Review
Tuberculoma of the central nervous system

https://doi.org/10.1016/j.jocn.2013.01.008Get rights and content

Abstract

Tuberculosis is among the oldest and most devastating infectious diseases worldwide. Nearly one third of the world’s population has active or latent disease, resulting in 1.5 million deaths annually. Central nervous system involvement, while rare, is the most severe form of tuberculosis. Manifestations include tuberculoma and tuberculous meningitis, with the majority of cases occurring in children and immunocompromised patients. Despite advancements in imaging and laboratory diagnostics, tuberculomas of the central nervous system remain a diagnostic challenge due to their insidious nature and nonspecific findings. On imaging studies tuberculous meningitis is characterized by diffuse basal enhancement, but tuberculomas may be indistinguishable from neoplasms. Early diagnosis is imperative, since clinical outcomes are largely dependent on timely treatment. Stereotactic biopsy with histopathological analysis can provide a definitive diagnosis, but is only recommended when non-invasive methods are inconclusive. Standard medical treatment includes rifampicin, isoniazid, pyrazinamide, and streptomycin or ethambutol. In cases of drug resistance, revision of the treatment regimen with second-line agents is recommended over the addition of a single drug to the first-line regimen. Advances in genomics have identified virulent strains of tuberculosis and are improving our understanding of host susceptibility. Neurosurgical referral is advised for patients with elevated intracranial pressure, seizures, or brain or spinal cord compression. This review synthesizes pertinent findings in the literature surrounding central nervous system tuberculoma in an effort to highlight recent advances in pathophysiology, diagnosis, and treatment.

Introduction

Tuberculosis is among the most lethal infectious diseases worldwide. Approximately 9 million cases occur with 1.5 million lives claimed each year. One third of the world’s population has a tuberculosis infection (TB for tubercle bacillus) and 10% will develop active disease.1 Although TB has been largely eradicated in developed nations, human immunodeficiency virus (HIV), multiple drug resistant (MDR) TB, and erosion of adherence to treatment guidelines contribute to a persistent global burden.2 Although the absolute number of TB cases has receded since a peak in 2005, TB remains a major public health concern, particularly in India, China, and South Africa, which ranked first, second and third in incident cases in 2010, respectively.1 While primarily a disease of the respiratory tract, central nervous system (CNS) TB represents 5-15% of extrapulmonary disease.3

Although only 1% of TB cases involve the CNS, these cases represent the most severe form of the disease and confer the highest rates of morbidity and mortality. In the United States in 2005, 6.3% of extrapulmonary TB patients had tuberculous meningitis (TBM), the most frequent form of CNS TB.4 Prior to the advent of anti-TB therapy, TBM was considered fatal.5 Likely concurrent and prerequisite to TBM are tuberculomas. These granulomas are formed by an interaction between the mycobacterial pathogen and the host’s immune response, and may cause hydrocephalus and other symptoms indicative of a CNS mass lesion. Tuberculomas may account for up to one third of all intracranial masses in TB-endemic areas.6

Section snippets

Etiology of tuberculosis infection

The clinical disease tuberculosis is in fact caused by at least one of numerous species of persistent mycobacteria varying by geographic region, drug resistance, and zoonotic vectors. Seven species have been implicated to date, collectively referred to as the Mycobacterium tuberculosis (MTB) complex.7 Human infection with species other than MTB may be referred to as mycobacteriosis (due to Mycobacterium bovis, for example). MTB is a slow growing, obligate aerobic bacillus; acid-fast

Pathophysiology of CNS tuberculoma formation and TBM

The cellular pathophysiology of tuberculoma formation is complex, as the host’s immune cells, particularly macrophages, are targeted by MTB.10 Upon initial infection, macrophages produce inflammatory signals resulting in recruitment of peripheral monocytes and macrophages, which can also become infected and subsequently migrate to local lymph nodes or disseminate throughout the body. Macrophages possess lysosomal enzymes and oxygen radicals needed to kill mycobacteria, then present their

Clinical presentation

Tuberculoma patients may present with headache, vomiting, drowsiness, papilledema, hemiparesis or seizures, mimicking other space occupying CNS lesions. In TBM, the most common signs and symptoms are fever, headache, meningismus, and drowsiness or abnormal mental status in adults, and hydrocephalus, fever, meningismus, and vomiting in children8 (Table 1). Intracranial tuberculomas may account for 5-30% of all mass lesions in children and nearly half of all non-neoplastic lesions depending on

Laboratory

Many established methods exist to detect TB. However, diagnosis of CNS tuberculoma remains challenging as granulomatous encasement may preclude MTB detection in serum or CSF samples. MTB is particularly slow growing with an observed doubling time of 15-37 hours.4 For comparison, Escherichia coli replicates in as little as 20 minutes under appropriate conditions. This indolence hinders MTB culture detection within a clinically relevant timeframe. Since culture and smear sensitivity diminish

Medical

Early CNS tuberculoma detection warrants an initial treatment strategy of anti-tuberculosis chemotherapy (ATT). Idris et al. report complete resolution of intracranial tuberculomas in 13/15 (87%) patients treated with ATT.39 Numerous medications exist to combat MDR TB and the alarming totally drug resistant TB. First line ATT consists of isoniazid, rifampicin, pyrazinamide, and either streptomycin or ethambutol. In drug resistant cases, a revised ATT regimen should be administered rather than

Future investigation and treatment of CNS tuberculosis

Work is underway to increase our basic understanding of CNS TB and tuberculoma formation. Hernández-Pando et al. have modeled cerebral TB infection in mice, elucidating the roles of specific immune system factors in the infection process and demonstrating the potential efficacy of oral M. vaccae as an immunotherapy for MDR TB.3, 48 Vaccines derived from recombinant M. smegmatis,49 and MTB antigens 85A and heat shock protein X50 have conferred immunity in mice and may augment or replace BCG.

Conclusions

While CNS tuberculoma prognosis has improved dramatically during the last several decades, from a nearly fatal diagnosis5 to over 80% survival with timely treatment;39 refinement of diagnostic, medical, and surgical procedures will further improve outcomes. While TB is rare in developed countries, awareness of tuberculoma must be maintained when assessing CNS masses to ensure appropriate treatment. TB remains prevalent worldwide, reinforcing the need for advancements in education and treatment

Conflicts of interest/Disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

Acknowledgements

Mr. Safaee received a grant from the Doris Duke Charitable Foundation. Dr. Oh received a National Research Service Award from the National Institutes of Health (F32NS073326-01). Dr. Parsa was partially funded by the Reza and Georgianna Khatib Endowed Chair in Skull Base Tumor Surgery.

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