Successful Treatment of Granulomatous Amoebic Encephalitis with Combination Antimicrobial Therapy

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1 CASE REPORT Successful Treatment of Granulomatous Amoebic Encephalitis with Combination Antimicrobial Therapy Hideki Kato 1, Shigehisa Mitake 1, Hiroyuki Yuasa 1, Shigemasa Hayashi 2, Tatsuru Hara 3 and Noriyuki Matsukawa 4 Abstract Granulomatous amoebic encephalitis (GAE) is a rare but fatal infection. Due to its nonspecific symptoms and laboratory and neuroradiological findings, it is rarely diagnosed antemortem. We herein present the case of a 72-year-old Japanese woman who was diagnosed with GAE following the detection of a pathogen similar to Balamuthia mandrillaris under a microscopic examination of cerebrospinal fluid sediment and who achieved remission with combination antimicrobial therapy. There are no previous reports of pathogens similar to B. mandrillaris being detected in cerebrospinal fluid antemortem; therefore, this case may be used as a benchmark for further studies. Key words: granulomatous amoebic encephalitis (GAE), antimicrobial therapy, free-living amoebae, cerebrospinal fluid (CSF) (Intern Med 52: , 2013) () Introduction Meningoencephalitis caused by free-living amoebae includes two clinical entities: primary amoebic meningoencephalitis (PAM) and granulomatous amoebic encephalitis (GAE). Both have a poor prognosis, usually resulting in death (1, 2). The pathogenic organism responsible for PAM is Naegleria fowleri. Infection with this organism generally progresses rapidly following the development of symptoms and leads to death within ten days. GAE, in contrast, is caused by Acanthamoeba species and Balamuthia mandrillaris and progresses from subacute to chronic over several weeks to two years, followed by death. Since B. mandrillaris was first isolated from the brain of a pregnant mandrill baboon in 1986, it has been found to cause GAE in humans (3), with almost 200 cases having been reported worldwide. Balamuthia encephalitis can develop in children and elderly individuals with normal immunity, while Acanthamoeba species usually cause encephalitis in immunocompromised hosts. The prognosis of patients with GAE caused by B. mandrillaris is very poor, with only eight reported cases of survival. Because GAE is a rare disease with nonspecific symptoms, making the diagnosis antemortem is difficult. Additionally, there are no reports in which the Balamuthia-like amoeba itself was found in cerebrospinal fluid (CSF) (4). The present report describes a case of GAE caused by amoebae with Balamuthia-like morphological characteristics detected in the CSF in which we administered antimicrobial therapy and were able to save the patient s life. Case Report A 72-year-old right-handed Japanese woman presented to our emergency department complaining of disordered consciousness and left-sided paralysis. She had a history of hypertension when she had traveled to Guam 20 years earlier. Approximately six months prior to admission, she increasingly complained of sleepiness and lethargy. Starting approximately two months prior to admission, her appetite had also decreased, and she was diagnosed with depression and treated at a psychiatric clinic. Upon arrival to the emergency department, the patient exhibited slightly impaired con- Department of Neurology, Tosei General Hospital, Japan, Department of Neurosurgery, Tosei General Hospital, Japan, Department of Parasitology, Kurume University School of Medicine, Japan and Department of Neurology, Nagoya City University, Japan Received for publication February 6, 2013; Accepted for publication April 19, 2013 Correspondence to Dr. Noriyuki Matsukawa, norim@med.nagoya-cu.ac.jp 1977

2 Figure 1. Magnetic resonance imaging (MRI) and MRA of the brain performed on admission (A- D) and day 9 posthospitalization (E, F). An axial T2-weighted image shows a high signal in the right insular cortex and left occipital lobe of the cerebrum (A). MRA shows occlusion of the right median cerebral artery (B). Diffusion-weighted MRI reveals a diffuse high signal in the right insular cortex and right parietal lobe (C, D). An axial T1-weighted image obtained following the administration of gadolinium shows nodular enhancement in the right insular cortex, meninges in the vicinity and left occipital lobe of the cerebrum (E, F). sciousness (Glasgow Coma Scale: E3V4M6). A physical examination revealed a normal blood pressure (134/87 mmhg) with tachycardia (pulse: 101 beats per min) and a low-grade fever (37.6 ). She had no skin rashes, and her lymph glands were not enlarged. A neurological examination revealed a slight loss of muscle strength in the left arm and leg with left spatial neglect. Blood tests showed a white blood cell count of 10,610/mm 3, a red blood cell count of /mm 3, an Hb level of 9.9 g/dl, a hematocrit level of 29.7%, a platelet count of /mm 3 and a