Striving to avoid an amebic nightmare: Recognizing cutaneous Balamuthia mandrillaris infection

By Warren R. Heymann, MD, FAAD
May 22, 2024
Vol. 6, No. 21

Having received the worry gene from my mother, I have nightmares about missing diagnoses that have potentially devastating outcomes. My anxiety level reached new heights over 20 years ago, listening to a presentation by Dr. Amit Pandya at a Medical Dermatology Society meeting. He discussed the case of fatal granulomatous amebic encephalitis due to Balamuthia mandrillaris (Bm) infection in an immunocompetent 89-year-old man. I was spellbound by watching the lesion progress from an indurated plaque to necrotic lesions of the nasal region (see image below). (1) I was unaware of the ameba; subsequently, the number of reported cases has increased. Bm amebic encephalitis is an emerging disease and a significant health concern, with few survivors despite therapeutic intervention. Early diagnosis is critical and requires familiarity with the condition and a high degree of suspicion on the part of the diagnostician. I promised to entertain the diagnosis in the right proper clinical context. This commentary was prompted by recent reports of Bm infection that implore greater awareness of the disease. Albeit rare, there is evidence that early recognition may be lifesaving in this otherwise likely fatal malady.

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The format of this commentary differs from my usual editorial. I will present excerpts of the abstract from the outstanding review of Bm by Bhosale and Parija (2); each italicized passage will be followed by other literature in addition to that presented in the review. (Please note that the review is only referenced once, but each section contains information from the manuscript.)

Balamuthia mandrillaris is an opportunistic, free-living ameba that is pathogenic to humans. It has a worldwide distribution but is mainly detected in warmer regions. Balamuthia infections are rare but have been reported in both immunocompetent and immunocompromised individuals of all ages.

Bm was first identified in 1986 in the brain of a pregnant mandrill baboon that died of encephalitis in the San Diego Zoo. Four genera of free-living ameba have been associated with human disease, including one species of Naegleria (N. fowleri); one species of Balamuthia (B. mandrillaris); several species of Acanthamoeba causing eye, skin, spinal cord, and CNS infections; and Sappinia pedata for which a single case of amoebic encephalitis has been described. Only Acanthamoeba and Bm cause cutaneous lesions. Bm infection is reported mainly in the Americas. According to Alvarez et al, “To date, approximately 200 cases of granulomatous meningitis by B. mandrillaris have been reported. This may underestimate the real incidence of the disease, considering the lack of pathognomonic findings, the difficulty in recognizing amoebas in skin biopsy tissues, and the fact that the initial cases were regarded as Acanthamoeba sp.” (3)

B. mandrillaris can enter through wounds on the skin or the nose and cause cutaneous lesions and the usually fatal Balamuthia amebic encephalitis (BAE). Infection usually spreads from the lungs or through nerve fibers, and attacks the central nervous system, forming granulomatous lesions and necrosis in the brain.

Soil and dust are the most likely sources of infection. Skin lesions may also be due to hematogenous dissemination. Solid organ transplantation may also cause transmission. (3)

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Balamuthia infection is usually chronic, and patients initially present with nonspecific symptoms, including headache, nausea, myalgia, and low-grade fever. As the disease progresses, the patient becomes paralyzed and comatose, often leading to death.

Cutaneous lesions may present 2 weeks to 5 years prior to diagnosis, with 73% having central nervous system involvement at diagnosis. Skin lesions typically present as single or multiple nontender erythematous plaques on the central face or extremities, which may progress to ulceration. (4) Lesions often may appear purplish; satellite lesions may be appreciated. The most common histopathologic pattern demonstrates ill-defined tuberculoid granulomas with multinucleated giant cells, associated with a diffuse superficial and deep inflammatory infiltrate composed of lymphocytes, plasma cells, and histiocytes. Bm trophozoites are challenging to visualize because of their scarcity and histiocyte-like appearance. When observed, they display a spherical nucleus with a large nucleolus and a cytoplasm with vacuoles, described as a “bubbly” appearance. The clinical and histopathologic differential diagnosis of cutaneous Bm infection includes leishmaniasis, sporotrichosis, lupus vulgaris, sarcoidosis, granulomatosis with polyangiitis, necrobiosis lipoidica, and natural killer and T-cell lymphomas. (3)

Lack of knowledge of predisposing factors, specific treatment, and standardized detection tools have resulted in a nearly [100 per] cent percent fatality rate.

