MKA, Volume 37, Nomor 3, Desember 2014

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Laporan Kasus

MULTIPLE INTRACRANIAL TUBERCULOMAS

Evita Mayasari1, Sufida2

Abstrak
Tuberkuloma adalah granuloma yang terbentuk akibat respons inflamasi terhadap infeksi
M. tuberculosis. Tuberkuloma dapat terbentuk di otak, dengan demikian disebut tuberkuloma
intrakranial. Tuberkuloma intrakranial adalah manifestasi tersering kedua dari tuberkulosis (TB)
sistem saraf pusat (SSP) pada pasien imunokompeten, dan sering menyebabkan kematian
maupun disabilitas di negara berkembang oleh karena kesulitan diagnostik dan kurangnya
fasilitas pengobatan. Indonesia adalah daerah endemik TB, dan di daerah ini TB merupakan
penyakit infeksi yang paling sering menyebabkan lesi desak ruang (space-occupying lesion)
pada SSP. Beberapa penyebab lain dari penyakit infeksi di Indonesia dapat dipertimbangkan
sebagai diagnosis banding lesi desak ruang pada SSP. Hasil pengamatan dari gejala klinis,
pemeriksaan histopatologik dari sediaan biopsi jaringan otak dan pemeriksaan mikrobiologik dari
spesimen histopatologik dapat membantu konfirmasi diagnosis tuberkuloma intrakranial. Pada
artikel ini dilaporkan kasus tuberkuloma intrakranial multipel pada seorang perempuan berusia
23 tahun, dengan keterlambatan tatalaksana pada tahap awal penyakitnya yang disebabkan
kesulitan diagnosis.
Kata Kunci: Tuberkulosis, tuberkuloma, intrakranial, multipel

Abstract
Tuberculoma is a granuloma formed as a result of inflammatory response to M.
tuberculosis infection. Tuberculoma formed in the brain known as intracranial tuberculoma.
Intracranial tuberculoma is the second most common manifestation of central nervous system
(CNS) involvement in immunocompetent tuberculosis (TB) patients and is the major cause of
death and disability in developing countries due to diagnostic difficulties and lack of treatment
facilities. Indonesia is an endemic region of TB, and TB is the most common infectious disease
causing CNS space-occupying lesions in this country. However, there are some other causes of
infection that should be considered in the differential diagnosis of CNS space-occupying lesions.
The clinical presentations, histopathological findings from brain biopsy and microbiological
staining of histopathological specimens are sufficient to confirm the diagnosis of intracranial
tuberculoma. We discuss a case of multiple intracranial tuberculomas found in a 23-year-old
female with delayed treatment because of diagnosis difficulties on the early stage of her illness.
Key Words: Tuberculosis, tuberculoma, intracranial, multiple
Afiliasi penulis: 1. Microbiology Department, Faculty of Medicine USU / Instalasi Mikrobiologi Klinik Rumah Sakit
Umum Pusat Haji Adam Malik (IMK-RSUP HAM) Medan. 2. Pathology Anatomy Department, Faculty of Medicine,
HKBP Nommensen University. Korespondensi: Evita Mayasari, jl. STM 14A Medan 20219, Sumatera Utara, Email:
evitamayasari@gmail.com, Telp\HP: 08126561909

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INTRODUCTION
Tuberculosis (TB) is still a major
health problem. According to Global
Tuberculosis Report 2012, there were an
estimated 8,7 million new cases of TB
[13% co-infected with Human Immunodeficiency Virus (HIV)] worldwide in 2011
and 1,4 million people died from TB,
including almost one million deaths
among HIV-negative and 430.000
among people who were HIV-positive.
Indonesia is the ninth country of highest
TB burden with estimates of TB burden
incidence (includes HIV+TB) was
450.000 and mortality (includes HIV+TB)
was 60.000 of 242 million population in
2011. Moreover, TB is one of the top
killers of women worldwide, with 300.000
deaths among HIV-negative and 200.000
deaths among HIV-positive women in
20111. Tuberculosis in human is the
result of infection with organisms of the
Mycobacterium tuberculosis complex,
which
include
M.
tuberculosis,
Mycobacterium bovis or Mycobacterium
africanum, a slender rod-shaped acidfast bacterium with very slow growth.
Initial infection is usually respiratory
following inhalation of an inoculum of the
organisms within tiny aerosol droplets,
predominantly produced by adults with
cavitary TB 2.
Tuberculosis involving structures
other than lung parenchyma is called
extrapulmonary tuberculosis (EPTB). It
may occur as result of spread of the
organisms to pleura or pericardium, also
by lympho-hematogenous or mucosal
spread. It is closely associated with
weakened cellular immunity. In the USA,
there were approximately 20% cases of
EPTB of all TB notifications between
2001 and 2003. In developing countries,

