Cure of Acanthamoeba Cerebral Abscess in a Liver Transplant Patient

Transcription

1 LIVER TRANSPLANTATION 14: , 2008 ORIGINAL ARTICLE Cure of Acanthamoeba Cerebral Abscess in a Liver Transplant Patient Konrad Tang-Tat Fung, 1 Amar Paul Dhillon, 2 James E. McLaughlin, 2 Sebastian B. Lucas, 3 Brian Davidson, 4 Keith Rolles, 4 David Patch, 1 and Andrew K. Burroughs 1 1 Liver Transplantation and Hepatobiliary Medicine and 2 Department of Histopathology, Royal Free Hospital, London, United Kingdom; 3 Department of Histopathology, King s College London School of Medicine, St. Thomas Hospital, London, United Kingdom; and 4 University Department of Surgery, Royal Free & University College School of Medicine, London, United Kingdom Acanthamoeba-related cerebral abscess and encephalitis are rare but usually fatal, being caused by free-living amoebic infections usually occurring in immunocompromised patients. In patients receiving transplants, a literature review showed that the infection is universally fatal. The diagnosis is often missed despite appropriate investigations including lumbar puncture, computerized tomography, and brain biopsy. We present the first reported liver transplant patient with Acanthamoeba cerebral abscess. The diagnosis was made in brain tissue removed at decompressive frontal lobectomy. He was successfully treated with a 3-month course of co-trimoxazole and rifampicin. There was no recurrence of the disease after 11 years of follow-up. Liver Transpl 14: , AASLD. Received June 7, 2007; accepted September 17, Central nervous system (CNS) infections by free-living amoebae, including Acanthamoeba species, Balamuthia mandrillaris, and Naegleria fowleri, have been recognized only in recent decades. The first two amoebae cause chronic granulomatous encephalitis, whereas the last one causes acute fulminant meningitis. Acanthamoeba-related infection is usually limited to immunocompromized patients, although infection in healthy children has been reported. 1 Unfortunately, most of the infections are fatal and are diagnosed at autopsy. 2,3 We report the first case of successfully treated Acanthamoeba cerebral infection following liver transplantation. CASE REPORT A 41-year-old male had liver transplantation with a cadaveric donor graft in our hospital in September 1994 for end-stage alcoholic liver cirrhosis. He had a previous history of abdominal tuberculosis in 1986 and was an insulin-dependent diabetic. He recovered well after the operation and was given maintenance immunosuppression of cyclosporine, azathioprine, and prednisolone. He received fluconazole and acyclovir prophylaxis, which he continued for 6 weeks after discharge, which took place 3 weeks after the operation. At 3 months after transplantation, his prednisolone was tailed off completely. He developed depression and resumed drinking alcohol about 9 months after transplantation without affecting his graft function. He was followed up by a psychiatrist specializing in alcohol and substance abuse. Azathioprine was also stopped at the same time because of neutropenia, which subsequently recovered fully. At 14 months after transplantation, the patient was admitted as an emergency because of pyrexia, sore throat, and green sputum for 2 days. Physical examination was normal apart from the abdominal scar of his surgery. Chest X-ray showed elevated right hemidiaphragm but was otherwise normal. Cytomegalovirus polymerase chain reaction in blood was positive. Otherwise, no positive culture or serological positivity for bacteria or viruses was obtained. Ganciclovir was started on day 4 of admission. However, the patient continued to have a high unremitting fever. On day 6, Abbreviations: CNS, central nervous system; CT, computerized tomography. Address reprint requests to Andrew K. Burroughs, Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, Pond Street, London NW3 2QG, United Kingdom. Telephone: ; FAX: ; andrew.burroughs@royalfree.nhs.uk DOI /lt Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 ACANTHAMOEBA IN LIVER TRANSPLANT 309 he developed several attacks of generalized tonic clonic convulsions and became drowsy. There was minimal neck stiffness. Subsequently, both left upper and lower limbs showed twitching. All 4 limbs withdrew to pain, and there were bilateral extensor plantar reflexes. Computerized tomography (CT) of the brain showed a suspicious low-attenuation lesion with mild ring enhancement in the left frontal lobe. No pressure effect was