Balamuthia mandrillaris brain abscess successfully treated with complete surgical excision and prolonged combination antimicrobial therapy

Case report

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Amoebic encephalitis is an uncommon and usually fatal condition. This case describes successful treatment of a Balamuthia mandrillaris brain abscess using prolonged antimicrobial agents with complete excision. It illustrates the risk of dissemination from cutaneous to cerebral amoebic lesions, potential progression with corticosteroid therapy, and the prospect for curative excision.

Abbreviation used in this paper: PCR = polymerase chain reaction.

Abstract

Amoebic encephalitis is an uncommon and usually fatal condition. This case describes successful treatment of a Balamuthia mandrillaris brain abscess using prolonged antimicrobial agents with complete excision. It illustrates the risk of dissemination from cutaneous to cerebral amoebic lesions, potential progression with corticosteroid therapy, and the prospect for curative excision.

Cerebral amoebic infections are uncommon and are rarely diagnosed antemortem. Recognition of the clinical scenario, appropriate diagnostic tests, and initiation of treatment is often delayed. A notable survivor is presented here to outline the clinical characteristics, investigative pathway, and operative approaches for others who may encounter these rare pathogens.

Case Report

History and Examination

This previously healthy 80-year-old woman from a rural area of Victoria, Australia, presented to our hospital with an abrasion to the dorsum of her right hand while gardening. She developed a large erythematous, violaceous, eroded plaque on the back of her right hand. This lesion was slow to heal, and a number of painless erythematous, violaceous 1–3-cm plaques and nodules began appearing more proximally over her arms. In the next 6 months, similar lesions appeared scattered asymmetrically on her torso, both arms, and buttocks.

Multiple skin biopsies were nondiagnostic, showing nonnecrotizing and nonsuppurative granulomas with a background of lymphocytes and plasma cells. Test results for bacterial, fungal, and mycobacterial stains and cultures were negative. A mycobacterial multiplex PCR test result was positive for 1 of 5 biopsy samples (in-house assay, Victorian Infectious Diseases Reference Laboratory) for an unknown species. There were no other physical symptoms or signs over an 18-month period. Other tests were nondiagnostic, including a negative Quantiferon Gold (γ-interferon release assay, Cellestis), nonreactive syphilis serology (rapid plasma reagin and enzyme immunoassay total antibody), nondetectable antinuclear and antineutrophil cytoplasmic antibodies, normal angiotensin-converting enzyme (67 U/L, reference range 12–68 U/L) and a normal serum calcium level (2.4 mmol/L). She was immunocompetent with normal results from a full blood examination.

Topical corticosteroid treatment had no effect on the lesions. The patient commenced a therapeutic trial of oral corticosteroids (prednisolone 25 mg daily) because an inflammatory etiology was proposed for her rash. This was followed within weeks by an increase in the size of her skin lesions (Fig. 1). A further skin biopsy was obtained at our institution 2 weeks prior to her acute presentation.

Fig. 1.
Fig. 1.

An erythematous, violaceous, eroded plaque measuring 4 × 3 cm located on dorsum of the right hand, characteristic of other lesions in our patient.

Four weeks into her steroid therapy, she collapsed at home with 2 generalized tonic-clonic seizures. On admission to the hospital, she had no focal neurological signs, but she had postictal confusion and mild disinhibition that resolved after 48 hours. After commencing phenytoin she suffered no further seizures. Basic hematological and biochemical test results were within normal limits. An MR imaging study of her brain demonstrated a solitary lesion in the medial right frontal lobe, at the gray-white matter junction. The lesion had an irregular enhancing rim with peripheral diffusion restriction, and surrounding vasogenic edema. Empiric brain abscess treatment of benzylpenicillin, ceftriaxone, and metronidazole was commenced.

An additional MR imaging study was performed 4 days later, showing that the lesion and the surrounding edema had increased in size (Fig. 2). Histological analysis of her recent skin biopsy showed a mixed inflammatory cell infiltrate within the dermis and subcutis including numerous Langhans-type dermal giant cells. Frequent amoebic trophozoites were identified within the areas of inflammation, often within giant cells (Fig. 3). No other organisms were identified on stains for fungi, acid-fast bacilli, or bacteria.

Fig. 2.
Fig. 2.

Axial T1-weighted MR images without (A and D) and with (B and E) intravenous contrast, and diffusion-weighted images (C and F) obtained preoperatively (upper) and 2 months postoperatively (lower), demonstrating a lesion in the right medial frontal lobe.

Fig. 3.
Fig. 3.

