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Cerebral tuberculomas in AIDS patients: a forgotten diagnosis?

Tuberculomas cerebrais em pacientes com AIDS: um diagnóstico esquecido?

Abstracts

The human immunodeficiency virus (HIV) infection epidemics increased the prevalence, multi-drug resistance and disseminated forms of tuberculosis. The central nervous system (CNS) tuberculosis has high mortality and morbidity, and it is usually divided into diffuse (meningitis) and localized (tuberculoma and abscess) forms. We report three cases of cerebral tuberculomas in AIDS patients: one with definitive diagnosis, confirmed with histopathology, and two with probable diagnosis, based on clinical information, radiological images, Mycobaterium tuberculosis isolation out of the CNS and adequate response to antituberculous treatment. Further, we discuss diagnostic, therapeutic and prognostic issues of tuberculomas, with emphasis in the distinction from cerebral tuberculous abscesses. Despite of their infrequent presentation, tuberculomas should be considered in the differential diagnosis of cerebral expansive lesions in patients with AIDS.

tuberculoma; tuberculosis; central nervous system; acquired immunodeficiency syndrome


A epidemia da infecção pelo vírus da imunodeficiência humana (HIV) aumentou a prevalência, multiresistência e formas disseminadas da tuberculose. O acometimento neurológico da tuberculose apresenta elevada morbidade e mortalidade, classificando-se em formas difusas (meningite) e localizadas (tuberculoma e abscesso). Relatamos três casos de tuberculomas cerebrais em pacientes com AIDS: um deles com diagnóstico definitivo, confirmado com histopatologia e dois com diagnóstico provável, baseado em informação clínica, radiológica, isolamento de Mycobaterium tuberculosis fora do sistema nervoso central e adequada resposta ao tratamento tuberculostático. Discutimos também aspectos diagnósticos, terapêuticos e prognósticos dos tuberculomas, enfatizando suas diferenças com os abscesos tuberculosos cerebrais. Apesar de serem relatados de forma infreqüente, os tuberculomas devem sempre ser considerados no diagnóstico diferencial das lesões expansivas cerebrais em pacientes com AIDS.

tuberculoma; tuberculose; sistema nervoso central; sindrome da imunodeficiência adquirida


Cerebral tuberculomas in AIDS patients: a forgotten diagnosis?

Tuberculomas cerebrais em pacientes com AIDS: um diagnóstico esquecido?

José E. VidalI; Adrián V. HernándezII; Augusto C. Penalva de OliveiraIII, IV; Alexandre Leite de SouzaI; Geraldine MadalossoI; Paula R. Marques da SilvaI; R. DauarIV

IDepartments of Infectology, Institute of Infectious Disease Emilio Ribas, Sao Paulo SP, Brazil

IICenter for Clinical Decisions Sciences, Department of Public Health, Erasmus University Medical Center, Rotterdam, The Netherlands

IIIDepartments of Neurology, Institute of Infectious Disease Emilio Ribas, Sao Paulo SP, Brazil

IVClinical Research Unit in Human Retrovirus, University of Campinas, Sao Paulo SP, Brazil

VDepartments of Neurosurgery, Institute of Infectious Disease Emilio Ribas, Sao Paulo SP, Brazil

ABSTRACT

The human immunodeficiency virus (HIV) infection epidemics increased the prevalence, multi-drug resistance and disseminated forms of tuberculosis. The central nervous system (CNS) tuberculosis has high mortality and morbidity, and it is usually divided into diffuse (meningitis) and localized (tuberculoma and abscess) forms. We report three cases of cerebral tuberculomas in AIDS patients: one with definitive diagnosis, confirmed with histopathology, and two with probable diagnosis, based on clinical information, radiological images, Mycobaterium tuberculosis isolation out of the CNS and adequate response to antituberculous treatment. Further, we discuss diagnostic, therapeutic and prognostic issues of tuberculomas, with emphasis in the distinction from cerebral tuberculous abscesses. Despite of their infrequent presentation, tuberculomas should be considered in the differential diagnosis of cerebral expansive lesions in patients with AIDS.

