Journal of Clinical Neuroscience 20 (2013) 1333–1341

Contents lists available at SciVerse ScienceDirect

Journal of Clinical Neuroscience

journal homepage: www.elsevier.com/locate/jocn

Review

Tuberculoma of the central nervous system

Arthur R. DeLance a, Michael Safaee a, Michael C. Oh a, Aaron J. Clark a, Gurvinder Kaur a, Matthew Z. Sun a,
Andrew W. Bollen b, Joanna J. Phillips a,b, Andrew T. Parsa a,⇑
a
Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Ave., Room 779M, San Francisco, CA 94143-0112, USA
b
Department of Pathology, Division of Neuropathology, University of California, San Francisco, San Francisco, CA, USA

a r t i c l e i n f o a b s t r a c t

Article history: Tuberculosis is among the oldest and most devastating infectious diseases worldwide. Nearly one third of
Received 8 September 2012 the world’s population has active or latent disease, resulting in 1.5 million deaths annually. Central ner-
Accepted 27 January 2013 vous 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 immuno-
compromised patients. Despite advancements in imaging and laboratory diagnostics, tuberculomas of the
Keywords: central nervous system remain a diagnostic challenge due to their insidious nature and nonspecific find-
Antitubercular agents
ings. On imaging studies tuberculous meningitis is characterized by diffuse basal enhancement, but
Central nervous system infections
Stereotactic biopsy
tuberculomas may be indistinguishable from neoplasms. Early diagnosis is imperative, since clinical out-
Tuberculoma comes are largely dependent on timely treatment. Stereotactic biopsy with histopathological analysis can
Tuberculosis provide a definitive diagnosis, but is only recommended when non-invasive methods are inconclusive.
Tuberculous meningitis Standard medical treatment includes rifampicin, isoniazid, pyrazinamide, and streptomycin or ethambu-
tol. In cases of drug resistance, revision of the treatment regimen with second-line agents is recom-
mended 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.
Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction rates of morbidity and mortality. In the United States in 2005,

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 devel-
op 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 In-
dia, 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 rep-
resent the most severe form of the disease and confer the highest
⇑ Corresponding author. Tel.: +1 415 353 9308.
E-mail address: ParsaA@neurosurg.ucsf.edu (A.T. Parsa).
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-en-
demic areas.6
2. Etiology of tuberculosis infection
The clinical disease tuberculosis is in fact caused by at least one
of numerous species of persistent mycobacteria varying by geo-
graphic region, drug resistance, and zoonotic vectors. Seven species
have been implicated to date, collectively referred to as the Myco-
bacterium tuberculosis (MTB) complex.7 Human infection with spe-
cies other than MTB may be referred to as mycobacteriosis (due to
Mycobacterium bovis, for example). MTB is a slow growing, obligate

0967-5868/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jocn.2013.01.008
1334 A.R. DeLance et al. / Journal of Clinical Neuroscience 20 (2013) 1333–1341

aerobic bacillus; acid-fast gram-positive rods range from 1-4 lm in

length and 0.3-0.6 lm in diameter.8
TB is transmitted via close contact with an infected individual.
Hosts project droplets containing MTB through coughing or sneez-
ing.9 When inhaled, MTB infects the alveolar macrophages of the
lung (Fig. 1). Latent tuberculosis infection (LTBI) usually results,
with containment of MTB within tuberculomas and no symptom-
atic illness, although 10% eventually develop active TB. Pulmonary
TB appears on chest radiographs (CXR) of patients with positive
tuberculin skin test (TST) results, while the spread of MTB may lead
to pathologic infection within the CNS.