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the reported prevalence varies from 5%

to more than 35% in 2004 and increased
significantly in the wake of HIV
epidemic2. Central nervous system
(CNS) TB only making up some 5% of
notified cases of EPTB in developed
countries, but it is the most serious form
of EPTB. It is a major cause of death and
disability in developing countries due to
diagnostic difficulties and lack of
treatment facilities3,4. About 10% of
immunocompetent TB patients manifest
CNS involvement. The most common
form is tuberculous meningitis (about
70%-80%), followed by intracranial
tuberculoma, and spinal arachnoiditis
(rare)2,4. Tuberculoma may still account
for up to 50% of intracranial mass
lesions in undeveloped countries.5
Tuberculoma is a granuloma (i.e: focal
aggregate of activated macrophages)
formed by inflammatory response to M.
tuberculosis infection3. Macrophages
induced by T-lymphocytes engulf the
bacilli and form giant cells. Caseous
material contains a few bacilli may
appear at the center, surround by gliosis
and lymphocytic infiltration. These
lesions are slow-growing with variable
perifocal edema, variable in size (up to
3-4 cm), mostly intraparenchymal. Any
part of the CNS may be involved but it is
more
common
in
the
cerebral
2,4
hemispheres . Intracranial tuberculomas can give rise to focal neurological
defects and seizures.
CASE PRESENTATION
A 23-year-old female was admitted to a private hospital in Medan with
the complaints of weakness of both
lower extremities. The symptoms began
three months ago and progressively
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worsened. Review of her previous

medical record revealed a history of a
generalized seizure with five minutes
duration, without consciousness impairment. Clinical diagnosis for her condition
at that time was neurocysticercosis and
treated symptomatically with anti-seizure
medications. The patient also complained a headache followed with blurred
vision eight months ago and diagnosed
as cerebral toxoplasmosis by her physicians. A 4-month regimen of treatment
was administered but there was no
improvement.
Physical examination revealed a
conscious patient with Glasgow coma
scale (GCS) score of 15 (E4M6V5). Vital
sign was normal. Exophthalmus (proptosis) was found on eye examination.
Thereafter, deterioration in the patients
neurological status was observed with
GCS score of 13/15 (E3M6V4). The
pupils were isocoric (4 cm in diameter)
with normal light reaction. Signs of
increased intracranial pressure such as
headache, projectile vomiting and
seizure developed as her condition
worsened. No meningeal and cerebellar
signs were noted. Motoric evaluations of
both upper extremities were normal but
there were muscle strength reductions
(grade 3/5) on them. No pathological
reflexes were noted and the sensoric
evaluation was normal. Her visual acuity
was 1/60 (right) and 2/6 (left) with
funduscopy showed papilledema. The
rest of cranial nerves examination was
unremarkable. The brain computed
tomography
(CT)
scan
showed
supratentorial multiple space occupying
lesions. No history of prior tuberculosis
or human immunodeficiency virus (HIV)
infection on her medical record. A biopsy
of the mass then perfomed by

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craniotomy and revealed the diagnosis.

Grossly the biopsied tissue volume is 3
ml; consist of white irregular solid mass.
Necrotic and hemorrhagic area found on
the tissue.

Figure 1. A white solid mass obtained from

brain biopsy of the patient with necrotic and
hemorrhagic area.

Histopathological review of the

tumor demonstrated cortex cerebral
tissue with multiple necrotizing granulomatous
inflammation
scattered
throughout the tissue (figure 2). The
granuloma had a central caseous
necrotic area surrounded by epithelioid
histiocytes, langhans giant cells, and
lymphocytes. The epithelioid histiocytes
contain single spindle shape nuclei with
eosinophilic cytoplasm. The langhans
giant cells contain multiple nuclei with
eosinophilic cytoplasm. The lymphocytes
contain single basophilic nuclei with
scanty cytoplasm. The surrounding brain
tissue is gliotic. No malignancy process
found in this slide.
The brain biopsy stained with
acid-fast by Ziehl-Neelsen method
showed only the tissue structures. There
was no sign of acid-fast bacilli in the
microscopic slide (Figure 3B). Truant
auramine-rhodamine
acid-fast
stain
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method of the specimen showed the cell

structures and the tubercle bacilli (Figure

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3C, 3D, 3E). We were unable to obtain

the fresh tissue for culture, and instead,
we got the paraffin embedded tissue for
microscopic examination.

Figure 2. Histopathological review of the tumor.

A & B. The tumor consist of cortex cerebral tissue with multiple necrotizing granulomatous inflammation
scattered throughout the tissue. (H and E, 100 X). C. The granuloma had a central caseous necrotic area
surrounded by epithelioid histiocytes, langhans giant cells, and lymphocytes. (H and E, 200 X). D. The
langhans giant cells contain multiple nuclei with eosinophilic cytoplasm. (H and E, 200 X).

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Figure 3. Microbiological Staining of Brain Biopsy Specimen.

Ziehl Neelsen stains of the biopsy tissue at 100x (A) and 400x (B) magnifications. Truant AuramineRhodamine Fluorochrome stains of the biopsy tissue examined using WIG filter at 400x magnification showed
granuloma and tubercle bacilli [C, D (zoom)], and examined using NIBA filter at 400x magnification (E).

Discussion
Indonesia is one of TB endemic
region. Together with Bangladesh,
China, India and Pakistan, Indonesia
account for half the new cases arising
each year. More cases of TB are
reported among men than women6. A
prevalence survey found that lower
detection of TB cases among women
than among men was most likely caused
by lack of awareness, i.e., not knowing
where to go for curative treatment, and
dependence on accompanying persons
or on a guardian7. The incidence rate is
highest among young adults6. There is
some evidence that young adult women

(1544 years) are more likely than men

to develop active TB following infection8.
In its endemic region, TB is the most
common infectious disease causing CNS
space-occupying lesions in person with
and without HIV9. The brain masses
caused by TB may be single but are
more often multiple10. These tuberculous
lesions are located in areas where blood
flow is greatest. They can occur
anywhere in the brain, mainly in the
cerebral or cerebellar hemispheres but
rarely in the brain stem and basal
ganglia11. Here we report the case of a
23-year-old
female
with
multiple
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intracranial tuberculomas in the cerebral

hemispheres of supratentorial region.
The diagnosis of tuberculoma is
often difficult. Up to two thirds of patients
will not have evidence of systemic TB
and 50% of patients will have normal
chest radiographs. Fever and signs of
systemic infection are rare. Patients
present with signs and symptoms of
increased intracranial pressure or with
focal neurologic deficits over month to
years5,11. There was no evidence of
systemic TB in this patient, otherwise we
found headache, projectile vomiting and
seizure, that may indicate increased
intracranial pressure. Complaints of
bilateral lower extremities weakness and
blurred visin may indicate a focal
neurologic problem. A review of
intracranial tuberculoma cases found
that intracranial hypertension was the
principal
sign
in
73%
patients,
manifesting
as
headache
and
12
papilloedema . Our patient also showed
papilledema on funduscopy. These
findings lead to the conclusion that
clinical presentations of this patient are
consistent with intracranial tuberculoma.
There is no imaging technique
that can differentiate tuberculoma
reliably from other intracranial mass
lesions. A report states that 80% of the
cases diagnosed on the basis of CT
appearance alone were false positive12.
Magnetic resonance imaging (MRI) is
commonly inconclusive in tuberculosis
and may not distinguish it from a brain
tumour, so the diagnosis is usually
established through brain biopsy13. In
this case, brain CT scan alone was not
sufficient to confirm the diagnosis of
tuberculoma, therefore her surgeon
performed an open brain biopsy in order
to accommodate histopathological diag-

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nosis
of
the
accessible
lesion.
Stereotactic brain biopsy is less invasive
technique compared with open brain
biopsy, but some surgeons still
considered the latter as a selected
method because stereotactic brain
biopsy has a high chance of picking up a
non-diagnostic tissue11. We obtained a
white solid mass for examination after
the brain biopsy (Figure 1).
Histopathologically, microscopic
examination of tuberculomas shows the
typical caseous necrosis with a
granulomatous reaction that includes
Langhans giant cells, lymphocytes, and
fibrosis. With time, the lesions become
fibrotic and calcified and M. tuberculosis
may be impossible to demonstrate10. In
this case, we found a similar
histopathological
characteristic
of
tuberculomas as explained above
(Figure 2). Then we proceeded the
biopsy examination to microbiological
stainings, Ziehl-Neelsen and Truant
Auramine-Rhodamine fluorochrome, the
results was explained in Figure 3.
Approximately 60% of tissue specimens
from tuberculomas have shown acid-fast
bacilli on smear. The organisms are
often
difficult
to
identify
from
histopathological specimens, therefore a
negative acid-fast stain does not
completely exclude the diagnosis. Nontuberculous mycobacteria may also
produce granulomatous inflammation,
but the granulomas are typically poorly
formed14. In this patient, multiple
necrotizing granulomatous inflammation
were well formed. The presence of
caseating granulomas and consistent
cellular morphology is invariable and is
thus the gold standard of diagnosis5. Our
findings were relevant for the diagnosis
of intracranial tuberculoma, and exclude
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the differential diagnosis such as

nontuberculous mycobacterial infection,
neurocysticercosis, cerebral toxoplasmosis and CNS cryptococcosis at once.
Antituberculous
chemotherapy
has given surgical intervention a
decreasing role in the management of
CNS tuberculomas. High dose steroids
have been used successfully to reduce
the symptoms of increased intracranial
pressure with no reported incidence of
overwhelming tuberculous infection.
Intracranial tuberculomas usually grow
without
permanently
destroy
the
surrounding neural tissue, thus enable a
good clinical recovery.
In a study,
patients treated only medically tended to
achieve significantly better functional
recoveries than those in whom surgical
exploration preceded the institution of
antituberculous therapy5. Prognosis of
the patient in this case is poor because
of late diagnosis and therefore she failed
to get antituberculous chemotherapy on
the early stage of infection. She had a
craniotomy before the chemotherapy that
may carry some potential risks. The most
significant risks during the procedure are
intracranial hemorrhage, brain edema,
and new focal neurologic deficits. Other
risks
include
cerebral
infarction,
infection, and scarring with formation of
an epileptic focus15.
Many lesions leave no radiological
traces following successful treatment.
However, newly developing or enlarging
intracranial tuberculomas may be
occasionally observed despite appropriate antituberculous therapy. The
tuberculoma activity may be judged by
the degree of contrast enhancement on
follow-up CT or MRI studies, therefore,
patients on antituberculous therapy who
develop signs of intracranial pressure or

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new neurological signs should have

urgent neuroimaging to exclude the
development of new lesions or the enlargement of existing granulomas2.
CONCLUSION
Central nervous system TB is the
most serious form of extrapulmonary TB,
and it is the most common infectious
disease causing CNS space-occupying
lesions in TB endemic region such as
Indonesia. We reported a case of
multiple intracranial tuberculomas in the
cerebral hemispheres of a 23-year-old
female with delayed treatment because
of diagnosis difficulties. Diagnosis was
just confirmed after histopathological and
microbiological examinations of her brain
tissue obtained via a craniotomy with the
possibilities of some risks during and/or
after the surgical procedure.
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