Medical Mycology March 2010, 48, 398–401 Multiple intracranial abscesses due to Cryptococcus neoformans: an unusual clinical feature in an immunocompetent patient and a short review of reported cases O . TORE* , S. AKCAGLAR* , E. KAZAK* , Y. HEPER*, H. AKALIN* , B. H AKYEMEZ† , B. ENER* , T. BOEKHOUT‡ § & F . HAGEN ‡§ *Department of Microbiology and Infectious Diseases, †Department of Radiology, U ludag University School of Medicine, B ursa, Turkey, ‡C BS Fungal Biodiversity Center, Department of Yeast and Basidiomycete Research, U trecht, T he Netherlands, and §Division of Acute Medicine and Infectious Diseases, University Medical Centre Utrecht, Eijkman-Winkler Centre for Medical Microbiology, Infectious Diseases and Infl ammation, U trecht, The Netherlands We present a case of multiple intracranial abscesses caused by C ryptococcus neofor- mans in a patient who presented with no symptoms of immunodefi ciency. Keywords multiple intracranial abscesses , C ryptococcus neoformans , review of reported cases Introduction Case report Cryptococcus neoformans is a yeast-like encapsulated fungus The patient was a previously healthy 54-year-old woman that is found worldwide in soil contaminated with bird excre- who presented with complaints of snoring and smelling ment, particularly pigeon droppings [ 1 ]. Humans become unpleasant odors of fi ve months duration and headaches, infected by inhaling the organism and may remain asymptom- along with hearing buzzing sounds for two months. She atic with infection limited to the lungs. When limited to the was lethargic and had superior oblique paralysis of the lungs in immunocompetent hosts, C . neoformans infection right eye. Cranial magnetic resonance imaging (MRI) may cause pneumonia, poorly defi ned mass lesions, pulmo- examination revealed cystic lesions in the posterior seg- nary nodules, and, rarely, pleural effusion [ 2] . In immunocom- ment of the left internal capsule at the level of the left promised hosts in whom there has been hematogenous basal ganglia and a second cystic lesion extending sub- dissemination, the fungus spreads primarily to the central ner- ependimally along the occipital horn of the left lateral vous system (CNS), resulting in meningitis or sometimes ventricle. There was no contrast enhancement around intracranial abscesses or cryptococcoma but may also affect these lesions, but there was widespread edema in the other organs [ 3 ]. Cryptococcosis can be fatal in patients who white matter of the temporo-parietal region and mass have impaired cell-mediated immunity caused by human effect with compression of the left lateral ventricle. Due immunodefi ciency virus (HIV) infection, malignancy, diabe- to the edema, midline shifting to the right was observed, tes mellitus (DM), or corticosteroid treatment [4 ]. Cryptococ- as well as a 1.5 cm-sized ring-enhancing lesion compress- cosis is one of the most common fungal infections affecting ing mesencephalone at the level of the right ambient the CNS, and most patients present with signs of meningitis cysterna (F ig. 1 ). and encephalitis [5 ]. We provide a case of multiple cryptococ- The stereotactic biopsy from the lesion in the left occip- cal abscesses in an immunocompetent patient. ital region did not provide suffi cient material for appropri- ate analysis. A second stereotactic biopsy was taken from the lesion near the mesencephalon. Examination of frozen Received 7 April 2009; Received in fi nal revised form 9 June 2009; sections established the diagnosis of an abscess, and a Accepted 8 July 2009 therapy course of ceftiaxon (2 g two times per day iv) and Correspondence: O. Tore, Uludag University School of Medicine Department of Microbiology and Infectious Diseases, Bursa, Turkey. metronidazole (500 mg three times per day iv) was initi- E-mail: okant@uludag.edu.tr ated immediately. © 2010 ISHAM DOI: 10.3109/13693780903170886 Downloaded from https://academic.oup.com/mmy/article/48/2/398/1016832 by Bursa Uludag University user on 13 September 2022 Multiple intracranial abscesses due to C. neoformans 399 Fig. 1 Cryptococcus neoformans abscess in different regions of the brain. Interrelated cystic lesions (gelatinous pseudocyst) can be seen in the left basal ganglion. Lesions have prominent surrounding edema but did not enhance after contrast administration (A–C) (long arrows). A distinct ring-enhancing lesion with minimal mass effect is visible, located between the