Key words: tuberculoma, tuberculosis, central nervous system, acquired immunodeficiency syndrome.

RESUMO

A epidemia da infecção pelo vírus da imunodeficiência humana (HIV) aumentou a prevalência, multiresistência e formas disseminadas da tuberculose. O acometimento neurológico da tuberculose apresenta elevada morbidade e mortalidade, classificando-se em formas difusas (meningite) e localizadas (tuberculoma e abscesso). Relatamos três casos de tuberculomas cerebrais em pacientes com AIDS: um deles com diagnóstico definitivo, confirmado com histopatologia e dois com diagnóstico provável, baseado em informação clínica, radiológica, isolamento de Mycobaterium tuberculosis fora do sistema nervoso central e adequada resposta ao tratamento tuberculostático. Discutimos também aspectos diagnósticos, terapêuticos e prognósticos dos tuberculomas, enfatizando suas diferenças com os abscesos tuberculosos cerebrais. Apesar de serem relatados de forma infreqüente, os tuberculomas devem sempre ser considerados no diagnóstico diferencial das lesões expansivas cerebrais em pacientes com AIDS.

Palavras-chave: tuberculoma, tuberculose, sistema nervoso central, sindrome da imunodeficiência adquirida.

Tuberculosis (TB) has become more frequent since the emergence of human immunodeficiency virus (HIV) infection epidemics. Nowadays, there are important challenges, which complicate the management of HIV-TB co-infected patients. Among them, it is emphasized the increase of disseminated and extra-pulmonary TB forms, the multi-drug resistance and the increase in mortality1.

The central nervous system (CNS) TB is found in 5-10% of patients with pulmonary TB2. These cases correspond to either latent infection reactivations or disseminated infections. Tuberculous meningitis is the most common clinical form and it is five times more frequent in patients with HIV infection than in patients without it3. The focal forms of CNS tuberculosis are infrequently described and they are divided into tuberculoma and abscess4.

We describe three cases of cerebral tuberculoma in AIDS patients and discuss diagnostic, therapeutic and prognostic issues, with emphasis in the distinction from cerebral tuberculous abscesses. This study was ethically approved by the institutional review boards of the Institute of Infectious Disease Emilio Ribas, Sao Paulo, Brazil.

CASES

Case 1 - A 36-year-old Brazilian man was admitted in December 2002 with a seven-days history of tiredness, headache, nausea and vomiting. He had diagnosed HIV and cerebral toxoplasmosis in October 2002. The patient irregularly used zidovudine, lamivudine, efavirenz, sulfadiazine, pyrimethamine, and folinic acid. On physical examination, he showed a decrease in consciousness level and no focal neurological signs. Altered laboratory tests included hemoglobin 9.2 g/dl, leucocytes 1100/mm3, platelets 95000/mm3 and sodium 128 mmol/l. A chest X-ray showed a scary lesion in upper right lung. Toxoplasma gondii serology was positive and CD4+ lymphocytes count was 7 cells/mm3. A cerebral computed tomography (CT) scan showed a solitary lesion in the left cerebellum, with contrast enhancement and mass effect (Fig 1). The cerebrospinal fluid examination (CSF) was normal. Empirical treatment for toxoplasmic encephalitis with sulfadiazine 6 g, pyrimethamine 25 mg and folinic acid 15 mg daily was initiated. Three weeks later, a new CT scan showed increase in size of the cerebellar lesion and surgery was indicated. The histological examination showed presence of few acid-fast bacilli (AFB), necrotic tissue and absence of microabscesses. Investigation for other causes, including bacteria and fungi, were negative. Thus, treatment with isoniazid 400 mg, rifampin 600 mg, pyrazinamide 2 g, and prednisone 50 mg daily was initiated. Four weeks later, the patient evidenced meaningful clinical and imaging improvement and he was discharged to complete nine months of antituberculous treatment.