3. Pathophysiology of CNS tuberculoma formation and TBM

The cellular pathophysiology of tuberculoma formation is com-

plex, as the host’s immune cells, particularly macrophages, are tar-
geted by MTB.10 Upon initial infection, macrophages produce
inflammatory signals resulting in recruitment of peripheral mono-
cytes and macrophages, which can also become infected and sub-
sequently migrate to local lymph nodes or disseminate throughout
the body. Macrophages possess lysosomal enzymes and oxygen
radicals needed to kill mycobacteria, then present their antigens
via major histocompatibility complex (MHC) class II to CD4+ T-
cells; CD4+ T-cells secrete interferon-gamma (IFN-c), which induce
macrophage activation and promote destruction of mycobacte-
ria.11 The host immune system eventually slows bacterial growth
with granuloma formation around infected and necrotic macro-
phages, although bacteria can persist within these granulomas
for years10 (Fig. 2). MTB is generally held in check by the immune
Fig. 2. Illustration of central nervous system tuberculoma with caseous necrotic
system, with reactivation occurring when host immunity wanes. center. (This figure is available in colour at www.sciencedirect.com).
However, inflammation is a ‘‘double-edged sword’’ since the gran-
ulomatous response that is intended to contain MTB can also erode
into the host airways and result in airborne dissemination of the study found that TB causes upregulation of components of the
pathogen.10 Furthermore, mycolic acid within the cell wall of fibrinolytic system, which increase gradually and peak during the
MTB can impede the host’s defense and antibiotic action.8 A recent chronic phase of disease.12 Expression of these factors may contrib-
ute to the chronic inflammation observed in TB infection.
In addition to increased risk of CNS TB in the young and those
Aerosolized Droplets Inhaled infected with HIV, genetic variation among individuals and MTB
Pulmonary Tuberculoma strains contributes to host susceptibility and strain-dependent
(Latent Tuberculosis Infection) neurotropism and neurovirulence. Single nucleotide polymor-
Endogenous phisms in the toll-interleukin 1 receptor domain containing adap-
Transmission
Reinfection tor protein and toll-like receptor 2 genes have been implicated in
Tuberculoma Liquefaction host susceptibility to TBM, and phenolic glycolipid gene variability
Rupture has been shown to contribute to strain-dependent extrapulmonary
Expectorated dissemination.3 MTB cell surface phenolic glycolipid (PGL) produc-
tion in a highly neurovirulent Beijing strain subtype suppresses the
Pulmonary host T helper (Th) 1 cell cytokine immunoprotective response, per-
Tuberculosis haps synergistically with other strain-specific virulence factors,
allowing for rapid CNS dissemination.13 While an early strong
Dissemination
Lymphatic Th1 response provides immunoprotection against MTB, a shift in
Hematologic the cytokine profile toward Th2 cytokines later in the infection
Risk:
course may confer neuroprotection by suppressing excessive Th1
Immunocompromised
(HIV +) activity and modulating inflammation that results in
Age 4-48 Months immunopathology.13
Prior TB Disease CNS
Although the role of Th2 cytokines is controversial, increased
Tuberculoma
chemokine (C-C motif) ligand 2 (CCL2) is believed to be a risk factor
for infection.13 TB, the TB vaccine Bacille Calmette-Guérin (BCG), or
recombinant antigens can induce CCL2, which regulates migration
and infiltration of monocytes, memory T-cells, and natural killer
Mass Effect Tuberculous
Symptoms Meningitis cells. Its anti-inflammatory properties are not completely under-
stood, but dependent upon the expression of chemokine (C-C mo-
tif) receptor 2 on regulatory T cells.14,15 Mendez et al. performed a
Fig. 1. Tuberculosis mode of transmission and central nervous system infection.
Dashed lines represent proposed mechanisms.9,23
study of TB patients in Veracruz, Mexico to identify potential asso-
CNS = central nervous system, HIV = human immunodeficiency virus, TB = tubercle ciations between cytokine profiles and the location of TB infection
bacillus. (This figure is available in colour at www.sciencedirect.com). (renal, meningeal, or pulmonary). The authors reported elevated
 A.R. DeLance et al. / Journal of Clinical Neuroscience 20 (2013) 1333–1341
CCL2 and decreased chemokine (C-C motif) ligand 18 (CCL18) in
patients with meningeal TB compared to renal or pulmonary TB;
the ratio of CCL18 to CCL2 was also lower in meningeal TB.13 There
was no difference in serum interleukin 12 levels, but soluble inter-
leukin 4 receptor was significantly decreased in all TB patients
compared to healthy controls, and significantly more reduced in
meningeal TB compared to pulmonary TB. Levels of interleukin 4
were similar among all TB patients.
There is a growing body of literature exploring specific TB geno-
types and differences in pathogenesis. Hernández-Pando et al.
examined three TB strains isolated from the cerebrospinal fluid
(CSF) of patients with meningeal tuberculosis in Columbia. Mice
infected with different strains had significantly different mortality
rates; the most virulent strain was associated with high lung bacil-
lary loads and tissue damage, as well as rapid increase in colony
forming units from blood cultures.13 More virulent strains also in-
duced lower levels of IFN-c, but rapid and high interleukin 4
expression in the post-infectious period. The most virulent strain
induced high, but transient tumor necrosis factor-alpha (TNF-a),
as well as low inducible nitric oxide synthase (iNOS) expression.
The inability of this strain to induce a robust protective immune
response likely contributes to its virulence.
Epidemiologic studies have shown that certain TB genotypes are
over-represented in certain areas, likely due to a combination of
evolutionary properties and host-pathogen compatibility.14,15 Most
studies focus on the Beijing subtype, which has been responsible
for multiple outbreaks worldwide. The virulence of the Beijing strain
is attributable to a variety of factors including its production of a
PGL, which reduces production of Th1-type cytokines (TNF-a, inter-
leukin 6, and interleukin 12) by macrophages.16–19 The Beijing strain
also exhibits differential expression of a-crystallin,20 a virulence fac-
tor, and a 50-fold increase in levels of dormancy regulon genes,
which are involved in the adaptive response to environmental
stressors.21 Although Beijing strains are generally more aggressive,
Aguilar et al. showed that there was variation in the virulence across
subtypes; mice infected with highly transmitted Beijing strains had
higher mortality rates compared to those with non-transmitted
strains.22 Highly virulent strains were associated with extensive tis-
sue damage, lower levels of IFN-c and iNOS, and transient elevations
in TNF-a compared to less virulent strains. These data suggest that
the Beijing genotype exhibits a spectrum of virulence phenotypes
as well as both transmissible and non-transmissible strains within
the same sublineage.22
TB primarily affects the lungs and spreads via lymphatic or
hematogenous dissemination. The characteristic miliary pattern of
TB, defined as numerous 1-3 mm round tubercles located bilaterally
in the pulmonary interstitium visualized with CXR, may or may not
be present in patients with disseminated TB.2 Dissemination and
TBM without an intermediary step of CNS tuberculoma formation
remains under debate.23 Rich’s focus, the historical name for a CNS
tuberculoma, comes from the work of Johns Hopkins pathologist Ar-
nold Rice Rich. Rich described CNS tuberculomas in 1933 and pro-
posed the long-accepted two step model of TBM development that
suggests TBM is preceded by metastatic seeding of MTB within the
parenchyma or meninges, growth and eventual maturation of the
caseous tuberculoma into a fluid-filled tuberculous abscess; rupture
of this abscess into the subarachnoid space causes TBM.24
CNS TB manifests intracranially as TBM, TB-encephalopathy,
TB-vasculopathy, TB-brain abscess and tuberculoma, and within
the spine as TB-spondylitis, non-osseous spinal tuberculoma, and
spinal meningitis.2 CNS TB is most common in children 4 months
to 4 years of age in high TB areas, while adult cases are more com-
mon in low TB regions.2 In TBM, a thick gelatinous exudate accu-
mulates within the basal cisterns of the brain and obstructive
hydrocephalus may result. Consequences of TBM include dysfunc-
tion of cranial nerves III, VI, and VII, cerebral vasculitis, ischemia,
1335
and basal ganglia infarction. Spinal TB or Pott disease, named after
surgeon Percivall Pott,25 infects the intervertebral discs, most com-
monly in the thoracic region and is a leading contributor to para-
plegia in TB-endemic regions. If two adjacent vertebrae are
affected, the avascular intervertebral disc may be deprived of
nutrients and degenerate leading to vertebral narrowing and col-
lapse. Non-osseous intramedullary spinal cord tuberculomas may
counter-intuitively expand during anti-TB treatment.26
4. 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, men-
ingismus, and vomiting in children8 (Table 1). Intracranial tubercu-
lomas may account for 5-30% of all mass lesions in children and
nearly half of all non-neoplastic lesions depending on regional TB
incidence.6 In the absence of active TB or TBM, the presenting
symptoms of tuberculomas may be interpreted as indicative of tu-
mors. While a published staging system characterizes TBM, no cor-
relate currently exists for tuberculoma.27 Orbital and orbital-
intracranial extending tuberculomas have been reported, with
the finding of choroid tubercles upon fundoscopy nearly pathogno-
monic for late stage TBM.2
5. Diagnosis
5.1. Laboratory
Many established methods exist to detect TB. However, diagno-
sis 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 lit-
tle as 20 minutes under appropriate conditions. This indolence hin-
ders MTB culture detection within a clinically relevant timeframe.
Since culture and smear sensitivity diminish rapidly following ini-
tiation of anti-TB treatment, it is best to obtain samples prior to
beginning empirical therapy.
The most widely used method of TB screening, the TST, indi-
cates prior MTB exposure but does not necessarily indicate active
disease. Twenty-nine to 95% of CNS TB patients are TST positive.8
Up to 10% of total CSF volume may be sampled for diagnostic eval-
uation safely.2 CSF leukocytosis and lymphocytosis are indepen-
dent predictors of TBM, while low CSF glucose and high CSF
protein are associated with TBM.28 Culture allows for drug sensi-
tivity testing, essential for appropriate treatment, especially with
MDR TB. A limitation of culture is its timeline, however, which
may take 1-2 months, while immediate treatment is vital and cor-
relates positively with overall outcome.
Modern techniques include polymerase chain reaction (PCR)
tests that offer high sensitivity and drug resistance detection.29 In
22 patients with TBM verified using PCR and BACTEC (BD, Franklin
Lakes, NJ, USA) culture, Baveja et al. found positive results in only
2/22 (9%) and 6/22 (27%) using Ziehl-Neelsen staining and Lowen-
stein-Jensen culture, respectively.30 Their results boast the strengths
of newer diagnostic tests as early diagnosis is critical given the rapid
time course of CNS TB. Since PCR does not offer sufficient sensitivity
to confidently rule out the diagnosis of TBM, however, CSF culture
and bacteriology, combined with CSF and serum PCR if available,
may be considered superior in detecting CNS TB.
QuantiFERON (QFT; Cellestis, Valencia, CA, USA) is among the
newest TB tests available. QFT involves overnight culture of whole
blood with MTB purified protein derivative and quantification of
1336 A.R. DeLance et al. / Journal of Clinical Neuroscience 20 (2013) 1333–1341