noted. Cerebrospinal fluid analysis revealed 152 cells/mm (90% mononuclear cells), 2.1 g/l protein, and 8.3 mmol/l glucose. No organism was grown or seen from the cerebrospinal fluid. Empirical sulfadiazine, pyrimethamine, cefotaxime, chloramphenicol, gentamicin, isoniazid, rifampicin, and pyrazinamide were given to cover toxoplasma, bacterial, and tuberculous infections. Phenytoin was given to control the seizures. A right (nondominant) frontal lobe biopsy on day 8 showed partly degenerate and inflamed cerebral tissue indicating encephalitis. No microorganism, viral inclusion, or granuloma was identified. Bacterial, viral, acid-fast-bacilli, and fungal cultures were negative. Acyclovir and amphotericin were added to cover herpes simplex virus and fungal infection, respectively. On day 10, the toxoplasma serology showed only low titers, so pyrimethamine was stopped, whereas sulfadiazine was continued to cover Nocardia infection. However, the patient did not improve. A CT scan of the brain on day 13 showed an increased extent of involvement in the right frontal lobe. His conscious level deteriorated further on day 29. An enlarged left frontal lobe lesion with corpus collosum involvement and midline shift was noted on the CT scan. Decompressive left frontal lobectomy was performed on day 31 with resection of a 5-cm diameter of the frontal lobe. The left lobectomy specimen showed diffuse hemorrhagic encephalitis with granulation tissue, scattered giant cells, focal acute inflammation, and areas of necrosis. Repeated bacterial and acid-fast-bacilli cultures were negative. The condition of the patient remained stable, although there was no further deterioration. On day 48, a CT scan of the brain showed multiple low-density lesions in the remaining left frontal lobe. The dosage of cyclosporine was reduced on day 59 in view of persistent sepsis, with the plasma concentration dropping from 93 to 58 ng/ml. Lumbar puncture was repeated on day 66, but no positive result was obtained. Review of the lobectomy specimen on day 79 showed 10- to 15- m amoebic cysts in the areas of necrosis; the cyst walls were also stained with Grocott silver and periodic acid-schiff stains; and with immunocytochemistry, these were characterized as Acanthamoeba spp. (Figs. 1-3). Rifampicin was continued at 600 mg twice daily, and co-trimoxazole was added at 960 mg twice daily for a total treatment course of 3 months. All other antibiotics were stopped. The fever subsided, and his general condition improved. Seizures were further controlled after the switch from phenytoin to carbamazepine. He initially had tetraplegia with contracture of 4 limbs, failed to sit stably, and was disorientated and unable to Figure 1. Inflamed brain and necrosis. In the center is a single empty cyst (hematoxylin-eosin stain). Figure 2. Amoebic cyst with a crenated wall and vacuolated contents (hematoxylin-eosin mucicarmine). speak. A gastrostomy tube was inserted to improve nutrition. He received intensive rehabilitation with substantial restoration of his motor and higher cerebral function over time. The patient is currently alive 11 years after the initial Acanthamoeba infection, is able to speak, stand, eat and drink, and walk with aids, but does require help at home. He has no evidence of recurrent infection. He is maintained on cyclosporine (75 mg twice daily), lamotrigine (100 mg twice daily), phenobarbitone (60 mg

3 310 FUNG ET AL. Figure 3. Immunostain identifying the cysts as of Acanthamoeba spp. (the slide is courtesy of Dr. David Warhurst, London School of Hygiene and Tropical Medicine). daily), carbamazepine (100 mg three times a day), and sulpiride (200 mg twice daily). DISCUSSION Acanthamoeba infection usually occurs in immunocompromized patients, including those with acquired immunodeficiency syndrome 2 or those with chronic debilitating illness. 4 It has been reported in 6 patients with bone marrow, 5-7 renal, 8 or lung transplantation 9 but has not been reported in patients with liver transplantation. In addition, a series of 3 patients with alcoholism has been reported. 10 It may be that the return to alcoholism in our patient predisposed him to infection, particularly as it was acquired late after transplantation, when immunosuppression had been reduced. Acanthamoeba is ubiquitous in the environment and can be found in the soil, fresh water, sea water, and even air. It does not require a host and can exist in the forms of dormant resilient cysts and infective trophozoites. Although the free-living amoeba usually causes keratitis in contact lens wearers, it may also involve the skin and CNS in immunocompromized patients. 