Case 2 - A 31-year-old Brazilian woman was admitted in August 2002 because of weight loss, tiredness, fever, headache and productive cough for four weeks and a convulsive episode one week before. She had been diagnosed as being infected with HIV infection since 1985 and she had Pneumocystis carinii pneumonia in 1999 and pulmonary TB in 2001. The patient irregularly used zidovudine, lamivudine, efavirenz and trimethoprim-sulfamethoxazole. On physical examination, she had fever, diffuse non-painful adenomegalia and no neurological signs. Laboratory tests showed hemoglobin 8.6 g/dl, leucocytes 2.900/mm3, alkaline phosphatase 460 UI/l, aspartate aminotransferase 83 UI/l, alanine aminotransferase 62 UI/l and lactose dehydrogenase 657 UI/l. A chest X-ray showed bilateral pleural thickness and enlarged mediastinal area. Her tuberculin skin test, using purified protein derivative (PPD), and T. gondii serology were negative. The CD4+ lymphocytes count was 31 cells/mm3 and the HIV viral load was 234000 copies/ml. An abdominal ultrasonography evidenced hepatosplenomegalia, intra-abdominal adenomegalia and ascitic fluid. A cerebral CT scan showed multiple nodular and ring-enhancing lesions (Fig 2A), and one lesion with central calcification and ring-enhancement. The CSF was normal and a cervical node biopsy yielded abundant AFB with caseous necrosis. Isoniazid 400 mg, rifampin 600 mg, pyrazinamide 2 g, ethambutol 1.2 g, sulfadiazine 6 g, pyrimethamine 25 mg, and folinic acid 15 mg daily were initiated. Three weeks later, the patient did not have any clinical improvement and the cerebral lesions remained unchanged. The culture of AFB yielded M. tuberculosis resistant to rifampin. Streptomycin 1 g was added to isoniazid, pyrazinamide and ethambutol, and the toxoplasmosis treatment was stopped. One month later, the patient was asymptomatic and she was discharged to complete nine months of treatment. Two months after, a CT scan showed moderate cortical and subcortical atrophy without focal lesions (Fig 2B).


Case 3 - A 30-year-old Brazilian woman was admitted in August 2002 with a three-weeks history of fever, productive cough, headache, abdominal pain, vomiting and diarrhea. She had diagnosed HIV infection in June 2001 and she had a history of disseminated TB (pulmonary and nodal) in September 2001, with abandonment of antituberculous treatment at the third month. On physical examination, the patient had important weight loss, moderate dehydration, abdominal distention, hepatosplenomegalia, ataxia and psychomotor slowness. Altered laboratory tests were hemoglobin 11.2 g/dl, leucocytes 3100/mm3, alkaline phosphatase 514 UI/l, aspartate aminotransferase 57 UI/l and alanine aminotransferase 53 UI/l, and lactose dehydrogenase 711 UI/l. A chest X-ray showed multiple micronodular lesions in both lungs compatible with miliary tuberculosis. The PPD and T. gondii serology were negative, the CD4+ lymphocytes count was 35 cells/mm3 and the HIV viral load was 54800 copies/ml. The direct examination of sputum for AFB was positive. A CT scan showed two cerebellar lesions, one of them multiloculated (Fig 3A). The CSF examination revealed a protein of 150 mg/L with both normal glucose level and white cell count. No AFB were seen on Ziehl-Neelsen staining and culture was negative. Treatment with isoniazid 400 mg, rifampin 600 mg, pyrazinamide 2 g, and ethambutol 1.2 g daily was started. One month later, the patient evidenced important clinical and imaging improvement and she was discharged to complete nine months of treatment. The culture of sputum yielded M. tuberculosis sensible to isoniazid, rifampin and pyrazinamide. Three months later, the patient was asymptomatic and had a normal cerebral CT scan (Fig 3B).


DISCUSSION

The introduction of highly active antiretroviral therapy (HAART) improved significantly the survival and quality of life of AIDS patients in developed countries and in Brazil5. TB prevalence has also decreased as a consequence of HAART. However, TB is still a public health problem in Brazil and represents the most frequent AIDS-defining disease5.

