion(s), neurological symptoms Deceased IFA (brain) No
Kodet et al. (1998) [41] 3 M Lethargy, seizure Deceased IFA (brain) No
Denney et al. (1997) [16] 32 M Nausea, emesis, headache Deceased IFA (brain) No
Reed et al. (1997) [67] 5 M Skin lesion(s) Deceased IFA (brain) No
Duke et al. (1997) [19] 3 M Pharyngitis, fever, chills, emesis, irritability, somnolence Deceased Not specified No
Rowen et al. (1995) [68] 5 M Extremity weakness, slurred speech Deceased IFA (brain) No
Rowen et al. (1995) [68] 15 M Headache, emesis, abdominal pain Deceased IFA (brain) No
Martinez et al. (1994) [52] 14 M Seizure, limb weakness, headache Deceased IFA (brain) No
Zagardo et al. (1997) [100] 34 F Seizure, fever, cranial nerve palsy, pronator drift Deceased IFA (brain) No
Lowichik et al. (1995) [49] 0 y 11 mo F Internal strabismus, unsteady crawling, difficulty grasping objects, cranial nerve palsy Deceased IFA (brain) No
Griesemer et al. (1994) [26] 2 M Otitis media, hemiparesis, aphasia, emesis, lethargy, fever, instability Deceased IFA (brain) No
Griesemer et al. (1994) [26] 13 F Headache, diplopia, hemiparesis, left facial weakness, emesis Deceased IFA (brain) No
Neafie et al. (1993) [55] 1 M Hemiplegia, lethargy Deceased IFA (brain) No
Gordon et al. (1992) [23] 52 M Skin lesion(s), headache, fever, chills Deceased IFA (brain & skin) No
Popek et al. (1992) [63] 0 y 5 mo F Sore throat, otitis media, seizures, fever Deceased IFA (brain) No
Chimelli et al. (1992) [10] 47 F Weakness, myalgia, fever, weight loss, headache Deceased IFA (brain) No
González-Alfonzo et al. (1991) [22] 7 M Pain, swelling, serous eye discharge Deceased IFA (brain) No
Taratuto et al. (1991) [83] 12 M Skin lesion(s), hyperthermia, headache, conjugate gaze deviation, facial palsy, dysarthria, hemiparesis Deceased IFA (brain) No
Anzil et al. (1991) [2] 36 M Headache, fever Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 2 F Headache Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 0 y 3 mo M Diarrhea, dehydration, fever, pneumonia Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 2.5 M Neurologic dysfunction, headache, emesis Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 72 M Chronic renal failure Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 0 y 9 mo F Diarrhea, cough, fever, cranial nerve palsy Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 61 M Altered mental status, prior skin lesion(s) Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 22 M Head injury, headache, seizure Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 11 F Seizure, headache, fever vomiting Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 39 M Seizure, cranial nerve deficits, coma Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 22 M Headache, seizure, nasal mass Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 30 M Headache, nausea, emesis, dizziness, diplopia Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 60 M Skin lesion(s) Deceased IFA (brain) No
Visvesvara et al. (1990) [87] 60 M Seizure, hemiparesis Deceased IFA (brain) No
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First identified in 1989 in a pregnant mandrill baboon at the San Diego Zoo Safari Park though use of immunofluorescence assay (IFA) [87], B. mandrillaris was retrospectively identified in human cases dating back to 1974 [87]. Since then, diagnostic modalities have evolved and include immunohistochemistry, immunofluorescence, and molecular techniques such as PCR, qPCR, RT-PCR, Sanger sequencing, and enzyme-linked immunosorbent assay. These tools have been applied to various specimens, including FFPE tissue, amoebic cultures, blood, and CSF, with varying success. While PCR is a cornerstone of infectious disease diagnostics, its sensitivity for B. mandrillaris remains suboptimal, with reported detection rates as low as 6%, underscoring the limitations of traditional diagnostic methods [11].

