Case Report: First Successful Treatment of Acanthamoeba Brain Abscess with Combination Surgical Excision and Miltefosine-Led Antimicrobial Therapy

ABSTRACT.

Acanthamoeba brain abscess is very rare and most often fatal. There remains no standardized regimen for its management. We report a case in northern Australia of an immunosuppressed 57-year-old man who presented with diarrhea and weight loss, and was diagnosed with multiple Acanthamoeba brain abscesses after neurological deterioration. This case is the first successful treatment with surgical excision followed by combination antimicrobial therapy including miltefosine. This case was treated initially as nocardiosis or melioidosis, emphasizing the importance of considering differentials such as Acanthamoeba during workup of atypical infection. We present a literature review of the 14 Acanthamoeba brain abscess cases reported in the English literature, of which five were successfully treated. Our review shows a predilection for multiple brain abscesses and an increased mortality rate compared with the general brain abscess population.

CASE REPORT

A 57-year-old white man was admitted to his local hospital in northern Australia with diarrhea and weight loss. He reported no history of fevers, night sweats, recent travel, swimming, or animal exposure. There was no history of HIV or intravenous drug use and he reported drinking town water only. He had been diagnosed with ulcerative colitis 1 year earlier and was receiving oral mesalazine, azathioprine, and a weaning dose of oral prednisolone for 8 months. He was diagnosed with an acute flare-up of ulcerative colitis and, because of its severity, he was managed with intravenous hydrocortisone and infliximab. Although his symptoms improved initially, his admission was complicated by Clostridium difficile diarrhea managed with oral vancomycin and Cytomegalovirus colitis treated with oral valganciclovir.

On day 32 of his admission, the patient experienced an episode of respiratory arrest and loss of consciousness for several minutes; no seizure activity was noted. His Glasgow Coma Scale score improved to 14, with subsequent confusion. He remained afebrile and hemodynamically stable, and there were no focal neurological deficits and no signs of meningism.

Blood tests at this time revealed a white cell count of 9.0 × 10⁹/L (normal range, 4–11 × 10⁹/L), a neutrophil count of 6.65 × 10⁹/L (normal range, 2–8 × 10⁹/L); lymphocytes, 1.65 × 10⁹/L (normal range, 1–4 × 10⁹/L); monocytes, 0.67 × 10⁹/L (normal range, 0.10–1 × 10⁹/L); eosinophils, 0.00 × 10⁹/L (normal, < 0.60 × 10⁹/L); basophils, 0.01 × 10⁹/L (normal, < 0.20 × 10⁹/L); and a C-reactive protein of 3.1 mg/L (normal, < 5.0 mg/L). Blood and urine cultures were unremarkable. A non-contrast computed tomographic scan of the brain was performed that did not demonstrate acute intracranial abnormality or hemorrhage to account for his neurological decline. A lumbar puncture was performed, and cerebrospinal fluid (CSF) analysis returned with a white blood cell count of 1 × 10⁶/L (insufficient cells for differential count); protein, 390 mg/L (reference range, 150–500 mg/L); and glucose, 2.7 mmol/L (reference range, 2.2–3.9 mmol/L). Gram-stain revealed no acid-fast bacilli, culture was sterile, cryptococcal antigen was negative, and polymerase chain reaction (PCR) tests for John Cunningham virus and Toxoplasma gondii were negative. Magnetic resonance imaging of the brain identified multiple intracranial lesions involving both cerebral hemispheres and a solitary cerebellar lesion. A computed tomographic chest scan revealed a right upper lobe lung lesion (Figures 1 and 2).

Figure 1.

Initial magnetic resonance brain image. (A, B) Enhanced axial T1-weighted image shows ring-enhancing lesions in the right parietal region. Axial diffusion (C) with corresponding apparent diffusion coefficient (D) demonstrates diffusion restriction of the right parietal lesion.

Figure 2.

Initial computed tomographic chest scan. Enhanced coronal image shows a right upper lobe lesion.

Pyogenic brain and lung abscesses were suspected, and intravenous meropenem and oral sulfamethoxazole–trimethoprim were commenced to treat possible nocardiosis or melioidosis empirically in the context of his immunosuppression. The patient’s confusion resolved the following day and he proceeded to bronchoscopy as well as a right upper lobe lung lesion biopsy. The biopsy was suggestive of an organizing pneumonia, and only Candida species were identified on culture. Although the patient remained stable, on follow-up imaging 2 weeks later, both intracranial and lung lesions were noted to have progressed, and an increase in the number of lesions was noted (Figure 3).