C-reactive protein level of 2.86 mg/dl. T2-weighted magnetic resonance imaging (MRI) demonstrated a high signal in the right insular cortex and left occipital lobe of the cerebrum (Fig. 1A). High signals were observed in the right insular cortex and right parietal lobe on diffusion-weighted imaging, while occlusion of the right middle cerebral artery (MCA) branch was observed on MR angiography (Fig. 1B, C, D). Transthoracic echocardiography did not show left ventricle enlargement or thrombus formation. Based on this information, the patient was diagnosed with a cerebral infarction (atherothrombotic infarction) and treated accordingly. Staring on day 3 of hospitalization, she complained of a headache and loss of appetite. On day 9 of hospitalization, a lumbar puncture was performed because she developed vomiting, a fever of 38 and nuchal rigidity. The initial pressure was 22 cmh2o, and the CSF appeared yellowish white and muddy. A CSF examination showed a cell count of 1,153 cells/mm 3 (46% neutrophils), a protein level of 134 mg/dl, a sugar level of 40 mg/dl (the blood sugar level was 119 mg/dl in blood collected simultaneously) and an adenosine deaminase level of 5.5 IU/L. A microscopic examination with India ink staining, bacterial and tuberculosis bacillus cultures and cerebrospinal cytological diagnoses were all negative. Axial T1-weighted imaging with gadolinium of repeated head MRI revealed nodular pathological changes in the right insular cortex, meninges in the vicinity and left occipital lobe of the cerebrum (Fig. 1E, F). Because bacterial and/or fungal meningitis was suspected, ceftriaxone at a dose of 2 g/day and fluconazole at a dose of 200 mg/ day were intravenously administered. Markers for several kinds of fungal antigens, viral antibodies and syphilis were all negative in both the serum and CSF. There were no abnormal findings on a random skin biopsy, and no malignant tumors were found in various tests. Anti-HIV antibodies were also negative. On day 32, a skull-opening brain biopsy was performed. A pure white, cheese-like, homogenous substance filled the right Sylvian fissure and adhered to the tissue so that the M1-M2 portion of the right MCA was covered. Although the external shape of the MCA was maintained, black discoloration characterized the middle of the M2 portion. The biopsied brain tissue manifested slight gliosis; however, there was no blood vessel inflammation or 1978

3 Figure 2. Amoebae observed on microscopy. The cerebrospinal fluid was centrifuged, and the sediment was observed with an optical microscope. Pseudopods branching off, which appear to be Balamuthia mandrillaris trophozoites, are visible. Scale bar: 100 μm. granuloma or tumor formation. We therefore considered a diagnosis of amoebic meningoencephalitis, and on day 40, we observed a number of living amoebae on a direct microscopic examination of the centrifuged CSF. The amoebae had extended, branched pseudopodia, a specific characteristic of B. mandrillaris amongst trophozoites of known pathogenic amoebae (Fig. 2). To determine the species of amoeba, we performed a polymerase chain reaction (PCR) test of the CSF and indirect immunofluorescence (IIF) staining of the biopsy specimens for B. mandrillaris, N. fowleri and Acanthamoeba species; however, all tests were negative. Although we were unable to identify the type of amoeba, we diagnosed the patient with GAE based on the morphology and initiated treatment with fluconazole (400 mg/day iv), pentamidine isethionate (200 mg/day iv), clarithromycin (800 mg/day po) and albendazole (600 mg/day po). Pentamidine caused persistent low blood sugar, while clarithromycin resulted in obvious QT prolongation, and both were therefore stopped. Flucytosine (3,000 mg/day po) was added to fluconazole and albendazole, and the treatment was continued. The patient s progress was good; there was no worsening of pathological changes on head MRI, and the number of cells in the CSF decreased. On day 90, the CSF was amoeba-free. Although the patient still had memory disturbance, impaired orientation and delusions, she left the hospital five months after admission. She was still taking fluconazole and albendazole 17 months after starting treatment, with no signs of recurrence. Discussion This case is an example of GAE with the onset of mental symptoms (decreased spontaneity, depression) actualized by a cerebral infarction. In the present case, we diagnosed the patient with GAE after observing free-living amoebae in the CSF on optical microscopy, although we were unable to determine the species. Combination therapy with albendazole, flucytosine and fluconazole effectively treated the GAE, resulting in remission. PCR analyses of the CSF and IIF staining of biopsy sections are usually used to diagnose GAE (4, 5). Recently, high-sensitivity real-time PCR targeting the RNase P gene has been developed (6). In the current case, however, the