If not recognized by standard clinicopathologic correlations, cultures are impractical for securing the diagnosis. PCR and next generation sequencing of cell-free DNA are potent tools for diagnostic confirmation. (5,6) According to the CDC, the indirect immunofluorescence assay is a test used to detect antibodies developed against Balamuthia amebas in the serum of infected patients. In contrast, immunohistochemistry and indirect immunofluorescence staining use specific antibodies against Balamuthia to detect the amebas. Regarding therapy, “Currently, treatment recommendations include the use of a combination of several drugs. Most cases of Balamuthia are diagnosed right before death or after the patient has died. This delay in diagnosis limits the amount of experience doctors have using different drugs to treat Balamuthia infection. Current treatment plans are based on lab studies of the ameba and the few cases where the patients have survived.” A combination of flucytosine, pentamidine, fluconazole, sulfadiazine, and either azithromycin or clarithromycin are prescribed for Bm infection. Recently, miltefosine in combination with some of these other drugs has shown some promise. (7) The quinolone nitroxoline demonstrates amebicidal activity against Bm, showing promise in a > 50-year-old man with granulomatous amebic encephalitis. (8)

As aptly stated by Gramp et al, “There is little evidence to guide treatment and outcomes are often poor; however, timely diagnosis may increase the chance of survival.” (4) Unfortunately, there no known Bm prevention strategies. If you are ever genuinely concerned about securing the diagnosis of a Bm infection, contact the CDC at cdc.gov. I conclude with another abstract excerpt from Bhosale and Parija:

Although only about 200 cases have been reported worldwide since its characterization in the 1990s, the number of reported cases has increased over the years. BAE is an emerging disease and a major health concern. Few patients have survived Balamuthia infections with antimicrobial treatment that has largely been empirical. Early diagnosis is the key and requires familiarity with the disease and a high degree of suspicion on the part of the diagnostician. There are currently no specific treatment and prevention recommendations.

Point to Remember: Dermatologists should be familiar with cutaneous infection by the ameba Balamuthia mandrillaris. Although rare, this is considered an emerging disease worldwide. Early recognition and treatment of cutaneous disease may decrease the risk of death from granulomatous amebic encephalitis.

Our experts’ viewpoints

Prudence Gramp MD, GradCertIDI
Dermatology Department, Gold Coast University Hospital, Gold Coast, Australia

Thank you to the American Academy of Dermatology for raising awareness of this rare but important dermatologic condition. Although the condition is uncommon and so is appropriately not considered on first presentation, it needs to be considered in cases of diagnostic uncertainty when common causes of granulomatous lesions have been ruled out.

In Australia, we have found the two most important learning points for dermatologists are:

1. Awareness and education:
   Dermatologists should be aware of cutaneous ameba as a differential as patients may present initially to dermatology with cutaneous lesions and no systemic findings early in the disease. Publishing of case reports is important to document prevalence, raise awareness, and increase the knowledge of the disease. Treatment regimens remain uncertain and so publishing of case reports increases clinician knowledge for treatment of new cases.

2. Difficulty in diagnosis:
   Histopathologically this organism is difficult to diagnose as the ameba can resemble macrophages and there is a spectrum of histopathologic findings that can mimic other diseases. In many cases multiple biopsies are taken and unfortunately not diagnosed until the ameba has spread systemically, just prior to or after death. PCR is a reliable method to help earlier diagnosis and while only offered in specialist centers, it should be considered early on in diagnostically uncertain conditions. Involving other specialties in a multidisciplinary approach, such as infectious disease, early on when infection is considered is also appropriate in these cases.