There is limited information about focal forms of cerebral TB in AIDS patients and recent reviews over CNS opportunistic infections did not include TB6,7. This is possible due to the fact that the number of CNS TB cases in developed countries is very limited, as demonstrated in a detailed neuropathological study8. In the AIDS era, Lesprit et al.9 found only 21 cases of cerebral TB (including tuberculomas and abscesses), and Vidal et al.10 found nine cases of tuberculous abscess. The lack of reports of CNS TB in developing countries, where the TB prevalence is high, can be due to underdiagnosis and underregister of cases and, indeed, to the lack of publications.

Tuberculomas can develop through four pathophysiological mechanisms. First, invasion of bacilli from the CSF (TB meningitis). Second, as a consequence of a disseminated TB. Third, paradoxical reaction in patients with antituberculous treatment, with or without antiretrovirals. Finally, local reactivation of latent foci2,11. Cerebral TB infection may produce local areas of cerebritis with formation of tuberculomas. It is unknown why an abscess is produced in some cases and in another it is a tuberculoma. Farrar12 considers that if the quantity of bacilli is high enough or the immunity is depressed, a focal cerebritis may progress to an abscess. On the other hand, the most of authors consider that the abscesses result from the liquefaction of tuberculomas13.

The focal forms of CNS TB show different anatomopathological characteristics, which were defined by Whitener14. Tuberculomas have a central region with caseous necrosis, a capsule of collagen and giant multinuclear, epitheliod and mononuclear cells. On the other hand, abscess require to fulfill the following criteria: (1) macroscopic evidence of pus, (2) inflammatory reaction in the abscess wall, which consists of granulate vascular tissue and acute and chronic inflammatory cells, and (3) demonstration of AFB in the purulent material or in the abscess wall, or positive culture of M. tuberculosis. Definitive diagnosis of cerebral tuberculoma needs histopathologic evidence in the cerebral tissue obtained by biopsy, trepanation or necropsy. Probable diagnosis of tuberculomas requires epidemiological, clinical and laboratorial information and also an adequate response to antituberculous treatment2.

The clinical presentation of tuberculomas and tuberculous abscesses is similar to the main CNS expansive lesions in AIDS patients9,10. However, the tuberculous abscesses usually have a more accelerated clinical course. Therefore, it is important to perform a detailed anamnesis and physical examination to find exposure information, previous TB disease and treatment as well as symptoms and signs out of the CNS.

Tomographic findings of the focal forms of CNS TB are unspecific and less clear than the findings of the magnetic resonance (MRI)4. However, it seems that there is an adequate correlation between histopathological and tomographic findings of tuberculomas. The radiological presentation depends on whether the granuloma is noncaseating, caseating with a solid center, or caseating with a liquid center4. The noncaseating granulomas are rounded or oval, multiple, isodense or lightly hypodense lesions, with nodular contrast enhancement. These are the classical lesions described for tuberculomas and they were present in the patient 2. The caseating granulomas with solid center and caseating granulomas with liquid center are isodense or hypodense lesions with annular contrast enhancement. The degree of surrounding edema is variable and is thought to be inversely proportional to the maturity of the lesion4. Usually, the caseating granulomas with solid center show thicker walls. On the other hand, the caseating granulomas with liquid center may be undistinguishable from the bacterial or TB abscesses. This fact was evident in patients 1 and 3. However, the TB abscesses might differ from tuberculomas because they show a more rapid course, usually have larger size (often > 3cm), thinner walls, and mostly unique and multiloculated lesions2,4,15. Moreover, there are tuberculomas which are solitary and large (patient 1), multiloculated (patient 3) and with an important mass effect9. The "target sign", defined as a central nest of calcification or a central contrast enhancement surrounded by a ring of enhancement, is characteristic of tuberculomas16,17. However, recent studies have suggested that only the "target sign" with central calcification is pathognomonic of tuberculoma4. Unfortunately, the "target sign" is an infrequent finding4,15.

In contrast to the cerebral TB abscesses, which require surgical and pharmacological treatment10,12,14, tuberculomas generally respond quite well with only pharmacological treatment16,17. Nevertheless, like was verified in some of our patients, the differentiation between this two diagnoses is difficult and complicates the surgical decision.