PCR test was negative for amoebae, including B. mandrillaris, N. fowleri and Acanthamoeba species. One possible reason for the negative PCR results is an insufficient number of amoebic cells in the CSF sample. A report by the California Encephalitis Project demonstrated that the rate of positive findings on PCR tests using CSF samples obtained from patients with presumptive Balamuthia amoebic encephalitis was only 25% (7). In the current case, IIF staining was also negative. This may have been due to the fact that the tissue biopsy specimen was almost necrotic and did not include the inflammatory site or blood vessels. However, we visualized a number of living amoebae with extending, branched, pseudopodia on a direct microscopic examination of the centrifuged CSF antemortem. Based on the available information, including the specific morphological characteristics and the patient s chronic clinical course, we considered the GAE to be due to B. mandrillaris rather than Acanthamoeba species or N. fowleri, although we were unable to determine the species using PCR tests of the CSF or IIF staining of biopsy specimens. There have been four reports of meningoencephalitis caused by B. mandrillaris in Japan. Although brain biopsies were performed antemortem in these cases, the biopsy findings did not lead to a diagnosis (8-10). Unlike N. fowleri (11), Acanthamoeba species and B. mandrillaris are usually not visible in the CSF on microscopic examinations antemortem. To our knowledge, only one case involving culture isolation of B. mandrillaris in the CSF postmortem has been reported (12). Unlike N. fowleri, neither Acanthamoeba species nor B. mandrillaris multiply rapidly, which is presumably why they are rarely detected in CSF. When a diagnosis of amoebic meningoencephalitis is suspected, as in this case, careful analyses of the CSF may lead to detection. In the current case, the disease itself was actualized by occlusion of the right MCA. Although an inflammatory mechanism was presumed based on the macroscopic findings of the tissue around the right MCA and the results of the skull biopsy, we did not perform a biopsy of the blood vessel itself, and the exact pathological changes in blood vessel invasion are unknown. However, occlusion of the blood vessels and bleeding have been reported in the brain tissue of patients with GAE, with vasculitis assumed to be the cause. Although there is usually invasion of small vessels, and necrosis is often observed over a small region, cases resulting in large vessel arterial infarction, as observed in this case, have also been reported (10, 13). The same mechanism has been reported to occur in cases of fungal meningitis, such as that involving aspergillosis, toxoplasma encephalitis, tuberculous meningitis and bacterial meningitis. Therefore, in cases in which psychological symptoms and cerebrovascular disorders proceed gradually, a diagnosis of 1979

4 Table. Comparison of Reported Successfully Treated Cases of Meningoencephalitis Caused by Balamuthia mandrillaris Authors & Year Deetz et al Deetz et al Jung et al, 2004 Age Sex Risk factor Presentation Means of diagnosis Effective treatment regimen Outcome Follow-up Reference 64 M immunocompetent skin lesions, rt hemiparesis, generalized seizures brain biopsy, IIF 5 F immunocompetent generalized seizure brain biopsy, IIF 72 F immunocompetent focal lt-sided seizure CEP, M NR seizure Seas et al Martinez et al Doyle et al Orozco et al present case brain biopsy, IIF serology, clarithromycin (2 years), flucytosine, fluconazole, sulfadiazine(5years), maintenance: fluconazole, sulfadiazine flucytosine, fluconazole, thioridazine, clarithromycin (1.9 years), maintenance: fluconazole, clarithromycin pentamidine, fluconazole, sulfadiazine, clarithromycin (unreported duration) 8 M NR NR NR albendazole,itraconazole(14 months) 21 F immunocompetent skin lesions 80 F immunocompetent skin lesions, generalized seizures skin biopsy, IIF, skin/brain biopsy, enablle to walk independently, to communicate well moderate performance ploblems in complete recovery 5 years years 15 6 months 16 NR NR 3 months 17 albendazole,fluconazole,meltefosine (7.5months) liposomal amphotericin (3 weeks), flucytosine, azithromycin, itraconazole, sulfadiazine (7 months), surgical excision(+) pentamidine,sulfadiazine,fluconazole, 27 M kidney recipient coma PCR(CSF),culture flucytosine, azithromycin,meltefosine, EVD(+) clarithromycin (2 weeks), fluconazole, 72 F immunocompetent lt hemiparesis microscopy of CSF albendazole, flucytosine (4 months), maintenance: fluconazole, albendazole (>17months) mild left hemiparesis Skin and CNS lesions healed complete recovery Severely disabled, need to family care gait disturbance, delusions NR: not reported, CEP: Calpholnia encephalitis project, IIF: immunofluorescence, CSF: cerebrospinal fluid, EVD: external ventricular drainage 3 years months months months months