Photomicrograph. A section of skin showing a mixed inflammatory cell infiltrate within the dermis including frequent giant cells, one of which contains an amoebic trophozoite (arrow). H & E, original magnification × 400.

Operation

A provisional diagnosis of amoebic encephalitis was made. Given the extremely poor prognosis of this condition, a neurosurgical assessment was sought for excision of the patient's brain lesion. A frameless stereotactic craniotomy was performed, and the lesion was excised en masse, with a surrounding margin of normal brain tissue. A macroscopic abscess with a central necrotic core was excised en bloc and similar to her skin biopsy, amoebic trophozoites were visualized in the brain tissue (Fig. 4). An Escherichia coli lawn culture of brain tissue failed to detect any further trophozoites and Balamuthia mandrillaris was identified by PCR (Center for Disease Control and Prevention). Amoebic serology and immunofluorescence analyses were not performed.

Fig. 4.
Fig. 4.

Photomicrograph. A section of the brain abscess showing necrotic tissue containing neutrophils, histiocytes, and scattered amoebic trophozoites (arrow). H & E, original magnification × 400.

Anitmicrobial therapy was broadened within the 1st week of presentation to include intravenous pentamidine 300 mg daily, oral azithromycin 600 mg daily, oral itraconazole 200 mg twice daily, oral sulphadiazine 1.5 mg 4 times a day, and oral flucytosine 1 g 3 times a day. Corticosteroids were weaned rapidly. Intravenous pentamidine was associated with significant hypotension, which occurred again on rechallenge, and intravenous liposomal amphotericin (3 mg/kg/day) was given instead for 4 weeks intravenous therapy in total. Mild renal impairment was observed in association with liposomal amphotericin therapy. Liver enzyme dysfunction was also observed, requiring a 50% dose reduction in the sulphadiazine.

Postoperative Course

The patient's postoperative course was complicated by a failure to wake, and she required intensive care for 1 week for airway support. Imaging revealed no evidence of postoperative intracranial hemorrhage. She was discharged home having made a full neurological recovery after a total of 7 weeks in the hospital and rehabilitation facility, and she was not taking antiseizure medication. The 4 oral agents were continued for 7 months in total, at which point her skin lesions and brain abscess had resolved.

She remains clinically well and stopped taking all antimicrobial agents 11 months ago. She had 1 self-limiting seizure during the period when she was not taking antimicrobial therapy, and she had no new skin or brain lesions. This seizure was attributed to postoperative scarring rather than disease recurrence.

Discussion

Granulomatous amoebic encephalitis caused by free-living amoebae is a rare condition that is difficult to diagnose, hard to treat, and generally fatal. Balamuthia mandrillaris has caused more than 125 confirmed cases of amoebic encephalitis, and only 4 survivors have been reported (Table 1).1,3,13

TABLE 1:

Comparison of reported successfully treated cases of Balamuthia encephalitis*

Authors & YearAge (yrs), SexPresentationRisk FactorsMeans of DiagnosisAntimicrobial TherapyOpOutcomeFU
Gelman et al., 20015, Fgeneralized seizuresimmunocompetentbrain biopsy, IIFinitial: pentamidine (2 wks); flucytosine, fluconazole, thioridazine, clarithromycin (1.5 yrs); maintenance (>2.5 yrs): fluconazole, clarithromycinpartial excision of 1 of 2 lesionsmoderate performance problems in school>2.5 yrs
Jung et al., 200435, MseizuresB cell lymphomaserology, PCRNRNRNRNR
Gelman et al., 200164, Mskin lesion, later rt hemiparesis & generalized seizuresimmunocompetentbrain biopsy, IIFinitial: pentamidine (<7 wks); flucytosine, fluconazole, sulfadiazine, clarithromycin (2 yrs); maintenance (>5 yrs): fluconazole, sulfadiazinebiopsy onlyrelapse at 6 mos, severe neurological deficits>5 yrs
Deetz et al., 200372, Ffocal lt-sided seizureimmunocompetentbrain biopsy, IIFinitial: pentamidine, fluconazole, sulfadiazine, clarithromycin (unreported duration)excision of 1 of 2 lesionscomplete recovery6 mos
present case80, Fskin lesions, 18 mos later generalized seizuresimmunocompetentskin/brain biopsy, PCRinitial: pentamidine (1 wk), then liposomal amphotericin (3 wks); flucytosine, azithromycin, itraconazole, sulfadiazine (7 mos); no maintenancecomplete excision of solitary abscesscomplete recovery18 mos

* FU = follow-up; IIF = immunofluorescence; NR = not reported.