Table 1
Tuberculous meningitis: Observations, signs and symptoms, and cerebrospinal fluid profile

Adults Children HIV positive

Mean Range Mean Range Mean Range
(%) (%) (%) (%) (%) (%)
History and associated observations
Duration of illness prior to admission 2 weeks 1 day-9 months 2 weeks 3 days-3 months 2 weeks 1 day-3 months
Close contact with tuberculosis 28 2–50 56 45–70 – –
History of tuberculosis 23 5–45 – – – –
Abnormal chest X-ray 45 25–55 61 35–75 59 55–65
Positive tuberculin skin test 51 40–70 72 50–95 29 –
Hyponatremia (plasma sodium level <135 meq/dl) 46 25–75 44 25–65 – –
Mortality 27 7–45 19 3–40 25 20–30
Signs and symptoms
Fever 72 55–85 76 45–95 82 75–90
Headache 67 45–85 34 20–40 79 60–100
Meningismus 67 55–90 62 25–75 65 –
Altered mental status 59 30–80 42 25–75 36 25–45
Hydrocephalus (CT scan) 52 40–65 85 75–100 42 –
Vomiting 43 30–70 58 30–70 27 –
Malaise-anorexia 41 45–65 52 30–70 27 –
Cranial nerve palsies 24 20–40 29 10–45 – –
Papilledema 15 5–30 9 9 – –
Hemiparesis/hemiplegia 12 5–20 24 5–40 – –
Seizures 11 7–10 25 10–55 3 –
Cerebrospinal fluid profile
Cell count (cells/ll) 223 0–4000 200 5–950 230 –
Neutrophilic pleocytosis (>50% neutrophils) 27 15–55 21 15–30 42 30–55
Normal cell count 6 5–15 3 1–5 11 –
Protein level (mg/dl) 224 20–1000 219 50–1300 125 50–200
Normal protein level 6 0–15 16 10–30 43 –
Decreased glucose level (<45 mg/dl or 40% of serum glucose) 72 50–85 77 65–85 69 50–85
Smear positive 25 5–85 3 0–6 – –
Culture positive 61 40–85 58 35–85 23 –

Adapted with permission from Garcia-Monco.8

HIV = human immunodeficiency virus.