We conclude that tuberculomas should be considered in the differential diagnosis of CNS expansive lesions in patients with AIDS. A careful individual evaluation, including clinical (anamnesis, physical examination), laboratorial (negative T. gondii serology, evidence of TB out of the CNS) and imaging information (previous or active images in chest X-ray, "target sign" in cerebral CT) could increase the diagnostic probability of tuberculoma. In contrast to TB abscesses, the conservative treatment of tuberculomas usually determines a good outcome.

Received 27 January 2004, received in final form 6 April 2004. Accepted 28 May 2004.

Dr. José E. Vidal - Rua Capote Valente 668/78 - 05409-002 São Paulo SP - Brasil. E-mail: jbermudez@emilioribas.sp.gov.br

This article has received corrections in agreement with the ERRATUM published in Volume 66 Number 2.

  • 1. Sepkowitz KA, Raffalli J, Riley L, Kiehn TE, Armstrong D. Tuberculosis in the AIDS era. Clin Microbiol Rev 1995;8:180-199.
  • 2. Zuger A, Franklin DL. Tuberculosis. In Scheld RJ, Whitley RJ, Durack DT (eds). Infections of the central nervous system. Philadelphia: Lippincott-Raven, 1997:417-443.
  • 3. Berenguer J, Moreno S, Laguna F, et al. Tuberculosis meningitis in patients infected with the human immunodeficiency virus. N Engl J Med 1992;326:668-672.
  • 4. Bernaerts A, Vanhoenacker FM, Parizel PM, et al. Tuberculosis of the central nervous system: overview of neuroradiological findings. Eur Radiol 2003;13:1876-1890.
  • 5. Marins JR, Jamal LF, Chen SY, et al. Dramatic improvement in survival among adult Brazilian AIDS patients. AIDS 2003;17:1675-1682.
  • 6. Mamidi A, DeSimone JA, Pomerantz RJ. Central nervous system infections in individuals with HIV-1 infection. J Neurovirol 2002;8:158-167.
  • 7. Skiest DJ. Focal neurological disease in patients with acquired immunodeficiency syndrome. Clin Infect Dis 2002;34:103-115.
  • 8. Gray F, Chretien F, Vallat-Decouvelaere AV, Scaravelli F. The changing pattern of HIV neuropathology in the HAART era. J Neuropathol Exp Neurol 2003;5:429-440.
  • 9. Lesprit P, Zagdanski A-M, de la Blanchardiere A, et al. Cerebral tuberculosis in patients with the acquired immunodeficiency syndrome (AIDS). Medicine (Baltimore) 1997;76:423-431.
  • 10. Vidal JE, Cimerman S, Silva PR, Sztajnbok J, Coelho JF, Lins DL. Tuberculous brain abscess in a patient with AIDS: case report and literature review. Rev Inst Med Trop Sao Paulo 2003;45:111-114.
  • 11. Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 2002;81:213-227.
  • 12. Farrar DJ, Flanigan TP, Gordon NM, Gold RL, Rich JD. Tuberculous brain abscess in a patient with HIV infection: case report and review. Am J Med 1997;102:297-301.
  • 13. Dastur HM. A tuberculoma review with some personal expiriences: I. Brain. Neurol India 1972;20:111-126.
  • 14. Whitener DR. Tuberculous brain abscess: report of a case and review of the literature. Arch Neurol 1978;35:148-155.
  • 15. Whiteman ML. Neuroimaging of central nervous system tuberculosis in HIV-infected patients. Neuroimaging Clin N Am 1997;7:199-213.
  • 16. Harder E, Al-Kawi MZ, Carney P. Intracranial tuberculoma: conservative management. Am J Med 1983;74:570-576.
  • 17. Gasparetto EL, Tazoniero P, Carvalho A Neto. Disseminated tuberculosis in a pregnant woman presenting with numerous brain tuberculomas: case report. Arq Neuropsiquiatr 2003;61:855-858.

Publication Dates

  • Publication in this collection
    04 June 2008
  • Date of issue
    Sept 2004

History

  • Accepted
    28 May 2004
  • Reviewed
    06 Apr 2004
  • Received
    27 Jan 2004
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