aquaductus Sylvii and the fourth ventricle. It is more heterogeneous than the others and has a thick capsule (D–F) (arrowhead). After isolating C ryptococcus neoformans from the sec- showed 90 mm− 3 WBC, and direct microscopic examina- ond biopsy material, the therapy protocol was changed to tion revealed budding yeasts but neither yeasts nor bacte- amphotericin B (1 mg/kg per day) and fl ucytosine (100 mg/ rial were recovered in culture. Due to renal failure, treatment kg per day). Due to problems in providing fl ucytosine, was changed to liposomal amphotericin B 5 mg/kg/d. At amphotericin B was continued as the sole antifungal. At day 17, the EVDS was withdrawn, and therapy continued day 3, an extraventricular drainage system (EVDS) was with fl uconazole (400 mg two times per day iv). introduced by neurosurgeons to drain cerebrospinal fl uid R epeated cranial MRI showed that cystic lesions, which (CSF) which resulted in the drainage of 5 cc of CSF every extended subependimally at the level of the left temporal and 3 h. Examination of the ventricular CSF showed 170 mm− 3 parietal lobes, decreased in size. But there were no signifi - white blood cell (granulocyte predominance), 5,000,000 cant differences in the size of lesions at the level of the mm −3 red blood cell, and 41 mg dl-1 glucose. aquaductus Sylvii. Because of edema around the lesions, the S erum tests for HIV antibodies were twice negative and left ventricle was compressed, and some images indicated her serum glucose values were between normal levels. evidence of hydrocephalus. The patient displayed substantial There was no history of direct contact with pigeons or bird regression in her neurological status, in that she experienced droppings. Examinations of her immune status showed no neck stiffness, spoke unconsciously, had memory loss, and pathological properties (IgA: 216 mg dl− 1; IgM: 123 mg failed to recognize her relatives. Due to vomiting after feed- dl− 1 ; Ig G: 1310 mg dl −1 ; C3c: 146 mg dl −1; C4:26.7 mg ing, mannitol was added to her therapy to suppress regurgi- dl −1; NBT: 100%; IgG subgroups were normal limits; only tation. There was no electrolyte imbalance. the ratio of CD4/CD8: 0.92). Due to a tonic-clonic seizure A t day 25, due to high fever and pyuria, Cefepim (1 g attack, an anti-epileptic drug (Epdantione, tab 3  100 mg) two times per day iv) was added but was later changed to was added to the therapy. At day 11, CSF examination Meropenem (1 g three times per day iv), according to the © 2010 ISHAM, Medical Mycology, 48, 398–401 Downloaded from https://academic.oup.com/mmy/article/48/2/398/1016832 by Bursa Uludag University user on 13 September 2022 400 Tore et al. Fig. 2 AFLP genotyping of original and control strains. Amplifi ed Fragment Length Polymorphisms (AFLP) fi ngerprint analysis (Boekhout et al., 2001 [6]) of the Cryptococcus strain cultured from the patient described in this report (clinical strain) including two reference strains from each serotype of Cryptococcus neoformans (CBS8710 and CBS9172 = Cryptococcus neoformans variety grubii; CBS10511 and CBS10513 = Cryptococcus neoformans variety neoformans). antibiogram of a positive urine culture. Her high fever and the fi ndings from routine hematological, biochemical regressed, but at day 38 she experienced another fever and CSF tests can overlap with those of a variety of non- attack. Teicoplanin (400 mg two times per day iv) was then infectious and infectious etiologies [ 2– 5 ]. added to her therapy and maintained at 400 mg per day iv. When immunocompromised patients develop cryptococ- At day 39, her condition worsened, and on the 40th day cal CNS infections, the clinical picture is nearly always after the start of treatment she died. severe, and most patients present with signs of meningitis and encephalitis [5 ]. Cryptococcoma and brain abscess is a Mycological studies rare entity, characterized by solid tumor-like masses usually found in the cerebral hemispheres or the cerebellum or more F ive days after the inoculation of biopsy samples on rarely in the spinal cord [7 , 8 ]. Cryptococcal brain abscesses Sabouraud dextrose agar, cream-colored mucoid colonies are often solitary, but in some instances they may be mul- were noted. Microscopic studies of Gram-stained and tiple. Five cases of multiple cryptococcal brain abscesses India ink preparations of portions of the colonies revealed have been described to date in the literature [9 – 13 ]. Clinical encapsulated yeasts cells. Germ tube tests were negative, properties of these cases were summarized in T able 1. there was no hyphal growth on cornmeal agar, urease test was Although HIV infection is very rare in Turkey, the number positive, and colonies grew at 25°C and 37°C. The isolate of cases of acquired immunodefi ciency syndrome (AIDS) is from the brain abscess was identifi ed as C ryptococcus neo- still rising, and cryptococcal brain abscesses may occur in formans using API 20C AUX (BioMerioux SA, Marcy- patients with AIDS or other immunocompromising disor- l’Etoile/FRANCE) and by the Rapid Yeast Plus Identifi cation ders. Immunocompetent patients must also be assessed care- System (REMEL Inc., Lenera, KS/USA). The C ryptococcus fully in order to avoid delayed diagnosis [ 14 ]. The prognosis isolate was further typed using a serotype agglutination test is better for HIV-associated cases of cryptococcal CNS (F. Dromer, Pasteur Institute, Paris, France) and genotyped by infection, including meningitis, than in non-HIV patients. In Amplifi ed Fragment Length Polymorphism (AFLP) fi nger- a 1992–2000 population-based surveillance study, 21% of print analysis, as described by Boekhout e t al. [ 6] . patients with non-HIV-associated cryptococcosis died dur- ing their fi rst hospital admission or within 30 days after their Discussion fi rst discharge (i.e., while receiving outpatient care). The corresponding fi gure for HIV-associated cases was 11%, I t is often diffi cult to reach a defi nitive diagnosis in cases with most of these deaths occurring within the fi rst several of cryptococcal CNS infection. The clinical presentation weeks of CNS involvement [1 5 ]. Delayed diagnosis is an Table 1 Summary of cryptococcal brain abscess cases Underlying disease and Reference Age, sex concurrent infection Culture samples Treatment outcome Infection Riccio TJ, et al. [9] NA NA NA NA NA Huang JL, et al. [10] 17, F SLE, meningitis and Blood and brain abscess Amp-B, 5-fl u, Fluc Resolved pulmonary infection Wang JH, et al. [11] 30, M HIV Blood and brain abscess Amp-B, Fluc Died Saigal G, et al. [12] 49, M None CSF Amp-B, 5-lu, Fluc Improved Athanassiadou F, et al. [13] 5, M B-ALL Urine + PCR + Cry-Ag Lam-B, ceftazidime Died NA, not available; M, male; F, female; SLE, systemic lupus erythematosus; B-ALL, B cell acute lymphoblastic leukemia; Cry-Ag, cryptococcus antigen;Amp-B, Amphotericin-B; 5-fl u, 5-fl ucytosine; Fluc, fl uconasole; Lam-B, liposomal amphotericin-B. © 2010 ISHAM, Medical Mycology, 48, 398–401 Downloaded from https://academic.oup.com/mmy/article/48/2/398/1016832 by Bursa Uludag University user on 13 September 2022 Multiple intracranial abscesses due to C. neoformans 401 important issue in the treatment of cryptococcosis. Shih et Declaration of interest: The authors report no confl icts of al . [ 16 ] reported a crude mortality rate of 19.1% (18 deaths) interest. The authors alone are responsible for the content in 94 cases of non-HIV-associated cryptococcal meningitis. and writing of the paper. Seven of these patients died before anti-fungal treatment was even administered and all were cases of delayed diagnosis. R eferences To avoid this situation, radiological imaging studies must be performed, and the patient should be evaluated according to 1 Y ilmaz A, Goral G, Helvaci S, et al. Distribution of Cryptococcus neoformans in pigeon feces. M icrobiol Bull 1989; 23: 1 21 – 126 . radiological fi ndings for stereotactic biopsy. In our case, the 2 Richardson MD , W arnock DW. C ryptococcosis. I n: Fungal Infections diagnosis of brain abscess was determined on the basis of Diagnosis and Management. 3rd edn. Massachusetts, U SA : Black- MR fi ndings ( Fig. 1) , and antibacterial therapy was imme- well Publishing, Inc., Malden, Massachusets, USA . 2003 : 2 15– 2 29 . diately initiated. After the isolation of C . neoformans from 3 K okturk N, Ekim N, Kervan F, et al. Disseminated cryptococcosis in the abscess material, obtained by the second stereotactic an immunodefi ciency virus-negative patient: a case report. M ycoses 2005; 4 8: 270– 2 74. biopsy, treatment was changed to amphotericin B and at day 4 A kcaglar S, Sevgican E, Akalin H, e t al. T wo cases of cryptococcal 17 switched to fl uconazole. meningitis in immunocompromised patients other than HIV. M ycoses S everal randomized controlled trials in patients with 2 007; 5 0: 2 35 –2 38 . AIDS-related cryptococcal meningitis have shown excel- 5 Lanzieri CF, Bangert BA, Tarr RW, e t al. Neuroradiology case of the lent results when induction therapy is administered in the day. CNS cryptococcal infection. Am J Radiology 1 997; 169: 295 – 299. 