In recent years, mNGS has emerged as a potential diagnostic tool for B. mandrillaris and has been applied to specimens including brain tissue, CSF, and, recently, blood. We identified 20 cases reporting positive B. mandrillaris mNGS testing results, with 6 positive tests performed on brain tissue, 14 on CSF, 2 on plasma, 1 on serum, and 1 that did not identify the specimen (see Table 2), with some testing more than one tissue type. One report identified B. mandrillaris using mNGS on serum, also with positive mNGS on CSF and brain [59]. One case reported negative mNGS on CSF in the setting of positive mNGS on brain biopsy in a patient who survived [105]. Our analysis found only two other reported instance of B. mandrillaris detected via plasma mNGS. In both of those cases, CSF was also positive via mNGS and/or PCR [36, 120]. In contrast, in our case, plasma mNGS successfully identified the pathogen, while CSF B. mandrillaris PCR and CSF mNGS were both reported negative.

Upon retrospective review of the CSF mNGS raw data for this case, two reads mapping to B. mandrillaris were identified—far below the assay’s reporting threshold of 50 reads. PCR on this sample was also negative. Our observation of subthreshold reads highlights the challenges of interpreting mNGS data and may reflect several factors, including pathogen distribution between compartments and timing of sample collections. We note that CSF was collected 7 days prior to plasma and thus mNGS of CSF sampled concurrently with plasma may have yielded a positive result. While mNGS of CSF shows utility for many organisms, its sensitivity for B. mandrillaris is unknown. A comprehensive study of nearly 5,000 CSF mNGS results from patients with suspected CNS infections detected subthreshold B. mandrillaris reads in CSF in 2 of 3 identified cases [104]. Detection of B. mandrillaris DNA in plasma but not in CSF raises plasma mNGS as a possible diagnostic tool if CSF testing is inconclusive. However, the sensitivity and specificity of plasma mNGS for the diagnosis of B. mandrillaris GAE are not established. In the absence of these data, results should be interpreted with caution. Diagnostic laboratories offering mNGS testing on CSF could potentially consider reporting rare and difficult-to-diagnose pathogens like B. mandrillaris even if below the usual threshold for reporting.

Acknowledgements

We thank the patient’s clinical team, including Hannah Breit, Grace Kuo, and Olga Manouvakhova.

Abbreviations

AFB

Acid-Fast Bacilli

B. mandrillaris

Balamuthia mandrillaris

CD

Cluster of Differentiation

CNS

Central Nervous System

Cp

Crossing Point (used in PCR)

CSF

Cerebrospinal Fluid

DNA

Deoxyribonucleic Acid

ELISA

Enzyme-linked immunosorbent assay

FFPE

Formalin-Fixed, Paraffin-Embedded

GAE

Granulomatous Amoebic Encephalitis

GMS

Gomori Methenamine Silver

H&E

Hematoxylin and Eosin

HBMECs

Human Brain Microvascular Endothelial Cells

IFA

Immunofluorescence Assay

IHC

Immunohistochemistry

mNGS

Metagenomic Next-Generation Sequencing

MRI

Magnetic Resonance Imaging

PAS

Periodic Acid-Schiff

PCR

Polymerase Chain Reaction

qPCR

Real-time Polymerase Chain Reaction

Author contributions

S.Y.E., A.H., and S.B.W. wrote the main manuscript text. S.Y.E and A.H. prepared all figures and Table 2. R.W.R and A.H. prepared Table 1. R.W.R., A.P.N., K.M.H., and D.C. edited the manuscript text. A.P.N. also performed the free-living amoeba PCR and interpretation. M.S.S. provided radiologic interpretation. C.K. and J.H.B. performed the autopsy. A.J.M. and K.M.H. provided surgical biopsy interpretation. All authors reviewed the manuscript.

Funding

No external funding was received for this study.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Informed consent for publication was obtained from the patient’s next of kin.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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