present report GAE should be considered, and the evidence should be carefully examined. The optimal therapy for GAE has not been determined. In this case, we treated the patient with the antimicrobial drugs used in reported surviving cases of GAE caused by B. mandrillaris or Acanthamoeba species. There are nine cases of survivors of meningoencephalitis caused by B mandrillaris (7, 14-19), and in most of these cases, combinations of drugs including fluconazole, flucytosine, pentamidine, amphotericin B, sulfadiazine, clarithromycin, albendazole and miltefosine were used (Table). Recently, a case of a complication of a brain abscess treated with a combination of antibacterial drugs and surgical removal was reported (14, 19). In the present case, clarithromycin, pentamidine, albendazole and flucytosine were added to fluconazole, which was administered in the first stage of treatment. Although pentamidine and clarithromycin were suspended due to side effects, the combination of the remaining drugs enabled the patient to achieve remission. We had assumed a diagnosis of fungal meningitis at an early stage and administered fluconazole, which may have suppressed the proliferation of the amoebae, ultimately resulting in remission. The development of new antimicrobial drugs is needed, and confirming the efficacy and safety of antimicrobials when used continuously for long periods, especially in combination with each other, is required. The authors state that they have no Conflict of Interest(COI). Acknowledgement We thank Dr. Kenji Yagita (Department of Parasitology, The National Institute of Infectious Diseases, Japan) for performing the immunofluorescence staining and Dr. Mari Yoshida (Institute for Medical Science of Aging, Aichi Medical University, Japan) for providing valuable comments on the biopsy specimens. References 1. Schuster FL, Visvesvara GS. Free-living amoebae as opportunistic and non-opportunistic pathogens of humans and animals. Int J Parasitol 34: , Visvesvara GS, Moura H, Schuster FL. Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS Immunol Med Microbiol 50: 1-26, Visvesvara GS, Schuster FL, Martinez AJ. Balamuthia mandrillaris, N. G.,N. Sp.,agent of amebic meningoencephalitis in humans and other animals. J Eukaryot Microbiol 40: , da Rocha-Azevedo B, Tanowitz HB, Marciano-Cabral F. Diagnosis of infections caused by pathogenic free-living amoebae. Interdiscip Perspect Infect Dis 2009: , Yagi S, Booton GC, Visvesvara GS, Schuster FL. Detection of Balamuthia mitochondrial 16S rrna gene DNA in clinical specimens by PCR. J Clin Microbiol 43: , Kiderlen AF, Radam E, Lewin A. Detection of Balamuthia mandrillaris DNA by real-time PCR targeting the RNase P gene. BMC Microbiol 8: 210, Schuster FL, Yagi S, Gavali S, et al. Under the radar: Balamuthia amebic encephalitis. Clin Infect Dis 48: , Shirabe T, Monobe Y, Visvesvara GS. An autopsy case of amebic meningoencephalitis. The first Japanese case caused by Balamuthia mandrillaris. Neuropathology 22: , Bando Y, Takahashi T, Uehara H, Kagegi T, Nagahiro S, Izumi K. Autopsy case of amebic granulomatous meninngoencephalitis caused by Balamuthia mandrillaris in Japan. Patho Int 62: , Yamasaki K, Sugimoto T, Futami M, et al. Granulo, matous amoe- 1980

5 bic encephalitis caused by balamuthia mandrillaris. Neurol Med Chir (Tokyo) 51: , Hara T, Fukuma T. Diagnosis of the primary amoebic meningoencephalitis due to Naegleria fowleri. Parasitol Int 54: , Jayasekera S, Sissons J, Tucker J, et al. Post-mortem culture of Balamuthia mandrillaris from the brain and cerebrospinal fluid of a case of granulomatous amoebic meningoencephalitis and using human brain microvascular endothelial. cells. J Med Microbiol 53: , Schumacher DJ, Tien RD, Lane K. Neuroimaging findings in rare amebic infections of the central nervous system. AJNR Am J Neuroradiol 16: , Orozo L, Hanigan W, Khan M, Fratkin J, Lee M. Neurosurgical intervention in the diagnosis and treatment of Balamuthia mandrillaris encephalitis. J Neurosurg 115: , Deetz TR, Sawyer MH, Billman G, Schuster FL, Visvesvara GS. Successful treatment of Balamuthia amoebic encephalitis: presentation of 2 cases. Clin Infect Dis 37: , Jung S, Schelper RL, Visvesvara GS, Chang HT. Balamuthia mandrillaris meningoencephalitis in an immunocompetent patient:. an unusual clinical course and a favorable outcome. Arch Pathol Lab Med 128: , CDC. Balamuthia amebic encephalitis---california, MMWR 57: , Martinez DY, Seas C, Bravo F, et al. Successful treatment of Balamuthia mandrillaris amoebic infection with extensive neurological and cutaneous involvement. Clin Infect Dis 51: e7-e11, Doyle JS, Campbell E, Fuller A, et al. Balamuthia mandrillaris brain abscess successfully treated with complete surgical excision and prolonged combination antimicrobial therapy. J Neurosurg 114: , The Japanese Society of Internal Medicine

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