Figure 3.

Magnetic resonance brain images at 2 weeks. Enhanced axial T1-weighted images show an increase in the number of enhancing lesions.

Because of the lack of a formal diagnosis of the intracranial lesions, he was referred to the regional neurosurgical unit. He underwent image-guided craniotomy and excision of the right frontal lesion. Histopathology was reported as a granulomatous inflammatory process with necrosis, and organisms with features of Acanthamoeba species (Figure 4). Only cyst forms were identified; there was no trophozoite form and no features of suppurative inflammation. Microbiology was negative for mycobacteria, fungi, and Toxoplasma gondii. Multiplex PCR detected the 18S recombinant RNA gene for Acanthamoeba spp. and was negative for Naegleria fowleri and Balamuthia mandrillaris.

Figure 4.

Histopathology from surgical excision. (A) Low-power view shows necrotizing granulomas (×40 magnification). (B) Hematoxylin–eosin stain demonstrates an encysted trophozoite with prominent nucleoli, vacuolated cytoplasm, and double-layer cyst wall (×1,000 magnification). (C) Periodic acid–fast stain highlights the double wall, with inner polyhedral and outer wrinkled walls. This figure appears in color at www.ajtmh.org.

The patient’s antimicrobial therapy was changed to oral sulfamethoxazole–trimethoprim, fluconazole, azithromycin, and miltefosine. He was treated for 12 months and remained completely healthy at follow-up. His final magnetic resonance brain image at 15 months demonstrated resolution of his intracranial abscesses with residual encephalomalacia (Figure 5).

Figure 5.

Magnetic resonance brain images at 15 months. Enhanced axial T1-weighted images show residual encephalomalacia.

DISCUSSION

First described in 1965 by Fowler and Carter¹ in Australia, Acanthamoeba is a small, free amoeba living in water and soil that was postulated to be the causative pathogen involved in four fatal central nervous system infections. They noted all patients developed symptoms of upper respiratory tract infection followed by acute meningitis. In addition to entry via the respiratory tract, it is thought that Acanthamoeba cysts or trophozoites can enter the body through the eyes or skin lesions.² In our patient, there was a history of respiratory arrest with a radiological diagnosis of a right upper lobe lung lesion. Unfortunately, samples from the lung biopsy were not processed for microbiology and we were thus unable to confirm the Acanthamoeba entry site. Acanthamoeba central nervous system infection may manifest commonly as encephalitis and very rarely as brain abscess. It is associated with immunosuppressed states that include AIDS or prolonged treatment with immunosuppressant medication for cancer, transplantation, and autoimmune conditions.²

A PubMed search conducted using the keywords Acanthamoeba, brain, and abscess revealed reports of 14 patients included in our review.^2–15 The details of these patients are compiled in Table 1. Our literature review shows the most common presenting symptoms were fever and headache. Other common symptoms included seizures, confusion, altered level of consciousness, and weakness—similar to the general brain abscess population.¹⁶

Table 1.

Summary of 14 patients with Acanthamoeba brain abscesses reported in the world literature

Patient; age (y), gender	Predisposing factors	Clinical features	Multiple abscesses	Abscess locations	CSF tested for Acanthamoeba	Surgery	Acanthamoeba isolated from	Acanthamoeba sub-species	Treatment	Survived	Reference
7, F	None	Right hemiparesis	No	Left parietal	No	Yes, excision of left parietal abscess	Histopathology, culture	Acanthamoeba palistinensis	Ketoconazole	Yes, alive at 8-month follow-up with persistent right hemiparesis	Ofori-Kwakye et al., 19863
55, F	Type 2 diabetes mellitus	Fever, vomiting, confusion, seizure	Yes	Supratentorial, including left occipital	Yes, negative	Yes, drainage of left occipital abscess	Histopathology, culture from Escherichia coli suspension	Acanthamoeba morphological species group III of Pussard and Pons	Chloramphenicol, 5-fluorocytosine, rifampicin	No, died on day 96 of admission	Harwood et al., 19884
33, M	HIV on highly active Antiretroviral therapy	Headache, confusion, left hemifield visual defect	No	Right occipital	No	Yes, excision of right parieto-occipital abscess	Histopathology, indirect immunofluorescence test	Acanthamoeba castellani	Sulfadiazine, pyrimethamine, fluconazole	Yes, alive at 22-month follow-up	Seijo Martinez et al., 20005
26, M	None	Headache	Yes	Right temporoparietal, left cerebellar	No	Yes, excision of right temporoparietal abscess	Histopathology, autopsy	Not stated	Not stated	No, died postoperative day 4	Velho et al., 20036
45, M	Acute myelogenous leukemia on chemotherapy, partially mismatched related donor peripheral blood stem cell transplant	Dizziness, lethargy, confusion	Yes	Cerebellar, right frontal, left parietal, right occipital	No	No	Autopsy, immuno-fluorescent staining	Acanthamoeba castellani	Amphotericin	No, died day 3 of admission	Castellano-Sanchez et al., 20047
51, M	Renal transplantation on prednisone, tacrolimus, mycophenolate mofetil, type 1 diabetes mellitus	Left-side facial partial seizures, left hemiparesis, lower limb skin ulcerations	No	Right frontal	Yes, negative	Yes, evacuation of right frontal abscess	Histopathology, immunofluorescence analysis, culture from E. coli suspension	Acanthamoeba genotype T1	Liposomal amphotericin B, pentamidine, rifampin, azithromycin, flucytosine, sulfadiazine, metronidazole	No, died 51 days after presentation	McKellar et al., 20068
41, M	Liver transplantation on cyclosporin	Fever, generalized seizure, altered level of consciousness	Yes	Left frontal	Yes, negative	Yes, left frontal lobectomy	Histopathology, Grocott silver stain, periodic acid–Schiff stain, immunocytochemistry	Not stated	Rifampicin, sulfamethoxazole– trimethoprim	Yes, alive at 11-year follow-up	Fung et al., 20089
38, M	None	Headache, partial seizures	Yes	Right parietal, right frontal, left temporal, left parietal	Yes, negative	Yes, sub-total excision of right parietal abscess	Autopsy, histopathology diagnosis	Not stated	Not stated	No, died postoperative day 5	Reddy et al., 20112
2, M	Acute lymphoblastic leukemia on chemotherapy, prednisone, dexamethasone	Fever, headache, left-side hemiparesis	Yes	Right frontal, right parietal	Yes, positive	No	CSF, PCR	Acanthamoeba group II genotype T4	Sulfamethoxazole–trimethoprim, fluconazole, pentamidine, miltefosine, granulocyte colony-stimulating factor	Yes, resolution of neurological symptoms at 4 months	Maritschnegg et al., 201110
53, M	HIV	Confusion, weakness, generalized seizure	No	Left parietal	No	Yes, sub-total excision of left parietal abscess	Histopathology, indirect immuno-fluorescence antibody, rabbit anti-Acanthamoeba serum	Not stated	Sulfadiazine, pyrimethamine, azithromycin, fluconazole	No, died ≈4 months after surgery	Pietrucha-Dilanchian et al., 201211
63, M	Renal transplantation on mycophenolate mofetil, tacrolimus	Altered level of consciousness	Yes	Left frontal, left posterior temporo-occipital	No	Yes, biopsy of left temporal abscess	Histopathology, technique not stated	Not stated	Sulfadiazine, fluconazole, flucytosine, azithromycin, miltefosine	No, died after 5 weeks	Zamora et al., 201412
28, M	Systemic lupus erythematous on prednisolone, hydroxychloroquine, methotrexate, cyclophosphamide	Headache, fever, confusion, altered level of consciousness	Yes	Bifrontal, left parietal, left occipital, left temporal, left basal ganglia, middle cerebellar peduncle	Yes, negative	No	Autopsy, periodic acid–Schiff stain	Not stated	Pulse methyl-prednisolone therapy	No, died on day 6 of admission	Thamtam et al., 201613
58, F	Pulmonary tuberculosis, prednisolone	Fever, altered level of consciousness, right hemiplegia	Yes	Pons, right cerebellum, right occipital, right frontal	No	Yes, excisional biopsy of right frontal abscess	Histopathology, molecular identification using Acanthamoeba genus-specific primers	Not stated	Metronidazole	No, no further details provided	Wara-Asawapati et al., 201714
19, M	Acute myeloid leukemia on chemotherapy	Fever, headache	No	Right parietal	Yes, negative	Yes, excision of right parietal abscess	Abscess fluid; histopathology, PCR	Not stated	Ketoconazole, rifampicin, sulfamethoxazole–trimethoprim, azithromycin	Yes, asymptomatic at initial follow-up	Nampoothiri et al., 201815
57, M*	Ulcerative colitis on mesalazine, azathioprine, prednisolone, hydrocortisone, infliximab	Respiratory arrest, altered level of consciousness	Yes	Right frontal, left parietal, right parietal, right basal ganglia, right cerebellum	No	Yes, excision of right frontal abscess	Histopathology, PCR	Not stated	Sulfamethoxazole–trimethoprim, fluconazole, azithromycin, miltefosine	Yes, asymptomatic at 15-month follow-up	2020

CSF = cerebrospinal fluid; F = female; M = male; PCR = polymerase chain reaction.

^*Current study case.

CSF samples were obtained in 7 of 14 cases. Only one of these cases was positive for Acanthamoeba, which was isolated using Acanthamoeba-specific PCR. It is notable that this was the only non-operative patient who survived. In our patient, CSF microscopy and culture were unremarkable. However, Acanthamoeba-specific PCR was not performed on our CSF sample. Although rare, had a diagnosis of Acanthamoeba been considered at the time, it may have led to an earlier diagnosis. Techniques for diagnosis of Acanthamoeba reported in our review included immunofluorescent staining using antibodies to Acanthamoeba; periodic acid-Schiff staining to assess for periodic acid-Schiff-reactive Acanthamoeba cysts, which is followed by re-staining with calcofluor white to detect the presence of chemofluorescent cysts; as well as culture on non-nutrient agar using an Escherichia coli suspension. In our case, multiplex PCR with specific primers and probe for Acanthamoeba spp., Naegleria fowleri, and Balamuthia madrillaris were performed on the intraoperative specimens sent for microbiology, and confirmed the diagnosis for Acanthamoeba spp. via the 18S recombinant RNA gene.

There is no standardized regimen for the management of Acanthamoeba brain abscesses. This is, in part, a result of the rarity of the condition as well as the variety of antimicrobial regimens used in the cases included in our review. The most common antimicrobials used in the five patients who survived were azole antifungals (two ketoconazole, two fluconazole) and sulfamethoxazole—trimethoprim (three cases) (Figure 6). Our treatment included both these agents. Miltefosine is an anti-parasitic agent recommended by the U.S. CDC in 2013 for treatment of infections secondary to Acanthamoeba spp., Naegleria fowleri, and Balamuthia mandrillaris. It interacts with lipids, inhibiting cytochrome c oxidase, causing apoptosis-like cell death.¹⁷ There were two reports of its use in Acanthamoeba brain abscesses (one survived, one died).^10,12 In our patient, miltefosine was commenced day 8 post-surgery and day 3 after the formal diagnosis of Acanthamoeba had been established. There was a logistical delay for us because miltefosine had to be sourced from outside Australia. This issue did not result in a clinically significant adverse outcome. D’Auria et al.¹⁸ reported a case of granulomatous amebic encephalitis where miltefosine was also ordered from overseas but did not arrive in time.

Figure 6.

Common antimicrobials used in the five patients who survived Acanthamoeba brain abscess.^3,5,9,10,15 * = current case. This figure appears in color at www.ajtmh.org.

Our review shows overall survival was 5 of 14 patients. Multiple brain abscesses resulted in greater mortality—seven of nine cases. In addition, multiple brain abscesses were associated with poorer outcomes regardless of immunocompetency status. Mortality in single brain abscess was observed in two of five cases. Other reviews of mortality in brain abscess reported rates between 6.3% and 22.75%.^16,19–21 Yang¹⁶ reported that only 45 of 400 cases manifested as multifocal brain abscess. In contrast, the majority of our review group presented with multiple brain abscesses. This may suggest a predilection for Acanthamoeba to develop multiple brain abscesses.

CONCLUSION

Acanthamoeba brain abscess is very rare and most often fatal. We report the first case treated successfully with surgical excision followed by combination therapy including miltefosine. This case was diagnosed initially as nocardiosis or melioidosis, emphasizing the importance of considering differentials such as Acanthamoeba during the workup of an atypical infection. Our review shows a predilection for multiple brain abscesses and an increased mortality rate compared with the general brain abscess population.