11 The higher incidence of Acanthamoeba keratitis in the United Kingdom has been attributed to the use of large standing rooftop storage tanks as a domestic water supply. 12 Such environmental conditions may have predisposed our patient to come into contact with Acanthamoeba. The infection may be acquired by inhaling the amoeba, which produces nasal and sinus infections. 13 The brain and lungs are involved via hematogeneous spread. 2 Acanthamoeba-related CNS infection includes encephalitis and cerebral abscess. There are no distinct clinical features sufficient to make a specific diagnosis. Patients may present with fever, headache, personality changes, seizures, and confusion, classically of subacute onset, which may persist up to 2 years. Physical signs include hemiparesis, cranial nerve palsies, ataxia, and meningeal signs. 1 Cerebrospinal fluid findings vary but usually show moderately elevated protein as in our patient, low to normal glucose, and lymphocytosis, although granulocytosis may be present; however, cerebrospinal fluid may be normal. Acanthamoeba is seldom isolated from cerebrospinal fluid by routine microscopy 12 or culture, and this was also the case in our patient. A CT scan of the brain may be normal or may show a solitary contrast-enhancing mass lesion or multiple contrast-enhancing mass lesions, hemorrhagic infarct, hydrocephalus, or meningeal enhancement. 1,2,5,14 Detection of antibodies against Acanthamoeba may be helpful, but its use currently remains investigational. 15 Histological examination of the brain biopsy may show granulomatous reaction with multinucleated giant cells, necrotizing vasculitis, and inflammatory perivascular infiltrate, although such an inflammatory reaction may be absent in immunocompromized patients. In our patient, cysts of Acanthamoeba were identified. Acanthamoeba is frequently missed, as evidenced by a retrospective slide review. 7 It is not possible to differentiate Acanthamoeba from B. mandrillaris by light microscopy. It is therefore necessary to perform indirect immunostaining as various species of Acanthamoeba and B. mandrillaris are antigenically distinct. Electron microscopy is also useful as the cyst wall of Acanthamoeba has 2 layers, whereas that of Balamuthia has 3. In addition, Acanthamoeba will grow in coculture with bacteria such as Escherichia coli or Enterobacter aerogenes, but B. mandrillaris will not. 2 Unfortunately, most patients have their diagnosis made at autopsy examination, probably because of the difficulty in identifying the amoeba in microscopy, the special requirements in culture, and the poor awareness of this rare but fatal disease. There is no established treatment for Acanthamoeba-related CNS infection. The outcomes of most of the patients have been uniformly fatal, despite various treatment regimens. Table 1 summarizes the results of transplanted patients with Acanthamoeba-related CNS infection identified from a Pubmed literature search from 1966 using the keywords Acanthamoeba, transplant, and transplantation. It is clear that there has been no significant advance in the management of Acanthamoeba-related CNS infection over these 4 decades as all 6 patients reported died from the disease. Among the patients with acquired immunodeficiency syndrome, the mortality rate is also high: just 1 of the 7 patients survived as identified from a Pubmed literature search from 1966 using the keywords Acanthamoeba and AIDS. 2,16-20 Our patient survived, without recurrence of the disease over 11 years of follow-up, after being treated by surgical excision of the abscess followed by rifampicin and co-trimoxazole for 3 months. These 2 antibiotics have been used successfully in immunocompetent or acquired immunodeficiency syndrome patients with Acanthamoeba-related CNS infection, although ketoconazole, fluconazole, metronidazole, sulfadiazine, and pyrimethamine have been added to their regimens. 1,2,21 Successful treatment in our patient could also be attributed to the relatively low dose of the immunosuppression that was