As climate change increases global temperatures, it is predicted that ameba will thrive and increase in our environment and so it is likely that dermatologists will see further cases of cutaneous ameba in the future and need to be equipped to manage them.

Amit G. Pandya, MD, FAAD
Director, Pigmentary Disorders Clinic, Palo Alto Medical Foundation, Sunnyvale, California
Adjunct Professor, Department of Dermatology, University of Texas Southwestern Medical Center

The patient was a retired rancher who lived south of Dallas, Texas. He had a few head of cattle but didn’t have much contact with them. At his first visit he had a small red plaque on the dorsal nose which showed changes consistent with rosacea on biopsy. He didn’t respond to standard treatment for rosacea, and over the next few months I was dismayed to see the slow and steady progression of his lesion to an ulcerated plaque. It was only after a third, incisional biopsy was obtained that the diagnosis of Balamuthia infection was made by a colleague in pathology with experience in tropical infectious disease. I remember how alarmed I was when the plaque ulcerated, the helpless feeling as we watched the progression of the infection to the brain and his unresponsiveness to treatment which finally led to his death. This was one of the most memorable cases of my career and taught me to be quick to consult colleagues outside dermatology when needed.

1. Pritzker AS, Kim BK, Agrawal D, Southern PM Jr, Pandya AG. Fatal granulomatous amebic encephalitis caused by Balamuthia mandrillaris presenting as a skin lesion. J Am Acad Dermatol. 2004 Feb;50(2 Suppl):S38-41. doi: 10.1016/s0190-9622(03)02090-5. PMID: 14726864.

2. Bhosale NK, Parija SC. Balamuthia mandrillaris: An opportunistic, free-living ameba - An updated review. Trop Parasitol. 2021 Jul-Dec;11(2):78-88. doi: 10.4103/tp.tp_36_21. Epub 2021 Oct 20. PMID: 34765527; PMCID: PMC8579774.

3. Alvarez P, Torres-Cabala C, Gotuzzo E, Bravo F. Cutaneous balamuthiasis: A clinicopathological study. JAAD Int. 2022 Jan 10;6:51-58. doi: 10.1016/j.jdin.2021.11.005. PMID: 35059659; PMCID: PMC8760460.

4. Gramp PE, Dooley J, O'Brien B, Jones A, Tan L, Robson J, Robertson T, Simos P, Fuller R, Gramp DV, Meumann EM. Fatal granulomatous amebic encephalitis initially presenting with a cutaneous lesion. Australas J Dermatol. 2023 Aug;64(3):e256-e261. doi: 10.1111/ajd.14068. Epub 2023 May 8. PMID: 37154242.

5. Liu J, Zhang W, Wu S, Zeng T, Luo F, Jiang Q, Yang R. A clinical case report of Balamuthia granulomatous amoebic encephalitis in a non-immunocompromised patient and literature review. BMC Infect Dis. 2023 Apr 18;23(1):245. doi: 10.1186/s12879-023-08228-6. PMID: 37072710; PMCID: PMC10114318.

6. Zheng J, Tan M, Chen J, Li C, Meng F, Wang L, Liao J. Diagnosis of cutaneous Balamuthia mandrillaris infection via next-generation sequencing in a Chinese woman. J Eur Acad Dermatol Venereol. 2023 Mar;37(3):e355-e357. doi: 10.1111/jdv.18747. Epub 2022 Nov 24. PMID: 36377799.

7. https://www.cdc.gov/parasites/balamuthia/treatment.html (accessed September 10, 2023)

8. Spottiswoode N, Pet D, Kim A, Gruenberg K, Shah M, Ramachandran A, Laurie MT, Zia M, Fouassier C, Boutros CL, Lu R, Zhang Y, Servellita V, Bollen A, Chiu CY, Wilson MR, Valdivia L, DeRisi JL. Successful Treatment of Balamuthia mandrillaris Granulomatous Amebic Encephalitis with Nitroxoline. Emerg Infect Dis. 2023 Jan;29(1):197-201. doi: 10.3201/eid2901.221531. PMID: 36573629; PMCID: PMC9796214.

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