IFN-c release. IFN-c is released by lymphocytes and stimulates the
immune response. Advantages of QFT include LTBI detection and
specificity that is relatively unaffected by the TB vaccine BCG. Sim-
mons et al. report an IFN-c assay-positive rate of 50% among cul-
ture-confirmed cases of TBM.31
Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) shows promise in
its ability to detect MTB and rifampicin resistance within 90 min-
utes. There is certainly a need for a diagnostic tool with increased
sensitivity and specificity for CNS tuberculoma. The potential im-
pact of improved diagnostic technology is great; studies are under-
way worldwide to assess the efficacy and pragmatic value of Xpert
MTB/RIF (Cepheid).32
Although the tests outlined above are essential in diagnostic
workup, with potentially cumulative probabilities of detecting
CNS TB, definitive assessment of CNS tuberculoma presence using
bodily fluid samples remains difficult. Tissue biopsies are therefore
invaluable in identifying the biology of the lesion. If symptoms of
CNS mass lesions are present, an effort to detect any extraneural
lesions may be the optimal initial course of action, including palpa-
tion of masses during physical examination and whole body X-ray
CT scan, since biopsy of extraneural lesions offers less risk than
brain or spinal cord biopsy and detection of tuberculomas else-
where raises the likelihood of tuberculoma in concurrent CNS le-
sions. Barring confirmation of CNS tuberculoma using the
methods outlined above, image guided stereotactic biopsy of the
suspected CNS lesion with histopathological analysis remains the
gold standard for diagnosis (Fig. 3).
5.2. Imaging
Making the diagnosis of intracranial tuberculoma is essential
for rapid treatment. Patients can present with single or multiple le-
sions with sizes varying from 1 mm to 8 cm;6 infratentorial tuber-
culomas are more common in children than adults.33 Although
often misdiagnosed as neoplasms, radiographic features of tuber-
culoma have been described (Table 2). They are generally hypo-
dense with ring enhancement on CT scans, however these
findings are generally non-specific; MRI with gadolinium enhance-
ment offers the greatest detail in visualizing anatomic location,
edema, and soft tissue involvement of suspected lesions6 (Fig. 4).
The radiographic characteristics of a tuberculoma can vary based
on whether the lesion is solid, noncaseating, caseating with a solid
center, or caseating with a liquefied center. Noncaseating lesions
are generally hypointense on T1-weighted MRI and hyperintense
on T2-weighted MRI. Caseating lesions with a solid center are
iso- to hypointense on T1- and T2-weighted MRI, while those with
liquefied centers are hypointense on T1- and hyperintense on T2-
weighted MRI; both demonstrate ring enhancement. The charac-
teristic ‘‘target sign,’’ an isointense region surrounded by a hyper-
intense ring of enhancement with a central nidus of calcification
was once thought to be a telltale sign of tuberculoma but has more
recently been acknowledged as a rather nonspecific feature of
radiographic evaluation. A ‘‘target sign’’ visualized on CT scans
pre-contrast may indicate tuberculoma, while its post-contrast
presence is less specific.
Advances in magnetization transfer (MT) imaging have im-
proved the ability to diagnose tuberculoma, particularly when try-
ing to distinguish them from metastases, lymphoma, or other
infectious granulomas. Tuberculomas can be distinguished from
cysticercus granulomas by their lower T2-weighted MT ratios,
which is due to their high lipid content.6,34 Although useful in iden-
tifying other CNS infections, fluid attenuated inversion recovery se-
quences have not provided a significant advantage over T1-
weighted MT imaging.35 Similarly, diffusion weighted imaging
 A.R. DeLance et al. / Journal of Clinical Neuroscience 20 (2013) 1333–1341 1337

Fig. 3. Hematoxylin and eosin stained photomicrograph showing necrotizing granulomatous inflammation in the spinal cord of a patient with central nervous system
tuberculoma. Multinucleated giant cells (inset) and epitheliod macrophages adjacent to an area of necrosis (asterisk). The patient was a 66-year-old woman who presented
with progressive quadraparesis. Original magnification  200 and inset  400. (This figure is available in colour at www.sciencedirect.com).

Table 2
Radiographic features of central nervous system tuberculomas

CT scan MRI signal intensity

Contrast enhanced Nonenhanced T1-weighted T2-weighted T1-weighted gadolinium
contrast
Caseating with solid Ring, central heterogeneous Hypo- to Iso- to Iso- to Ring enhancement
center enhancement hyperdense hypointense hypointense
Caseating with liquid Ring enhancement Hypodense Hypointense Hyperintense Ring enhancement
center
Noncaseating Homogenous Hypo- to isodense Hypointense Hyperintense Homogenous
6,28
Data compiled from references.

Fig. 4. (A) Axial T1-weighted MRI showing an isointense mass occupying the left midbrain and thalamus with a homogenously enhancing central component. (B) Axial fluid
attenuated inversion recovery MRI showing expansile T2-weighted hyperintensity extending laterally into the left insular, parietal, and posterior temporal region and white
matter bilaterally. (C) Axial T1-weighted MRI showing nearly complete resolution of the lesion and associated enhancement with a small residual after medical anti-tubercle
bacillus therapy.

(DWI) is useful in identifying infectious processes, however tuber- Magnetic resonance spectroscopy (MRS) can shed insight on
culomas with liquid necrosis will show DWI restriction while those biochemical and physiological processes in the CNS. Gupta et al.
with solid necrosis do not. DWI is also useful in differentiating have characterized the MRS ‘‘fingerprint’’ of tuberculomas by iden-
tuberculoma from lymphoma. tifying specific lipid resonances that correspond to terminal
1338 A.R. DeLance et al. / Journal of Clinical Neuroscience 20 (2013) 1333–1341

methyl, methylene, and fatty acyl chain components.36 Other ad-
vanced techniques include dynamic contrast enhanced (DCE)
MRI, which allows for the quantification of angiogenesis in neo-
plastic lesions. Gupta et al. performed DCE imaging to correlate rel-
ative cerebral blood volume with microvascular density and
vascular endothelial growth factor in patients with tuberculomas;
additional studies have demonstrated an ability to use DCE MRI to
quantify matrix metalloproteinase 9 (MMP-9), a marker of
blood—brain barrier disruption.37 Diffusion tensor imaging (DTI)
is a widely used technique for identifying white matter tracts in
a variety of clinical settings. Fiber tracking is important in identify-
ing critical structures and guiding operative planning, particularly
in eloquent lesions. Additionally, recent work by Gupta et al. has
demonstrated the ability to use DTI to characterize MMP-9 expres-
sion and response to anti-tubercular therapy.38
Non-invasive techniques for the diagnosis of CNS tuberculoma
are important in minimizing the risk of complications and improv-
ing overall outcomes by virtue of early diagnosis and treatment.
Tuberculomas are relatively rare among CNS mass lesions and their
ring enhancing appearance may resemble toxoplasmosis, pyogenic
abscesses or aggressive neoplasms, stressing the need for improved
diagnostic markers. Interestingly, new tuberculomas may appear
paradoxically following anti-TB therapy, thus providers should
maintain reasonable suspicion in this patient population.26 Unfor-
tunately, the burden of tuberculoma lies mainly in developing
countries, many of which may lack readily accessible imaging
modalities such as MRS and DTI, and in some cases even conven-
tional CT scanners. Although advanced imaging techniques im-
prove our ability to distinguish tuberculomas from other
infectious or neoplastic processes, the clinical exam and laboratory
findings will always play an essential role in the diagnosis and
treatment of these lesions.
6. Treatment
6.1. 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 com-
bat 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 addition of a sin-
gle drug.2 Second line ATT agents include ethionamide, kanamycin,
cycloserine, and para-amino salicylic acid40 (Table 3). Corticoste-
roids may improve outcome by modulating inflammation and
reducing intracranial pressure (ICP), and patients that do not re-
spond to ATT may benefit from thalidomide.33 Consensus ATT
duration ranges from 9-12 months, extending beyond radiographic
resolution of lesions and cessation of symptoms. BCG vaccination
reduces the likelihood of CNS tuberculoma.41
6.2. Surgical
Neurosurgical evaluation should be performed immediately in
patients with elevated ICP despite medical treatment, seizures,
brainstem compression, or other serious neurological and physio-
logical symptoms (Fig. 5). Lumbar puncture or lumboperitoneal
shunting can alleviate elevated ICP in communicating hydroceph-
alus, while ventriculoperitoneal shunting may be the most appro-
priate treatment for noncommunicating hydrocephalus. If MR
ventriculography is not available to distinguish communicating
hydrocephalus from non-communicating hydrocephalus, limited

Table 3
Recommended directly observed treatment regimen for central nervous system tuberculoma

Daily dose CSF penetration % Route Duration Considerations to monitor for

of plasma (months)
Adults Children
(inflamed meninges)
(maximum dose) (maximum dose)
First line agents
Rifampicin 10 mg/kg 10-20 mg/kg – (610%) Oral 9–12 Hepatotoxicity
+ (600 mg P50 kg) (600 mg) Multiple drug interactions
(450 mg <50 kg) including protease inhibitors for
HIV therapy
Isoniazid 5 mg/kg 10-15 mg/kg (300 mg) 20% (90%) Oral 9–12 Hepatotoxicity
+ (300 mg) Peripheral neuropathy (add
pyridoxine to avoid)
Pyrazinamide 25-30 mg/kg 25-30 mg/kg 95–100% Oral 2 Hepatotoxicity
+ (2.0 g P50 kg) (2.0 g) (95–100%) Arthralgia
(1.5 g <50 kg) Gastrointestinal upset
Ethambutol 15 mg/kg (1.0 g) 15–20 mg/kg (1.0 g) – (10–50%) Oral 2 Optic neuritis
Or
Streptomycin 15 mg/kg (1.0 g) 20–30 mg/kg (1.0 g) – (25%) IM 2 Vestibular, auditory, and kidney
>59 years of age: 10 mg/kg (750 mg) toxicity
Second line agents
Cycloserine 10–15 mg/kg 10–15 mg/kg (1.0 g) 45–75% 18–24 Neuropsychiatric effects
(1.0 g)
Ethionamide 15–20 mg/kg 15–20 mg/kg (1.0 g) 50–75% Oral 18–24 Peripheral neuropathy (add
(1.0 g) pyridoxine to avoid)
Amikacin-kanamycin 15 mg/kg (1.0 g) 15–30 mg/kg (1.0 g) 5–25% IM 6 Vestibular, auditory, and kidney
>59 years of age: 10 mg/kg (750 mg) toxicity
Capreomycin 15 mg/kg (1.0 g) 15–30 mg/kg (1.0 g) – IM 6 Vestibular, auditory, and kidney
>59 years of age: 10 mg/kg (750 mg) toxicity
p-Aminosalicylic acid 8.0–12.0 g in 2-3 200–300 mg/kg in – Oral 18–24 Gastrointestinal upset
divided doses 2-4 divided doses (10 g) Hypersensitivity
Ciprofloxacina (750 mg 2x/day) Unknown 15–35% Oral 2 Medium dosage
a
Gatifloxacin (400 mg/day) Not 35–55% Oral 2 provides optimal
Levofloxacina (500 mg 2x/day) approved40 60–80% Oral 2 outcome51

CSF = cerebrospinal fluid, HIV = human immunodeficiency virus, IM = intramuscular.

Data compiled from references.8,27,40
a
Fluroquinolone therapy for central nervous system tuberculosis remains under investigation.51
 A.R. DeLance et al. / Journal of Clinical Neuroscience 20 (2013) 1333–1341 1339

air-encephalography may be employed.42 In this test, 5-8 cc of air
is injected into the CSF space via lumbar puncture, followed imme-
diately by lateral skull radiography. Air within the ventricular sys-
tem, usually the lateral ventricles, indicates communicating
hydrocephalus, while air visualized at the base of the brain such
as the prepontine cistern with no air visible within the lateral ven-
tricles indicates noncommunicating hydrocephalus. Endoscopic
third ventriculostomy (ETV) may provide the best benefit to risk
ratio in HIV patients due to a reduced volume of basal exudate that
can cloud the surgeon’s vision to the floor of the third ventricle and
increase the chance of accidental damage to the basilar artery. In
addition, the heightened risk of shunt infection in HIV patients is
avoided with the ETV procedure.43
Tuberculomas may require resection to resolve mass effects,
including cases of drug resistance or paradoxical worsening, when
immediate removal is likely to confer improvement in overall out-
come. Surgical approach is largely dependent upon the tubercu-
loma location(s), the surrounding vascular, nerve, and cortical
structures, and the preference of the operator.44 While total exci-
sion is ideal, subtotal resection may provide optimal benefit versus
risk when there is relative uncertainty of interaction with adjacent
tissues, as adjuvant ATT is likely to resolve any remaining tubercu-
loma. Image guided endoscopic biopsy is preferred to open brain
biopsy whenever possible.
Emerging techniques, including trans-sphenoid endoscopy, may
provide viable options in excising tuberculomas while minimizing
sequelae and postoperative recovery times.45 Ersahin et al. report
overall success in a series with 12 patients with confirmed intra-
cranial tuberculoma treated using stereotactic microsurgical exci-
sion.46 Tuberculomas may be well suited to endoscopic
aspiration and microsurgery due to their caseating and relatively
avascular nature. The appropriate goals for surgery may include
reduction of the space occupying effect, resolution of associated
symptoms, and the diagnostic utility of surgical specimens. A care-
ful risk assessment should be exercised in each patient, considering
the benefits of total removal in reducing likelihood of recurrence,
and the possibilities of drug resistance and paradoxical enlarge-
ment. ATT should be administered either before surgery or periop-
eratively to minimize the possibility of postoperative TBM.
6.3. Treatment and management considerations
Up to 25% of medically treated TB patients may experience par-
adoxical tuberculoma enlargement or development of new tuber-
culomas during ATT. This unintended consequence occurs more
frequently in extrapulmonary cases such as CNS TB; successful
treatment revisions include addition of corticosteroids and surgical
intervention. Continuation of ATT beyond 18 months in patients
with intracranial tuberculoma that persist for 2 years or longer
provides no additional benefit.26 The American Thoracic Society
and Centers for Disease Control and Prevention recommend
against rifampicin-pyrazinamide therapy for LTBI due to liver in-
jury and mortality; instead, an isoniazid-rifapentine regimen con-
sisting of 12 weekly doses with direct observation is recommended
in patients aged 12 years or older.47 Drug-induced hepatitis is a
possible complication of ATT; Thwaites et al. describe the reintro-
duction of ATT following its occurrence.27
Unique challenges exist in the management of immunocompro-
mised patients including HIV positive CNS TB cases. Corticoste-
roids, which may improve outcome in TBM, also act as
immunosuppressants. Immune reconstitution inflammatory syn-
drome with paradoxical worsening of TB may occur following
anti-retroviral therapy, due to immune system recovery and a
hyperimmune response.26 Extra caution should be exercised in

Patient Presents With

Neurological Symptoms
Suspected Tuberculoma or TBM • Seizures Medically
Non-Responsive?
MRI/CT of the
Head and Spine • Elevated ICP Medically
Non-Responsive?
Sample
Blood, CSF - No • Brainstem Compression?
CNS Lesion?
Culture,
PCR, DS
Yes

Whole Body
MRI/CT Diagnosis
Treatment
Image Guided
Extraneural No
Stereotactic Biopsy
Lesion? Histology, PCR, DS
Yes

Extraneural Lesion Considerations/Possibilities:

No
Biopsy MTB Positive? Surgery
Histology, PCR, DS • Revise ATT Regimen (2nd Line Agents)
Yes
• 2nd Biopsy and DS
No
MTB Positive? Begin ATT +
Anti-Inflammatory • If Symptoms Resolve and Tuberculoma
Yes Child: + Corticosteroid is Stable Then Monitor

Begin Anti-Tuberculosis
Chemotherapy (ATT) No

Follow-Up at 1, 3, 6 Lesions Yes

Continue ATT:
Months MRI/CT Resolving? 12 Months If Resolved
Assess CNS Lesion 18 Months If Stable

Fig. 5. Diagnosis and treatment algorithm for central nervous system tuberculoma.
ATT = anti-tuberculosis chemotherapy, CNS = central nervous system, CSF = cerebrospinal fluid, DS = drug sensitivity testing, ICP = intracranial pressure, MTB = Mycobacte-
rium tuberculosis, PCR = polymerase chain reaction, TBM = tuberculous meningitis. (This figure is available in colour at www.sciencedirect.com).
1340 A.R. DeLance et al. / Journal of Clinical Neuroscience 20 (2013) 1333–1341
these patients including proper isolation and usage of yellow quar-
antine respiratory masks to avoid unnecessary pathogen exposure.
7. 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 mod-
eled 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. Novel anti-
TB agents are being evaluated for efficacy and CSF penetration,
and clinical vaccine and ATT trials for MDR and CNS TB are in pro-
gress.51 Human gamma globulins have demonstrated a protective
effect when administered prior to pathogen exposure in a mouse
model, suggesting a role for humoral immunity in protection
against TB, but further studies are needed.52 While the search for
biomarkers and molecular pathways of CNS TB remains challeng-
ing given the immune response in tuberculoma formation, contin-
ued research efforts will help develop and refine the optimal
diagnostic and treatment course.
8. 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 diagnos-
tic, medical, and surgical procedures will further improve out-
comes. 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
strategies. Diagnostic criteria and scientific investigation should
guide treatment rather than empirical evidence. When extraneural
lesions cannot be located or alternative methods of diagnosis are
inconclusive, image guided stereotactic needle biopsy with histo-
pathological analysis is recommended. Addressing the underlying
issues of overcrowding and malnutrition, and adhering to vaccina-
tion and treatment standards are likely to provide great benefit in
squelching CNS tuberculoma.
Conflicts of interest/Disclosures
The authors declare that they have no financial or other con-
flicts 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.
References
1. World Health Organization. Global tuberculosis control. In: World Health
Organization report 2011. Geneva: World Health Organisation; 2011. p.1–258.
2. Cherian A, Thomas SV. Central nervous system tuberculosis. Afr Health Sci
2011;11:116–27.
3. Hernandez Pando R. Modelling of cerebral tuberculosis: hope for continuous
research in solving the enigma of the Bottom Billion’s Disease. Malays J Med Sci
2011;18:12–5.
4. Hopewell PC. Clinical features of tuberculosis. In: Kaufmann SHE, van Helden P,
editors. Handbook of tuberculosis: clinics, diagnostics, therapy and
epidemiology. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA;
2008. p. 89–113.
5. Campbell MH. Tuberculoma of the brain. Can Med Assoc J 1945;53:41–3.
6. Trivedi R, Saksena S, Gupta RK. Magnetic resonance imaging in central nervous
system tuberculosis. Indian J Radiol Imaging 2009;19:256–65.
7. Kahla IB, Henry M, Boukadida J, et al. Pyrosequencing assay for rapid
identification of Mycobacterium tuberculosis complex species. BMC Res Notes
2011;4:423.
8. Garcia-Monco JC. CNS tuberculosis and mycobacteriosis. In: Roos KL, editor.
Principles of neurologic infectious diseases. New York: McGraw-Hill; 2005. p.
195–213.
9. Cardona PJ. A dynamic reinfection hypothesis of latent tuberculosis infection.
Infection 2009;37:80–6.
10. Huynh KK, Joshi SA, Brown EJ. A delicate dance: host response to mycobacteria.
Curr Opin Immunol 2011;23:464–72.
11. Hernandez-Pando R, Orozco H, Aguilar D. Factors that deregulate the protective
immune response in tuberculosis. Arch Immunol Ther Exp 2009;57:355–67.
12. Rodriguez-Flores E, Campuzano J, Aguilar D, et al. The response of the
fibrinolytic system to mycobacteria infection. Tuberculosis 2012;92:497–504.
13. Hernandez Pando R, Aguilar D, Cohen I, et al. Specific bacterial genotypes of
Mycobacterium tuberculosis cause extensive dissemination and brain infection
in an experimental model. Tuberculosis 2010;90:268–77.
14. Gagneux S, DeRiemer K, Van T, et al. Variable host-pathogen compatibility in
Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2006;103:2869–73.
15. Hanekom M, van der Spuy GD, Streicher E, et al. A recently evolved sublineage
of the Mycobacterium tuberculosis Beijing strain family is associated with an
increased ability to spread and cause disease. J Clin Microbiol 2007;45:1483–90.
16. Manca C, Tsenova L, Bergtold A, et al. Virulence of a Mycobacterium
tuberculosis clinical isolate in mice is determined by failure to induce Th1
type immunity and is associated with induction of IFN-alpha /beta. Proc Natl
Acad Sci USA 2001;98:5752–7.
17. Manca C, Tsenova L, Freeman S, et al. Hypervirulent M. tuberculosis W/Beijing
strains upregulate type I IFNs and increase expression of negative regulators of
the Jak-Stat pathway. J Interferon Cytokine Res 2005;25:694–701.
18. Reed MB, Domenech P, Manca C, et al. A glycolipid of hypervirulent tuberculosis
strains that inhibits the innate immune response. Nature 2004;431:84–7.
19. Tsenova L, Ellison E, Harbacheuski R, et al. Virulence of selected Mycobacterium
tuberculosis clinical isolates in the rabbit model of meningitis is dependent on
phenolic glycolipid produced by the bacilli. J Infect Dis 2005;192:98–106.
20. Sherman DR, Voskuil M, Schnappinger D, et al. Regulation of the
Mycobacterium tuberculosis hypoxic response gene encoding alpha-
crystallin. Proc Natl Acad Sci USA 2001;98:7534–9.
21. Reed MB, Gagneux S, Deriemer K, et al. The W-Beijing lineage of
Mycobacterium tuberculosis overproduces triglycerides and has the DosR
dormancy regulon constitutively upregulated. J Bacteriol 2007;189:2583–9.
22. Aguilar D, Hanekom M, Mata D, et al. Mycobacterium tuberculosis strains with
the Beijing genotype demonstrate variability in virulence associated with
transmission. Tuberculosis 2010;90:319–25.
23. Donald PR, Schaaf HS, Schoeman JF. Tuberculous meningitis and miliary
tuberculosis: the Rich focus revisited. J Infect 2005;50:193–5.
24. Rich AR, McCordick HA. The pathogenesis of tuberculous meningitis. Bull Johns
Hopkins Hosp 1933;52:2–37.
25. Pott P. The chirurgical works of Percivall Pott, F.R.S., surgeon to St.
Bartholomew’s Hospital, a new edition, with his last corrections. 1808. Clin
Orthop Relat Res 2002;4–10.
26. Wasay M. Central nervous system tuberculosis and paradoxical response. South
Med J 2006;99:331–2.
27. Thwaites G, Fisher M, Hemingway C, et al. British Infection Society guidelines
for the diagnosis and treatment of tuberculosis of the central nervous system in
adults and children. J Infect 2009;59:167–87.
28. Pasco PM. Diagnostic features of tuberculous meningitis: a cross-sectional
study. BMC Res Notes 2012;5:49.
29. Takahashi T, Tamura M, Takasu T. The PCR-Based diagnosis of central nervous
system tuberculosis: up to date. Tuberc Res Treat 2012;2012:831292.
30. Baveja CP, Gumma V, Jain M, et al. Newer methods over the conventional
diagnostic tests for tuberculous meningitis: do they really help? Trop Doct
2009;39:18–20.
31. Simmons CP, Thwaites GE, Quyen NT, et al. Pretreatment intracerebral and
peripheral blood immune responses in Vietnamese adults with tuberculous
meningitis: diagnostic value and relationship to disease severity and outcome. J
Immunol 2006;176:2007–14.
32. Bhanot N. Rapid molecular detection of tuberculosis. N Engl J Med
2011;364:183. author reply 184–5.
33. Buonsenso D, Serranti D, Valentini P. Management of central nervous system
tuberculosis in children: light and shade. Eur Rev Med Pharmacol Sci
2010;14:845–53.
34. Gupta RK, Prakash M, Mishra AM, et al. Role of diffusion weighted imaging in
differentiation of intracranial tuberculoma and tuberculous abscess from
cysticercus granulomas-a report of more than 100 lesions. Eur J Radiol
2005;55:384–92.
35. Saxena S, Prakash M, Kumar S, et al. Comparative evaluation of magnetization
transfer contrast and fluid attenuated inversion recovery sequences in brain
tuberculoma. Clin Radiol 2005;60:787–93.
36. Gupta RK, Roy R, Dev R, et al. Finger printing of Mycobacterium tuberculosis in
patients with intracranial tuberculomas by using in vivo, ex vivo, and in vitro
magnetic resonance spectroscopy. Magn Reson Med 1996;36:829–33.
 A.R. DeLance et al. / Journal of Clinical Neuroscience 20 (2013) 1333–1341
37. Gupta RK, Haris M, Husain N, et al. Relative cerebral blood volume is a measure
of angiogenesis in brain tuberculoma. J Comput Assist Tomogr 2007;31:335–41.
38. Gupta RK, Haris M, Husain N, et al. DTI derived indices correlate with
immunohistochemistry obtained matrix metalloproteinase (MMP-9)
expression in cellular fraction of brain tuberculoma. J Neurol Sci
2008;275:78–85.
39. Idris MN, Sokrab TE, Arbab MA, et al. Tuberculoma of the brain: a series of 16
cases treated with anti-tuberculosis drugs. Int J Tuberc Lung Dis 2007;11:91–5.
40. Rock RB, Olin M, Baker CA, et al. Central nervous system tuberculosis:
pathogenesis and clinical aspects. Clin Microbiol Rev 2008;21:243–61.
41. Wasay M, Ajmal S, Taqui AM, et al. Impact of bacille Calmette-Guerin
vaccination on neuroradiological manifestations of pediatric tuberculous
meningitis. J Child Neurol 2010;25:581–6.
42. Lorber J. Studies of the cerebrospinal fluid circulation in tuberculous meningitis
in children. Part II. A review of 100 pneumoencephalograms. Arch Dis Child
1951;26:28–44.
43. Figaji AA, Fieggen AG, Peter JC. Endoscopy for tuberculous hydrocephalus.
Childs Nerv Syst 2007;23:79–84.
44. Parsa AT, Pincus DW, Feldstein NA, et al. Pineal region tumors. In: Keating RF,
Goodrich JT, Packer RJ, editors. Tumors of the pediatric central nervous
system. New York: Thieme; 2001. p. 308–25.
45. Aghi MK. Management of recurrent and refractory Cushing disease. Nat Clin
Pract Endocrinol Metab 2008;4:560–8.
1341
46. Ersahin M, Hakan T, Ayan E, et al. Diagnostic and therapeutic role of CT-guided
stereotactic surgery in the management of intracranial tuberculomas. Turk
Neurosurg 2010;20:295–302.
47. Centers for Disease Control and Prevention. Recommendations for use of an
isoniazid-rifapentine regimen with direct observation to treat latent
Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep
2011;60:1650–3.
48. Hernandez-Pando R, Aguilar D, Orozco H, et al. Orally administered
Mycobacterium vaccae modulates expression of immunoregulatory
molecules in BALB/c mice with pulmonary tuberculosis. Clin Vaccine Immunol
2008;15:1730–6.
49. Sweeney KA, Dao DN, Goldberg MF, et al. A recombinant Mycobacterium
smegmatis induces potent bactericidal immunity against Mycobacterium
tuberculosis. Nat Med 2011;17:1261–8.
50. Jeon BY, Kim SC, Eum SY, et al. The immunity and protective effects of antigen
85A and heat-shock protein X against progressive tuberculosis. Microbes Infect
2011;13:284–90.
51. Thwaites GE, Bhavnani SM, Chau TT, et al. Randomized pharmacokinetic and
pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis.
Antimicrob Agents Chemother 2011;55:3244–53.
52. Olivares N, Puig A, Aguilar D, et al. Prophylactic effect of administration of
human gamma globulins in a mouse model of tuberculosis. Tuberculosis
2009;89:218–20.