There are 4 genera of free-living amoeba associated with human infection. Naegleria fowleri tends to cause an amoebic meningoencephalitis characterized by a hemorrhagic necrotizing infection of CNS occurring in previous healthy children and young adults.5,16 Sappinia spp. have been described as a cause of brain abscess in immunocompetent hosts.2,9 Acanthemoeba spp. and Balamuthia mandrillaris, both causes of granulomatous amoebic encephalitis, are associated with immunocompromised states, and can also involve the lung and skin, including keratitis associated with contact lenses.5,7,16

These protozoa are widely distributed in the natural environment, including fresh water, soil, domestic water supplies, and air conditioning.5,6,13 Amoeba can also serve as reservoirs in the environment for pathogenic bacteria such as Legionella and Mycobacterium.6 It is biologically plausible that the positive Mycobacterium PCR in this case detected cellular components within the amoebae. Exposure to free-living amoebae is thought to be common from water and soil contact, with antibodies found in serum samples from healthy humans.5

Corticosteroid use has been associated with amoebic encephalitis.10,13 Steroids can lead to immunosuppression and could therefore potentially facilitate passage of amoebae across the blood-brain barrier.15 The concern of steroids worsening parasitic infections is biologically plausible and is supported by the temporal relationship in this patient. However, there are no other reports to date of a clear relationship between corticosteroid use and abrupt dissemination of Balamuthia infection.

Diagnosis of amoebic encephalitis is rarely made antemortem.4 Data from the California Encephalitis Project suggested that imaging modalities such as MR imaging may demonstrate single or multiple heterogeneous enhancing lesions.13 Cerebrospinal fluid analysis may show a mononuclear pleocytosis, increased protein, and low glucose, but Balamuthia has not been found directly in CSF.13 Free-living amoebae are difficult to recognize in tissue and require careful histopathological examination for trophozoites and cystic phases. Morphologically, Balamuthia and Acanthamoeba are difficult to distinguish, which is clinically problematic given differences in antimicrobial susceptibility.8 To further identify amoebae, immunofluorescence and serological assays are used in reference laboratories; however, they remain research tools.14 A multiplex PCR for Acanthamoeba, Balamuthia, and Naegleria based on sequence of mitochondrial 16S rRNA gene has a high specificity and sensitivity (96%–98% and 99%, respectively) from fresh brain tissue, but a lower sensitivity from deformalinized specimens, and a sensitivity of only 25% from CSF.13,17,18

Antimicrobial recommendations are based only on in vitro evidence of activity against Balamuthia mandrillaris isolates or limited case reports of in vivo use. In vitro testing suggests the most efficacious agents are pentamidine or ketoconazole; however, azithromycin, clarithromycin, fluconazole, and amphotericin B also had some suppression of amoeba growth.12 Voriconazole and miltefosine appear to be less effective in vitro.11 Among case reports of survivors, sulfadiazine and flucytosine were used in more than half of the reported cases.1,3 Albendazole and itraconazole have been used successfully in cases of cutaneous Balamuthia infection.13 In this case, 5 agents from 5 classes of drug were used all with known antiparasitic activity. Expert opinion and previous reports concur with this approach.13

The exact duration needed to completely treat an amoebic brain abscess is uncertain. There are no validated biochemical markers of response to treatment, with 2 survivors continuing on 2 antimicrobial agents (fluconazole plus either clarithromycin or sulfadiazine) for at least 2 years.1 We chose to use 7 months of therapy given the patient's age, toxicities, and knowing that surgery had completely removed the lesion.

The role of surgery in Balamuthia infection has previously been confined to diagnostic biopsy. In the 4 patients who have been successfully treated for Balamuthia infection, they either had multiple abscesses at diagnosis, or only underwent excision or biopsy of 1 lesion (Table 1). This case appears to be the first reported excision of a solitary Balamuthia abscess. As well as aiding in the diagnosis, we propose that surgical removal of the intracerebral infection contributed to our patient's favorable outcome.

Conclusions

To our knowledge, this case is the first report in which the combination of excision and broad antimicrobial use resulted in a favorable outcome. While we were unable to prove that prednisolone caused disseminated Balamuthia infection, we observed a clear temporal relationship in this case. We recommend avoiding steroids in clinical settings where amoebic infection may be possible.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Doyle, Campbell, Fuller. Acquisition of data: Doyle, Campbell, Fuller, Cameron, Malham, Lewin. Analysis and interpretation of data: Doyle, Campbell, Fuller, Spelman. Drafting the article: Doyle, Campbell. Critically revising the article: Fuller, Spelman, Cameron, Gin, Lewin. Reviewed final version of the manuscript and approved it for submission: all authors.

Acknowledgment

The authors thank Dr. Harsha Sheorey for assistance in the microbiological identification in this case.

This article contains some figures that are displayed in color online but in black and white in the print edition.

Portions of this work were presented as proceedings of the 50th Interscience Conference on Antimicrobial Agents and Chemotherapeutics (ICAAC), Boston, Massachusetts, September 13, 2010.

References

  • 1

    Deetz TRSawyer MHBillman GSchuster FLVisvesvara GS: Successful treatment of Balamuthia amoebic encephalitis: presentation of 2 cases. Clin Infect Dis 37:130413122003

  • 2

    Gelman BBRauf SJNader RPopov VBorkowski JChaljub G: Amoebic encephalitis due to Sappinia diploidea. JAMA 285:245024512001

  • 3

    Jung SSchelper RLVisvesvara GSChang HT: Balamuthia mandrillaris meningoencephalitis in an immunocompetent patient: an unusual clinical course and a favorable outcome. Arch Pathol Lab Med 128:4664682004

  • 4

    Kansagra APMenon JPYarbrough CKUrbaniak KWaters JDBorys E: Balamuthia mandrillaris meningoencephalitis in an immunocompromised patient. Case report. J Neurosurg 111:3013052009

  • 5

    Marciano-Cabral F: Free-living amoebae as agents of human infection. J Infect Dis 199:110411062009

  • 6

    Marciano-Cabral FCabral G: Acanthamoeba spp. as agents of disease in humans. Clin Microbiol Rev 16:2733072003

  • 7

    Matin ASiddiqui RJayasekera SKhan NA: Increasing importance of Balamuthia mandrillaris. Clin Microbiol Rev 21:4354482008

  • 8

    Pritzker ASKim BKAgrawal DSouthern PM JrPandya AG: Fatal granulomatous amebic encephalitis caused by Balamuthia mandrillaris presenting as a skin lesion. J Am Acad Dermatol 50:2 SupplS38S412004

  • 9

    Qvarnstrom Yda Silva AJSchuster FLGelman BBVisvesvara GS: Molecular confirmation of Sappinia pedata as a causative agent of amoebic encephalitis. J Infect Dis 199:113911422009

  • 10

    Reed RPCooke-Yarborough CMJaquiery ALGrimwood KKemp ASSu JC: Fatal granulomatous amoebic encephalitis caused by Balamuthia mandrillaris. Med J Aust 167:82841997

  • 11

    Schuster FLGuglielmo BJVisvesvara GS: In-vitro activity of miltefosine and voriconazole on clinical isolates of free-living amebas: Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri. J Eukaryot Microbiol 53:1211262006

  • 12

    Schuster FLVisvesvara GS: Axenic growth and drug sensitivity studies of Balamuthia mandrillaris, an agent of amebic meningoencephalitis in humans and other animals. J Clin Microbiol 34:3853881996

  • 13

    Schuster FLYagi SGavali SMichelson DRaghavan RBlomquist I: Under the radar: Balamuthia amebic encephalitis. Clin Infect Dis 48:8798872009

  • 14

    Schuster FLYagi SWilkins PPGavali SVisvesvara GSGlaser CA: Balamuthia mandrillaris, agent of amebic encephalitis: detection of serum antibodies and antigenic similarity of isolates by enzyme immunoassay. J Eukaryot Microbiol 55:3133202008

  • 15

    Siddiqui RKhan NA: Balamuthia amoebic encephalitis: an emerging disease with fatal consequences. Microb Pathog 44:89972008

  • 16

    Visvesvara GSMoura HSchuster FL: Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS Immunol Med Microbiol 50:1262007

  • 17

    Yagi SBooton GCVisvesvara GSSchuster FL: Detection of Balamuthia mitochondrial 16S rRNA gene DNA in clinical specimens by PCR. J Clin Microbiol 43:319231972005

  • 18

    Yagi SSchuster FLVisvesvara GS: Demonstration of Balamuthia and Acanthamoeba mitochondrial DNA in sectioned archival brain and other tissues by the polymerase chain reaction. Parasitol Res 102:4914972008

Article Information

* Drs. Doyle and Campbell contributed equally to this work.

Address correspondence to: Joseph S. Doyle, M.B.B.S., M.Sc., Infectious Diseases Registrar, Victorian Infectious Diseases Service, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria, 3052, Australia. email: joseph.doyle@alumni.unimelb.edu.au.

Please include this information when citing this paper: published online November 12, 2010; DOI: 10.3171/2010.10.JNS10677.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    An erythematous, violaceous, eroded plaque measuring 4 × 3 cm located on dorsum of the right hand, characteristic of other lesions in our patient.

  • View in gallery

    Axial T1-weighted MR images without (A and D) and with (B and E) intravenous contrast, and diffusion-weighted images (C and F) obtained preoperatively (upper) and 2 months postoperatively (lower), demonstrating a lesion in the right medial frontal lobe.

  • View in gallery

    Photomicrograph. A section of skin showing a mixed inflammatory cell infiltrate within the dermis including frequent giant cells, one of which contains an amoebic trophozoite (arrow). H & E, original magnification × 400.

  • View in gallery

    Photomicrograph. A section of the brain abscess showing necrotic tissue containing neutrophils, histiocytes, and scattered amoebic trophozoites (arrow). H & E, original magnification × 400.

References

1

Deetz TRSawyer MHBillman GSchuster FLVisvesvara GS: Successful treatment of Balamuthia amoebic encephalitis: presentation of 2 cases. Clin Infect Dis 37:130413122003

2

Gelman BBRauf SJNader RPopov VBorkowski JChaljub G: Amoebic encephalitis due to Sappinia diploidea. JAMA 285:245024512001

3

Jung SSchelper RLVisvesvara GSChang HT: Balamuthia mandrillaris meningoencephalitis in an immunocompetent patient: an unusual clinical course and a favorable outcome. Arch Pathol Lab Med 128:4664682004

4

Kansagra APMenon JPYarbrough CKUrbaniak KWaters JDBorys E: Balamuthia mandrillaris meningoencephalitis in an immunocompromised patient. Case report. J Neurosurg 111:3013052009

5

Marciano-Cabral F: Free-living amoebae as agents of human infection. J Infect Dis 199:110411062009

6

Marciano-Cabral FCabral G: Acanthamoeba spp. as agents of disease in humans. Clin Microbiol Rev 16:2733072003

7

Matin ASiddiqui RJayasekera SKhan NA: Increasing importance of Balamuthia mandrillaris. Clin Microbiol Rev 21:4354482008

8

Pritzker ASKim BKAgrawal DSouthern PM JrPandya AG: Fatal granulomatous amebic encephalitis caused by Balamuthia mandrillaris presenting as a skin lesion. J Am Acad Dermatol 50:2 SupplS38S412004

9

Qvarnstrom Yda Silva AJSchuster FLGelman BBVisvesvara GS: Molecular confirmation of Sappinia pedata as a causative agent of amoebic encephalitis. J Infect Dis 199:113911422009

10

Reed RPCooke-Yarborough CMJaquiery ALGrimwood KKemp ASSu JC: Fatal granulomatous amoebic encephalitis caused by Balamuthia mandrillaris. Med J Aust 167:82841997

11

Schuster FLGuglielmo BJVisvesvara GS: In-vitro activity of miltefosine and voriconazole on clinical isolates of free-living amebas: Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri. J Eukaryot Microbiol 53:1211262006

12

Schuster FLVisvesvara GS: Axenic growth and drug sensitivity studies of Balamuthia mandrillaris, an agent of amebic meningoencephalitis in humans and other animals. J Clin Microbiol 34:3853881996

13

Schuster FLYagi SGavali SMichelson DRaghavan RBlomquist I: Under the radar: Balamuthia amebic encephalitis. Clin Infect Dis 48:8798872009

14

Schuster FLYagi SWilkins PPGavali SVisvesvara GSGlaser CA: Balamuthia mandrillaris, agent of amebic encephalitis: detection of serum antibodies and antigenic similarity of isolates by enzyme immunoassay. J Eukaryot Microbiol 55:3133202008

15

Siddiqui RKhan NA: Balamuthia amoebic encephalitis: an emerging disease with fatal consequences. Microb Pathog 44:89972008

16

Visvesvara GSMoura HSchuster FL: Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS Immunol Med Microbiol 50:1262007

17

Yagi SBooton GCVisvesvara GSSchuster FL: Detection of Balamuthia mitochondrial 16S rRNA gene DNA in clinical specimens by PCR. J Clin Microbiol 43:319231972005

18

Yagi SSchuster FLVisvesvara GS: Demonstration of Balamuthia and Acanthamoeba mitochondrial DNA in sectioned archival brain and other tissues by the polymerase chain reaction. Parasitol Res 102:4914972008

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