6 B oekhout T, T heelen B, D iaz M, et al. Hybrid genotypes in the form of amphotericin B combined with fl ucytosine, fol- pathogenic yeast C ryptococcus neoformans . Microbiology 2001; 47: lowed by consolidation therapy with fl uconazole [ 17] . The 8 91 – 907. recommended treatment in the absence of HIV is the same 7 T roncoso A , F umagalli J, Shintza R, e t al. C NS cryptococcoma in an for both cryptococcal CNS infection and meningitis HIV-positive patient . J Int Assoc Physicians in AIDS Care 2 002; 1 . patients, although no controlled trials have been conducted 8 Cryptococcus neoformans . Mycology online. Available at http// mycology.adelaide.ed.au . comparing the azoles with amphotericin B in this popula- 9 Riccio TJ. Gd-DTPA-enhanced MR of multiple cryptococcal brain tion [1 8 ]. Research has also indicated that high-dose fl u- abscesses. Am J Neuroradiol 1 989; 10: S65 – 66. conazole treatment is an effective and safe initial treatment 10 H uang JL, C hou ML, H ung J, Hsieh H. M ultipl cryptococcal brain for cryptococcal meningitis in patients with AIDS [1 9] . abscesses in systemic lupus erythematosus. Br J Rheumatol 1996; 35: In conclusion, although uncommon, C. neoformans infec- 1334– 1 335. 11 Wang JH, H sieh SP, Liu UC, et al. C ryptococcal meningitis and tion should always be considered in cases of meningitis, primary lymphoma in a patient with acquired immunodefi ciency meningoencephalitis, or brain abscesses that occur in patients syndrome. Chin Med J 1997; 5 9: 50 –5 4 . with immunocompromising conditions other than AIDS, as 12 Saigal G, Pst MJD, Lolayekar S, Murtaza A. U nusual presentation of well as in immunocompetent patients. As was observed in central nervous system cryptococcal infection in an immunocmpetent this case, if there are ring-enhancing lesions in MR studies, patient. Am J Neuroradiol 2005; 2 6: 2522 –2 526. 13 Athanassiadou F, Tragianidis Papageorgiou T, Velegraki A. Fungal cryptococcosis must be considered, as well as other etiologic brain abscesses in leukemia. I nd Pediatr 2006; 43: 991 –9 94. agents, and detailed studies must be performed to identify 14 Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS – 100 the causative organism [ 13 ,19 ]. To ensure accurate and defi n- years after the discovery of Cryptococcus neoformans. C lin Microbiol itive diagnosis, if stained or unstained yeast or yeast-like Rev 1 995; 8: 5 15– 548. cells are observed on direct microscopic examination of 15 M irza SA, Phelan M, R imland D. The changing epidemiology of cryptococcosis: an update from population-based active surveillance clinical material, the material should be centrifuged and an in 2 large metropolitan areas,1992–2000. Clin Infect Dis 2003; 36: India ink preparation should always be prepared for analysis. 710 –7 18 . Furthermore, this case indicates that it can take 5–6 days 16 Shih CC, C hen YC, Chang SC, L uh KT, H sieh WC. C ryptococ- before fungal growth appears on culture media in cryptococ- cal menigitis in non-HIV infected patients. Q J Med 2000; 93: cal infections. This suggests that microbiologic cultures must 245– 2 51 . 17 Pappas PG, Perfect JR, Cloud GA, et al. C ryptococcosis in human be incubated longer than usual in this patient group. defi ciency virus negative patients in the era of azole therapy. C lin Infect Dis 2001; 3 3: 690 – 699 . 18 Larsen RA, Bauer M, T homas AM, G raybill R. A mphotericin B Acknowledgements and fl uconazole, a potent combination therapy for cryptococcal men- The authors thank Dr Francoise Dromer (National ingitis. A ntimicrob Agents Chemother 2004; 48: 985 – 991 . 19 S tevens DA. Azoles in the management of systemic fungal infections. Reference Center for Mycoses Pasteur Institute, France) I nfect Dis Clin Pract 2004; 1 2: 81 – 92 . for serotyping and Dr Koncuy Sivrioglu for manuscript 20 Awasthi M, P atankar T, S hah P, Castillo M. Cerebral cryptococcosis: revision. atypical appearances on CT. B r J Rheumatol 2 001; 74: 83 –8 5 . This paper was fi rst published online on Early Online on 01 February 2010. © 2010 ISHAM, Medical Mycology, 48, 398–401 Downloaded from https://academic.oup.com/mmy/article/48/2/398/1016832 by Bursa Uludag University user on 13 September 2022