4 ACANTHAMOEBA IN LIVER TRANSPLANT 311 TABLE 1. Outcomes of Transplanted Patients with Acanthamoeba-Related CNS Infection Patient Year of (Reference) Occurrence 1 (8) Not reported (before 2006) Age Organ Transplanted 2 (5) Allogenic 3 (4) Autologous stem cell 4 (6) Not reported (before 1994) 5 (6) Not reported (before 1994) Type of CNS Infection Time of Establishing the Diagnosis Treatment Received Outcome 60 Lung Encephalitis Postmortem Amphotericin, itraconazole, imipenem, ciprofloxacin, vancomycin Encephalitis Postmortem Amphotericin stem cell 39 Autologous bone marrow 32 Allogenic bone marrow Encephalitis, myelitis Postmortem Rifampicin, isoniazid, pyrazinamide, pyrimethamine, sulfadiazine, ceftriaxone Meningoencephalitis Postmortem Amphotericin, fluconazole, cotrimoxazole, metronidazole, doxycycline Meningoencephalitis Postmortem Amphotericin, fluconazole, cotrimoxazole, pyrimethamine, isoniazid, rifampicin, pyrazinamide 6 (7) Kidney Cerebral abscess Antemortem (brain biopsy) Not reported used during therapy of the infection and subsequently during maintenance as compared to the other transplanted patients who had fatal outcomes. REFERENCES 1. Singhal T, Bajpai A, Kalra V, Kabra SK, Samantaray JC, Satpathy G, et al. Successful treatment of Acanthamoeba meningitis with combination oral antimicrobials. Pediatr Infect Dis J 2001;20: Martinez MS, Gonzalez-Mediero G, Santiago P, Rodriguez de Lope A, Diz J, Conde C, et al. Granulomatous amebic encephalitis in a patient with AIDS: isolation of Acanthamoeba sp. group II from brain tissue and successful treatment with sulfadiazine and fluconazole. J Clin Microbiol 2000;38: White JM, Barker RD, Salisbury JR, Fife AJ, Lucas SB, Warhurst DC, et al. Granulomatous amoebic encephalitis. Lancet 2004;364: Cha JH, Furie K, Kay J, Walensky RP, Mullins ME, Hedley- Whyte ET. Case records of the Massachusetts General Hospital (case ). N Engl J Med 2006;355: Feingold JM, Abraham J, Bilgrami S, Ngo N, Visvesara GS, Edwards RL, et al. Acanthamoeba meningoencephalitis following autologous peripheral stem cell transplantation. Bone Marrow Transplant 1998;22: Castellano-Sanchez A, Popp AC, Nolte FS, Visvesvara GS, Thigpen M, Reedy I, et al. Acanthamoeba castellani encephalitis following partially mismatched related donor peripheral stem cell transplantation. Transpl Infect Dis 2003;5: Anderlini P, Przepiorka D, Luna M, Langford L, Andreeff M, Claxton D, et al. Acanthamoeba meningoencephalitis after bone marrow transplantation. Bone Marrow Transplant 1994;14: Martinez AJ. Acanthamoebiasis and immunosuppression. Case report. J Neuropathol Exp Neurol 1982;41: Duarte AG, Sattar F, Granwehr B, Aronson JF, Wang Z, Lick S. Disseminated acanthamoebiasis after lung transplantation. J Heart Lung Transplant 2006;25: Martinez AJ. Is Acanthamoeba encephalitis an opportunistic infection? Neurology 1980;30: Awwad ST, Petroll WM, McCulley JP, Cavanagh HD. Updates in Acanthamoeba keratitis. Eye Contact Lens 2007; 33: Kilvington S, Gray T, Dart J, Morlet N, Beeching JR, Frazer DG, et al. Acanthamoeba keratitis: the role of domestic tap water contamination in the United Kingdom. Invest Ophthalmol Vis Sci 2004;45: Vernon SE, Acar BC, Pham SM, Fertel D. Acanthamoeba infection in lung transplantation: report of a case and review of the literature. Transpl Infect Dis 2005;7: Singh P, Kochhar R, Vashishta RK, Khandelwal N, Prabhakar S, Mohindra S, et al. Amebic meningoencephalitis: spectrum of imaging findings. Am J Neuroradiol 2006;27: Schuster FL, Honarmand S, Visvesvara GS, Glaser CA. Detection of antibodies against free-living amoebae Balamuthia mandrillaris and Acanthamoeba species in a population of patients with encephalitis. Clin Infect Dis 2006; 42: Calore EE, Cavaliere MJ, Calore NM. Cerebral amebiasis

5 312 FUNG ET AL. in the acquired immunodeficiency syndrome. Acta Neurol Belg 1997;97: Gordon SM, Steinberg JP, DuPuis MH, Kozarsky PM, Nickerson JF, Visvesvara GS. Culture isolation of Acanthamoeba species and leptomyxid amebas from patients with amebic meningoencephalitis, including two patients with AIDS. Clin Infect Dis 1992;15: Di Gregorio C, Rivasi F, Mongiardo N, De Rienzo B, Wallace S, Visvesvara GS. Acanthamoeba meningoencephalitis in a patient with acquired immunodeficiency syndrome. Arch Pathol Lab Med 1992;116: Gardner HA, Martinez AJ, Visvesvara GS, Sotrel A. Granulomatous amebic encephalitis in an AIDS patient. Neurology 1991;41: Wiley CA, Safrin RE, Davis CE, Lampert PW, Braude AI, Martinez AJ, et al. Acanthamoeba meningoencephalitis in a patient with AIDS. J Infect Dis 1987;155: Petry F, Torzewski M, Bohl J, Wilhelm-Schwenkmezger T, Scheid P, Walochnik J, et al. Early diagnosis of Acanthamoeba infection during routine cytological examination of cerebrospinal fluid. J Clin Microbiol 2006;44: