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Neurotuberculosis: An Overview

Article  in  Central Nervous System Agents in Medicinal Chemistry(Formerly Current Medicinal Chemistry - Central Nervous System Agents) · December 2011
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246 Central Nervous System Agents in Medicinal Chemistry, 2011, 11, 246-260

Neurotuberculosis: An Overview

Murilo Gimenes Rodrigues1, Antônio José da Rocha2, Marcelo Rodrigues Masruha1 and
Thais Soares Cianciarullo Minett3,4,*

1
Department of Neurology and Neurosurgery – Federal University of São Paulo, São Paulo – Brazil; 2Department of
Radiology – Faculty of Medical Sciences of Santa Casa of São Paulo – Brazil; 3Department of Preventive Medicine –
Federal University of São Paulo, São Paulo – Brazil; 4Department of Public Health and Primary Care - Cambridge
University, Cambridge – UK

Abstract: Although pulmonary tuberculosis is the most common form of this disease, neurotuberculosis is more severe
and presents higher morbidity and mortality. Its diagnosis continues to challenge physicians all over the world. Contribut-
ing to this fact is the nonspecificity of its clinical manifestations, the low density of bacilli in the cerebrospinal fluid
(CSF), and the delayed recovery of Mycobacterium tuberculosis through culture techniques. Thus, the diagnosis is largely
based on suspicious symptoms, and the prognosis is directly related to the stage of the disease at the beginning of treat-
ment. Even thought there is no consensus regarding the best therapeutic regimen, the WHO recommends using the same
regimen used for pulmonary tuberculosis with a longer treatment time. It is important to note that in most cases, the doctor
will not have a definite diagnosis at the beginning of the treatment. However, this should not delay the initiation of ther-
apy. A delay in initiating treatment, in most cases, is directly associated with a poor prognosis. This review gives an over-
view of the current state of the neurotuberculosis research. It covers the epidemiological aspects of the infection, patho-
genesis, principal clinical presentations, diagnosis highlighting neuroimaging, where a series of imaging are presented,
prognosis, prevention and therapeutic regimens.
Keywords: Tuberculosis, meningitis, diagnosis, treatment, central nervous system.

INTRODUCTION • TM with miliary tuberculosis.

Tuberculosis (TB) is a secular disease [1] that, according
to the latest WHO report (2009) [2], still represents a major
cause of morbidity and mortality worldwide, mainly in Asia
and Africa. In 2007, there were 9.2 million new cases of TB
and 1.7 million deaths from it, of which 1.3 million cases
and 450,000 deaths were of people infected with human im-
munodeficiency virus (HIV). In developing countries, it is
estimated that there are approximately 1.3 million cases un-
der 15 years of age, with an incidence of 450,000 deaths
annually [3, 4].
The WHO identifies the following factors as the main
causes of the severity of the current TB situation in the
world: social inequality, the rise of acquired immunodefi-
ciency syndrome (AIDS), aging of the population, and hu-
man migration [5]. However, the upsurge of TB is primarily
attributed to HIV [6-8]. These same factors operate in areas
of urban poverty in developing countries.
The term neurotuberculosis refers to various forms of TB
in the central nervous system (CNS) according to the follow-
ing classification [9]:
Intracranial
• Tuberculous encephalopathy.
• Tuberculous vasculopathy.
• Space-occupying lesions, tuberculoma (single or multi-
ple), multiple small tuberculoma with miliary tuberculo-
sis, tuberculous abscess.
Spinal
• Pott's spine and Pott's paraplegia.
• Tuberculous arachnoiditis (myeloradiculopathy)
• Non-osseous spinal tuberculoma.
• Spinal meningitis.
The clinical onset and disease progression in each cate-
gory are highly variable, overlapping with other CNS infec-
tions, vascular syndromes, and expansive lesions [10].
Although pulmonary TB is more common, neurotubercu-
losis is the more severe form of tuberculosis, causing death
or major neurological sequelae in more than 50% of patients
despite treatment. In addition, it represents the usual mode of
termination of almost all other forms of TB [11-13].

• Tuberculous meningitis (TM) The incidence of neurotuberculosis is an epidemiological

*Address correspondence to this author at the Department of Public Health
and Primary Care, University Forvie Site, Robinson Way, – Cambridge,
UK. Post code: CB2 0SR; Tel: 00-44-1223-763837;
Fax: +44 (0) 1223-330330
E-mail: thais.minett@medschl.cam.ac.uk
indicator that is closely related to the incidence of positive
bacilliferous cases in the adult population, which depends on
the socioeconomic and hygienic conditions of the commu-
nity [14]. Approximately 8% of TB patients have CNS in-
volvement [9, 14, 15].

1871-5249/11 $58.00+.00 © 2011 Bentham Science Publishers

Neurotuberculosis: An Overview Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 4
Most cases of neurotuberculosis are caused by Mycobac-
terium tuberculosis or Koch bacillus. M. bovis and M. afri-
canum are responsible for a small percentage of cases, espe-
cially in developing countries [15-17]. Neurotuberculosis
caused by a typical mycobacteria is extremely unusual, al-
though there are records of their isolation in the CSF [18].
In populations with a high prevalence of TB, neurotuber-
culosis is a children's disease with a peak incidence at four
years of age. It is uncommon in children under the age of 6
months and rare before 3 years [19]. It is commonly a com-
plication of a primary infection with or without miliary
propagation, and it develops three to six months after this
infection [20]. In populations with a low prevalence of TB,
most cases occur in adults, whose risk factors are alcoholism,
diabetes mellitus, cancer, and recent use of corticosteroids
[21, 22]. Coinfection with HIV is currently the main risk
factor [19].
The high prevalence of this infection at the age of 4 years
is caused by close household contact with positive patients.
Thus, it can be said that TB in children is a reflection of the
disease in adults, and a case of tuberculosis diagnosed during
childhood probably means that there is an adult with conta-
gious TB at home [23].
PATHOGENESIS
The initial lesion occurs in any organ directly accessible
to the bacillus, including lungs, intestine, skin, tonsils, eyes,
or ears; that is, all organs in direct contact with the disease
agent. Considering that TB infection mainly occurs through
airways, the lungs are usually the first organ involved [24].
Due to their small size (1-5 μ), droplets can remain air-
borne for hours after a person with pulmonary or laryngeal
TB coughs, sneezes or talks. After droplets contaminated
with the bacillus are inhaled and reach the alveoli, M. tuber-
culosis is phagocytosed by alveolar macrophages, which
initiates a cascade of events that result either in containment
of the infection or disease progression (primary progressive
TB). Due to their high resistance to destruction, mycobacte-
ria replicate within these macrophages at a slow but steady
rate and spread, via the lymphatic system, through the lymph
nodes [25].
Upon reaching a lymph node, the infection will tend to
spread through the lymphatic vessels, and then it will spread
throughout the body via the hematogenous system [24]. This
spreading of a few bacilli is considered "benign"; the bacilli
remain dormant or are destroyed by the action of the immune
system. Early in the third week, normal organisms that rec-
ognize the presence of foreign elements are able to mobilize
specific immune defense systems aimed at the destruction or
inactivation of the pathogenic agent.
At this point there is a small rounded site of 1 to 2 mm in
the lung at the site of initial inoculation that is whitish, soft
and consists mainly of caseous material. This lesion is sur-
rounded by an influx of lymphocytes, epithelioid cells (acti-
vated and modified macrophages) and macrophages (primary
lesion); it is mainly located in the middle third of the lung,
which comprises the bottom of the upper lobe, the middle
lobe, and particularly the apex of the inferior lobe. Typically,
this lump is unique and has the previously given dimensions;
247
however there are reports of the existence of multiple pri-
mary sites and larger sites. The association of the primary
site with satellite ganglia in the region is called the primary
complex of Ranke. About 90% of the infected population
can block the advance of this process after the formation of
the primary complex of Ranke and remain only as infected
[26].
When the body's immune response cannot contain the
replication of M. tuberculosis, active disease occurs. This
evolution is most common in children under five years of
age and immunocompromised adults [25].
The pathogenesis of neurotuberculosis and its relation to
the stage of lung involvement has long been a matter of de-
bate. The temporal relationship of neurotuberculosis with
miliary TB suggests that hematogenous dissemination is an
important factor [27]; however, the work of Rich and
McCordock argues against the hematogenous route [28].
These authors performed autopsies on patients who died of
tuberculous meningoencephalitis: in 77 of the 82 cases, there
was evidence of older caseous lesions in the brain paren-
chyma and meninges. Based on these findings and previous
experimental studies [29], the authors verified that tubercu-
lous meningitis is absent in some cases of miliary TB, even
in extreme cases when other organs are affected. The age and
characteristics of miliary tubercles in the viscera of patients
who die of tuberculous meningitis and miliary TB are differ-
ent. This argues against a concomitant origin of the lesions
as many cases of tuberculous meningitis occur in the absence
of miliary TB. The experimental introduction of M. tubercu-
losis in the bloodstream of susceptible animals produces mil-
iary TB but fails to cause meningitis simultaneously, even
when the bacillus is introduced directly into the carotid ar-
tery. Moreover, introduction of M. tuberculosis directly into
the subarachnoid space produces typical diffuse meningitis.
Thus, they proposed the hypothesis that current neurotuber-
culosis is a direct and immediate result of a hematogenous
infection of the meninges [14, 28, 30].
Based on these observations, Rich and McCordock [28]
postulated that tuberculous meningitis arises in two stages.
Initially, small tuberculous lesions called "Rich nodules"
form in the brain or meninges through the hematogenous
spread of bacilli during a primary infection, or as a less
common form, in the course of chronic TB. The cortical or
meningeal nodules thus originated can immediately release
TB bacilli and antigens, or they can remain as quiescent ba-
cilli and be carried for months or years. Nevertheless, there
is always the potential for destabilization as a result of local
conditions or lowering of the immune capacity of the host
[10, 14, 28].
The association of neurotuberculosis with traumatic brain
injury suggests that intracranial nodules can also be destabi-
lized by physical factors [10].
Currently, it is well accepted that the caseation of Rich
nodules in the cerebral cortex or meninges is how bacilli
reach the subarachnoid space; however this theory cannot be
applied to all cases of neurotuberculosis [27, 30-32].
Seeking to reconcile the importance of miliary TB in the
pathogenesis of neurotuberculosis (particularly in children),
Donald et al. [30] conducted a reinterpretation of the work of
248 Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 4
Rich and McCordock, keeping the concept of the Rich node.
They proposed that the hematogenous spread of bacilli from
the primary complex establishes a cortical or meningeal fo-
cus (a Rich node). Soon after, it progresses to caseation and
releases its contents into the subarachnoid space. In young
children, this form of evolution often accompanies miliary
TB. Moreover, in a minority of patients, hematogenous
spreading establishes a caseous lesion in the choroid plexus
or in the walls of the ventricles, and neurotuberculosis can
develop. Hematogenous dissemination at the time of primary
infection, or after it, establishes a cortical or meningeal le-
sion (a Rich node). This process is initially controlled, and it
may later undergo caseation and release its contents into the
subarachnoid space. The process extends from caseous adja-
cent structures (such as vertebrae or the middle ear) to the
subarachnoid space.
CLINICAL PICTURE
The most common manifestations are fever, nuchal rigid-
ity, vomiting, drowsiness, and headache. Rodrigues, in a
pediatric series, observed fever (96%), nuchal rigidity (79%),
vomiting (63%), drowsiness (50%), and headache (36%)
[33].
The most common form of neurotuberculosis described
as "meningitis" should actually be called meningoencephali-
tis [14, 34]. This usually has an insidious and progressive
onset, but in some cases, especially in infants, it may have an
abrupt onset, indistinguishable from meningitis due to other
bacteria. [10, 14, 35]. The stages defined by the British
Medical Research Council (BMRC) in 1948, which subse-
quently underwent small changes, are well documented pre-
dictors of disability and mortality [12, 14, 15, 36-41].
Stage I or prodromal - nonspecific symptoms such as
fever, anorexia, headache, vomiting, constipation, muscle
pain. It follows drowsiness and behavioral changes such as
apathy or irritability.
Stage II or meningeal irritation - exacerbation of head-
ache and vomiting, signs of meningeal irritation, declining
level of consciousness, cranial nerve involvement. Some-
times temporary remission of symptoms occurs, which can
lead to diagnostic errors.
Stage III or terminal - coma, decerebrate or decorticate
posture, irregular breathing, persistent hypertonia.
Atypical presentations of TM include progressive demen-
tia, acute meningitic syndrome simulating pyogenic meningi-
tis, seizures, focal neurological deficits, cranial nerve palsy
(sixth nerve most common, followed by third and fourth),
internuclear ophthalmoplegia, and hydrocephalus [42].
The polymorphism of neurotuberculosis injuries under-
lies the complexity and variability of the clinical picture
[35].
The primary event is the formation of a thick gelatinous
exudate and its expansion into the subarachnoid space [15].
This exudate predominates in the basal cisterns, brainstem,
lateral sulcus (of Sylvius), and cerebellum [43]. The con-
vexities of the brain are relatively unaffected. Ependymitis is
often present [14, 15]. Vasculitis that mainly involves the
vessels of the brain stem is an important feature of neurotu-
Rodrigues et al.
berculosis, both in clinical and pathological terms. Vascular
changes are diffuse and involve arteries of large, medium,
and small caliber and veins. Due to the characteristic distri-
bution of the basilar exudate, the anterior and middle cere-
bral arteries are involved most of the time [14].
Histopathologic examination of the arteries involved re-
veals inflammatory, proliferative and degenerative altera-
tions [14]. The involvement of the adventitia is an extension
of the tuberculosis originating in the subarachnoid space, and
it consists of cellular infiltration and necrotic caseation. The
middle layer may show no evidence of injury or a lympho-
cytic infiltrate and fibrinoid changes. Intimal lesions are var-
ied and include endothelial proliferation, degeneration,
caseation, and fibrinoid-hyaline changes [14, 43].
The meningeal veins that cross the inflammatory exudate
show various degrees of phlebitis, which in turn can lead to
thrombosis and partial or complete occlusion of their lumens
[14].
The degree and extent of brain involvement are variable.
The most important parenchymal lesions are the "bordering
zone" reaction, infarct, hydrocephalus, tuberculoma, tubercu-
lous abscess and tuberculous encephalopathy [14, 44].
Hydrocephalus
Hydrocephalus is more frequent, earlier, and more severe
in children than in adults [45].
Communicating hydrocephalus is the most common
form, and it is the result of a blockage of the basal cisterns
by inflammatory exudate (early stages) or by spidery adhe-
sions (later stages). The rarer type is obstructive hydro-
cephaly caused by narrowing or occlusion of the aqueduct or
by blocking the foraminal exit of the fourth ventricle [9, 14,
46, 47]. The narrowing of the aqueduct is usually due to
edema of the midbrain and brainstem compression by the
surrounding meningeal exudate. In an unusual manner, a
subependymal tuberculoma or a stopper of ependymal exu-
date can block the aqueduct [14].
In a study conducted in 12 university hospitals in Turkey
with 434 patients (children and adults), hydrocephalus was
found in 44% of cases [12]. In other studies with children
only, hydrocephalus was found in 98% to 100% of patients
[36, 39, 48, 49].
In children, hydrocephalus is often present after six
weeks of the disease [45].
The frequent occurrence of hydrocephalus highlights one
of the basic pathophysiological phenomena of neurotubercu-
losis, which is the inefficient cerebrospinal fluid drainage
that occurs mainly in the basal cisterns due to meningitis at
the base of the brain.
In a study of 60 patients (36 children and 24 adults) with
serial CT scans, Bhargava et al. [45] found that the incidence
of hydrocephalus increases with disease progression and
decreases with the age of the patient. Severe hydrocephalus
was present in 87% of the children and 12% of the adults, a
fact attributed to increased complacency of the ventricular
system due to reduced resistance to stretching of white brain
matter that is not yet fully myelinated. Areas of infarction
were seen in 28% of cases, and 10% had associated tubercu-
Neurotuberculosis: An Overview Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 4
lomas. Only the children had a severe basal exudate level.
Patients without a baseline contrast have a good prognosis
when treated, and patients with enhanced exudate have a
poor prognosis despite medical or surgical treatment [45].
Altunbasak et al. (1994) [39] studied 52 children and
found hydrocephalus in 98% of patients. They found a sig-
nificant association between clinical stage, degree of hydro-
cephalus, and prognosis. Patients with advanced disease had
more severe hydrocephalus and worse prognosis. They con-
cluded that while communicating hydrocephalus is not spe-
cific to neurotuberculosis, when associated with other clini-
cal and laboratory data, it is very useful for early diagnosis
and early treatment.
Schoeman et al. (1995) [50] prospectively studied 198
children with serial CT scans and found a significant associa-
tion between clinical staging and hydrocephalus. It was pre-
sent in 83% of patients and it was more pronounced in pa-
tients in advanced stages of disease; however, they found no
association between clinical outcomes or mortality and ven-
tricular size at admission.
In a series of 40 patients with bacteriologically proven
neurotuberculosis, Tan et al. (1999) [51] concluded that hy-
drocephalus was the only variable that implied a poor prog-
nosis.
Infarctions
The vascular changes described above may result in
ischemic injury or, occasionally, a hemorrhagic infarction
[34, 44]. Most infarctions are seen in the region of the mid-
dle cerebral artery. They may be superficial, but they often
reach the basal ganglia and the hypothalamus due to the in-
volvement of perforating vessels. Tiny infarcts have also
been seen (even microscopic) in the brainstem [14]. There
may be hemorrhagic transformation of infarcted tissue [9,
10, 14]. In a review of the pathological features of tubercu-
lous cerebral vasculitis, varying degrees of arteritis was
found in 20 of 27 cases studied, and it included eight cases of
obstructive thrombophlebitis associated with hemorrhagic
infarction [34]. Therefore, vasculitis is a common finding in
patients who have died by neurotuberculosis, and it repre-
sents a factor that contributes significantly to the neurologi-
cal deficits [10].
Reaction of the Boundary Zone
The brain tissue immediately underlying the tuberculous
exudate shows a variable degree of edema, perivascular infil-
tration and microglial reaction [14].
Intracranial Tuberculoma
The pathogenesis of intracranial tuberculoma is identical
to that of tuberculous meningoencephalitis [15]. Tuberculo-
mas are masses of small avascular granulomatous spherical
tubers [9]. A tuber consists of a central area of epithelioid
cells surrounded by lymphocytes and Langerhans giant cells
[15]. The interior of this mass may contain necrotic areas
composed of caseous material, occasionally thick containing
pus, in which Koch's bacilli can be detected. Tuberculomas
can occur at any age. In developing countries, children and
young adults are predominantly affected, whereas in devel-
249
oped countries, tuberculomas are more common in older
patients [9]. In children, they occur predominantly in the
infratentorial region, whereas in adults, they are more fre-
quent in the supratentorial region. Tuberculomas of the sellar
and suprasellar regions are occasionally seen [15, 52-54]. A
plaque tuberculoma is an unusual manifestation that devel-
ops by enlargement of one or more meningeal tubers leading
to the formation of an adherent flat mass [15].
Tuberculous Abscess
When the caseous center of a tuberculoma liquefies, it
results in the formation of a tubercular abscess [15]. They are
reported in 4% to 7.5% of patients with neurotuberculosis in
developing countries [9]. They are usually large, single or
multiple, multilocular, and they occur more frequently in
immunocompromised individuals. They are less common
and cause more edema and more mass effect than do tuber-
culomas. In contrast to a tuberculoma, an abscess has pus
with a large amount of bacilli and polymorphonuclear cells
[15].
Tuberculous Encephalopathy
This variant of neurotuberculosis was first described in
Indian children with disseminated TB and it was called "tu-
berculous encephalopathy" [55, 56]. These children have a
diffuse brain disorder resulting in coma, convulsions, invol-
untary movements, pyramidal signs and no signs of menin-
geal irritation or focal deficits. Their cerebrospinal fluid
(CSF) is normal or may show modestly elevated proteins or
cells. Pathologically, there is diffuse cerebral edema, demye-
lination and sometimes bleeding - a scenario that is more
typical of post-infectious allergic encephalomyelitis [56, 57].
This encephalopathy, once thought unique to children [15,
58], also occurs occasionally in adults [10, 59]. The menin-
geal syndrome is characterized by its pathological changes:
the involvement of cranial nerves, hydrocephalus, and hypo-
thalamic changes [35]. Under microscopic examination, the
exudate consists of polymorphonuclear leukocytes, macro-
phages, lymphocytes, and erythrocytes with a variable num-
ber of bacilli in a fibrin network [43]. As the disease pro-
gresses, lymphocytes and connective tissue elements become
predominant [15].
DIAGNOSIS
Diagnosing neurotuberculosis is still a challenge for the
clinician [39, 60-62]. As of now, there is no sensitive and
rapid test, and the diagnosis is based on a high index of sus-
picion when the TB bacillus is a possible cause for insidious
cases and acute infections [10, 15, 35, 61, 62]. However, the
prognosis is directly related to the stage of disease at the time
of treatment onset [19, 33, 37, 63-65]. The gold standard
confirmation of neurotuberculosis is isolation of the agent in
cerebrospinal fluid [10, 62, 66]. As the isolation of M. tuber-
culosis is not the rule, in practice, the decision to treat a pa-
tient for neurotuberculosis is often presumptive and based on
clinical data such as an epidemiological history of close con-
tact with contagious TB, no vaccination, and nonspecific
laboratory tests such as a tuberculin skin test (TST), chest
radiography, and cytological and chemical CSF [62, 67-69].
Because of the difficulty of isolating M. tuberculosis
from CSF, to enable an early and definitive diagnosis, sev-
250 Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 4
eral tests have been developed to search for antigens or anti-
bodies, including agglutination of latex particles with bacte-
rial antigen in an enzyme linked immunosorbent assay
(ELISA) and polymerase chain reaction (PCR) to identify
fragments of deoxyribonucleic acid (DNA) [9, 19, 70-73].
Cerebrospinal Fluid Examination
Lumbar puncture usually reveals elevated pressure, and
the cerebrospinal fluid is clear or slightly opalescent; it is
often compared to coconut water [10, 74]. If the CSF is left
undisturbed, a delicate network of fibrin known as the Mya
reticulum may form on its surface, and it is unlike the coarse
clot that forms in cases of purulent meningitis [10, 74]. The
CSF changes in neurotuberculosis reflect an intrathecal tu-
berculin hypersensitivity reaction caused by the presence of
tuberculoproteins. Consequently, it results in CSF pleocyto-
sis usually at the expense of lymphomononuclear cells, and
this is associated with increased protein levels and decreased
glucose. In the initial stages of the disease (and sometimes
during its progression), a predominant polymorphonuclear
response is observed. In some patients, the CSF may initially
be normal [67, 75]. Wide variations can be seen depending
on the sensitivity of the patient and the amount of tuberculo-
proteins in the CSF [14].
Classically, the CSF exhibits lymphocytic pleocytosis,
with most patients presenting between 100 and 500 cells per
mm3, increased protein, and low glucose [10, 14, 27]. In the
initial stages of the disease, a predominance of polymor-
phonuclear leukocytes is observed in the CSF [14, 76].
Sometimes, the cerebrospinal fluid may contain few cells or
even rarely be acellular [77], which has been well docu-
mented in several studies [31, 78, 79].
During the course of the disease, a predominant poly-
morphonuclear leukocyte reaction can occur that is acute,
transient, and often associated with clinical deterioration of
the patient, a "therapeutic paradox" that is said to be almost
pathognomonic of tuberculous meningoencephalitis [10, 80].
Some authors with a more critical view of classical de-
scriptions of cerebrospinal fluid in tuberculous meningoen-
cephalitis state that early in the disease, the hypercytosis
consists of a predominance of polymorphonuclear leuko-
cytes, which are being gradually replaced by lymphocytes as
the disease evolves into the chronic stage; they have insisted
that the cerebrospinal fluid in tuberculous meningoencepha-
litis changes its appearance in the course of the disease, with
the latter, even under treatment, evolving by successive reac-
tivations. During these recurrences, polymorphonuclear neu-
trophil leukocytes have been observed [81, 82].
The concentration of proteins in cerebrospinal fluid var-
ies from 100 mg/100 ml to 500 mg/100 ml in most patients.
Protein concentrations above 1 g/100 ml may be found in
more advanced stages of the disease in combination with a
spinal block [10, 14]. The glucose concentration is below 40
mg/100 ml, i.e., equivalent to 50% of glucose taken simulta-
neously in 50% to 85% of patients on admission, and it tends
to decline as the disease progresses to a level between 15 and
35 mg/100 ml [10, 14].
The microscopic examination of cerebrospinal fluid in
the search for alcohol-acid resistant bacilli is the most impor-
Rodrigues et al.
tant procedure for an early definitive diagnosis. However,
the frequency with which the bacillus is found via direct ex-
amination varies markedly between different series and de-
pends primarily on the time spent examining, the number
and volume of samples and the examiner's experience [10,
14, 70]. There are reports ranging from 0% to 91% positivity
[69, 83, 84].
In a series of 143 patients in Brazil at a time when no
treatment was available, Reis et al. [75] demonstrated bacilli
in 36% of the cases. Positivity rates between 10% and 40%
are more commonly reported [67, 68, 85-87].
CSF culturing continues to represent the most specific
form of confirmation, but the determination time is long and
the sensitivity low. Positivity rates for TB bacillus cultures
vary from 45% to 90% depending on the amount of cerebro-
spinal fluid examined and laboratory conditions; neverthe-
less, in developing countries, lower numbers such as 10% to
20% have been reported [14], and Hosoglu et al. [84] re-
ported 9.9%.
Changes in the biochemistry of the CSF are related to
prognosis in adults. Increased mortality has been described
in patients with glucose below 40 mg/ml, protein above 200
mg/100 ml, and chlorides below 650 mg/100 ml [88]. The
authors found a worse prognosis in patients with hypoglycor-
rhachia [84, 89] and in those with high protein levels [84,
90].
Immunological Diagnosis - Tuberculin Skin Test (TST)
A positive TST only means that the person was previ-
ously infected by the bacillus (virulent or attenuated), and it
is not possible to confirm whether the patient carries the dis-
ease. As a tool for diagnosing tuberculous meningoencepha-
litis, the test has revealed negativity rates ranging from 5% to
50% of cases [12, 68, 91-94].
The test can be negative in the following circumstances:
severely debilitated or malnourished patients, those in ad-
vanced stages of terminal illness, advanced age, the presence
of a disease such as measles during the use of corticoster-
oids, use of inactivated PPD, incorrect application technique,
or incorrect reading of the test, and in 5% to 10% of cases,
there is no known reason [14].
In an analysis of 192 cases of tuberculous meningoen-
cephalitis, a higher positivity rate was observed among chil-
dren with miliary TB, and a higher incidence of negative
tests occurred with disease progression [95].
The tuberculin skin test is one of the parameters that should
be considered as a tool in diagnosing neurotuberculosis;
however, some aspects of the test bear examination:
a) Cutaneous hypersensitivity to tuberculin takes two to ten
weeks to develop after pre-infection with tuberculosis;
b) Patients with active TB, particularly in severe forms
with hematogenous dissemination, may test negative.
The test can be positive in the early stage of the disease
and become negative as the situation worsens. On the
other hand, negative tests in the early stage of the dis-
ease can become positive with improvement in the over-
all condition of the patient and with the time required for
the development of cutaneous hypersensitivity [23].
Neurotuberculosis: An Overview
The lack of reactivity occurs because patients in ad-
vanced stages of the disease are usually malnourished and
also have very low cellular immunity [88]. This could ex-
plain the lack of reactivity in 11 of 24 patients in our series
who died because they were in a coma when they were
tested.
Succi (1990) [23] observed that there was greater general
and neurological impairment in children whose initial tuber-
culin test was negative and remained at that stage during
hospitalization. By contrast, of the 12 children whose initial
(tuberculin) test was negative but became positive in the
course of hospitalization, 10 improved significantly with
treatment. Likewise, children that reacted to tuberculin after
the beginning of hospitalization exhibited a better general
condition and a higher mean age than non-reactive children.
Blood-Based Assays
There are two available commercial assays: the T-Spot
(Oxford Immunotec, UK) and the Quantiferon-TB Gold
(Cellestis, Australia). They rely on stimulation of host blood
cells with M. tuberculosis-specific antigens and measure the
production of interferon
. Even though blood-based assays
are more specific than the TST [96, 97], the interpretation of
whether the tuberculosis infection is latent or active is still
dependent on the clinical context. Its performance in very
young children and in immunocompromised populations is
not yet fully understood [98, 99].
The Chest X-Ray
Radiological findings of active or previous TB are de-
scribed in 50% of patients with neurotuberculosis [11]; how-
ever, these findings lose specificity in countries with a high
prevalence of TB [58]. Nevertheless, miliary TB is highly
suggestive of multiple organ involvement and is very helpful
when detected on a chest radiograph [100] because it sug-
gests primary infection rather than reinfection, even if the
age of the miliary lesions have no direct relationship with the
caseous lesion in the brain [101].
Lincoln et al. (1960) [92] also found no association be-
tween the presence of miliary TB and a worse prognosis. In
their review of 74 patients, 30% of deaths occurred in pa-
A B
Fig. (1). Tuberculosis meningitis. An axial FLAIR image (A) and a comparative FLAIR after intravenous gadolinium injection (B) shows the
common triad of neuroradiological findings in TM characterized by basal meningeal enhancement, hydrocephalus and brain stem infarction.
Note a faint hypersignal on FLAIR confirmed on a diffusion-weighted image (C) as acute brain stem ischemia (arrow).
Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 4 251
tients with meningitis, and 29% of deaths occurred in pa-
tients with meningitis and miliary TB.
Neuroimaging
Several studies have emphasized the importance of neu-
roimaging (CT and MRI) in the diagnosis and monitoring of
patients with neurotuberculosis. [15, 45, 64, 102, 103]. Bhar-
gava et al. [45], who studied serial CT in 60 cases of
tuberculous meningoencephalitis in adults and children,
found only three normal outcomes. Hydrocephalus was the
most frequent finding and was detected in 87% of children
and 12% of adults. In addition to hydrocephalus, enhance-
ment of basal cisterns, infarcts and tuberculomas are the
most frequently reported findings [12].
To main findings in neuroimaging of neurotuberculosis are
illustrated in the figures below:
• TM with hydrocephalus and brain stem infarction
Fig. (1).
• TM with miliary tuberculosis and hydrocephalus
Fig. (2).
• Single tuberculoma Fig. (3).
• Multiple tuberculomas associated with miliary tubercu-
losis Fig. (4).
• Tuberculous abscess Fig. (5).
• Spinal meningitis Fig. (6).
• TM with communicating hydrocephalus Fig. (7).
PROGNOSIS
The severity of neurotuberculosis is reaffirmed by its
high mortality rates. Some studies have indicated that the
following are indicators of prognosis: age (especially the
extremes of life), disease stage at diagnosis, the presence of
neurological deficits, the negativity of a tuberculin test, asso-
ciation with other forms of TB, association with other dis-
eases, malnutrition, CSF changes, seizures, hydrocephalus,
and drug resistance [12, 67, 104].
Rodrigues et al. analyzed 141 patients diagnosed with
neurotuberculosis. Seventeen percent of the cases resulted in
C
252 Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 4 Rodrigues et al.

A B

C D
Fig. (2). TM with miliary tuberculosis. A chest x-ray (A) shows a typical bilateral pattern of pulmonary miliary tuberculosis. MR images
demonstrate cisternal exudate on FLAIR (B) obliterating perimesencephalic and lateral cisterns. The focal hyperintensity seen in the left lat-
eral aspect of the midbrain was interpreted as border zone encephalitis. Gadolinium administration on T1WI (C-D) showed cisternal en-
hancement. Note the hydrocephalus and the course of arteries inside the cisternal exudate.

A B C
Fig. (3). Tuberculoma. A focal lesion in the subcortical region of the left subcentral gyrus with peripheral hypointense signal on FLAIR (A)
associated with vasogenic edema and ring enhancement after gadolinium intravenous administration on T1WI (B). A chest x-ray (C) con-
firmed bilateral apical tuberculosis.
Neurotuberculosis: An Overview Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 4 253

A B

C D
Fig. (4). Multiple tuberculomas associated with miliary tuberculosis. Axial CT images after iodinated contrast injection (A-B) show multiple
small nodules compatible with brain tuberculomas and surrounding vasogenic edema. A chest x-ray (C) was less reliable than high-resolution
CT (D) for detecting miliary tuberculosis in the lungs.

death. Coma at diagnosis, lack of contact with tuberculosis,
and a non-reactive PPD were the most important predictors
of fatality in their series [33].
Age
In a series of 549 cases of tuberculous meningoencephali-
tis in Britain, Lorber [105] noted that the mortality rate
among children under 3 years (64.9%) was significantly
higher than that among children aged between 3 and 14 years
(47, 7%). This author believed that the value of age as a
prognostic factor was not as high as the stage of disease at
admission, stating that the higher mortality in younger chil-
dren was due to delays in diagnosis in this age group.
Barrett-Connor [106], Hosoglu et al. [12], Paganini et al.
[107], and Gusmão Filho [108] found no association between
age and prognosis. Hosoglu et al. [12] speculate that these
findings may be related to the fact that they considered death
and sequelae separately. In addition, the estimated age
ranged from 13 to 83 years, which practically excludes the
pediatric age group.
Al-Abbasi [109] evaluated 224 patients in Iraq with ages
ranging from 6 months to 72 years, and 30% of the patients
were younger than 5 years. The mortality rate was 21%, and
when only patients under 5 years were considered, the mor-
tality was 19%.
Humphries et al. [64] observed that age is an independent
factor for prognosis: the younger the patient, the higher the
mortality.
Succi [23] found that the mortality of patients decreases
progressively with increasing age, and this finding is attrib-
uted to the fact that the clinical presentation of the disease is
very uncharacteristic in young children and the high fre-
quency of other diseases that precipitate the evolution of the
tuberculosis primary complex such as malnutrition, measles,
and chicken pox, among others.
History of Contagion
Intra-domiciliary contacts are more often infected than
extra-domiciliary contacts. The aeration conditions of the
254 Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 4 Rodrigues et al.

B
Fig. (5). Tuberculous abscess. Note the anfractuous ring enhancement after intravenous gadolinium administration on T1WI (A) delineating a
liquid center on the left precentral gyrus. MR spectroscopy showed a prominent lipid/lactate peak (B). The other metabolites were not signifi-
cant. Surgical drainage confirmed this unusual pattern of parenchymal tuberculosis.

A B
Fig. (6). Spinal meningitis. This patient has TM confirmed on T1WI outlining the cervical cord by pial enhancement (A). Small nodules were
also observed peripherally, probably due to granulomas. Note the extensive cisternal enhancement after gadolinium administration (B).
Neurotuberculosis: An Overview Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 4 255

Fig. (7). Tuberculous meningitis with communicating hydrocephalus. Follow-up imaging of TM in a two-year-old boy. Axial CT images
show the left lateral fissure obliterated by inflammatory exudate (A-B), which exhibited enhancement after intravenous iodinated contrast
injection (C-D). Comparative CT images in weekly monitoring confirmed persistent inflammatory exudate and a progressive left basal gan-
glia infarction attributed to arteritis, which affected small perforating branches of the middle cerebral artery (first week E-F / second week
G-H /third week I-J).
environment where the infection is established are also im- Intra-domiciliary contact, previous significant contact or
portant. Ventilated environments decrease the possibility of current contact with a person with contagious TB is the most
transmission. Children are the main risk group because they important epidemiological factor and is very helpful in sug-
have low natural resistance to disease and remain at home gesting a strong early diagnosis [14]. The family often with-
for longer periods of time, which is usually an environments holds this information in the first meeting with the doctor
with low aeration [23].
256 Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 4
and confirms the existence of TB only after being questioned
thoroughly [23].
Finding the source of infection is important to making an
early diagnosis and beginning treatment, whereas not finding
it represents a lost opportunity to isolate and treat one or
more TB patients [110].
The absence of a history of infection delays the diagnosis
and treatment, along with other factors such as a lack of
knowledge of the clinical picture of neurotuberculosis and
restricted access to specialized services [12].
It is interesting to note that although some authors [12,
107] have indicated that a lack of an extra-meningeal infec-
tion focus in children with neurotuberculosis is an independ-
ent factor for a worse prognosis, it is possible that its absence
delays the diagnosis. From another point of view, the authors
who claim that a history of contagion is the most important
epidemiological data and very useful for early diagnosis [14,
84] claim no such relationship of this factor with prognosis.
Altunbasak et al. [39] concluded that evidence of pulmo-
nary TB, positive family history, reactivity to PPD and CT
findings are important data for establishing an early diagno-
sis and a specific therapy. However, they did not relate the
history of infection to these variables.
Hosoglu et al. [84] affirmed that a history of contagion is
the most important epidemiological factor and is very useful
for early diagnosis, but they found nothing about its influ-
ence on prognosis even though in their study the patients in
stage III of the BMRC had a poor prognosis at admission.
Succi [23] found no significant difference in mortality
among patients with a positive history of infection, but mor-
tality was significantly lower than among children with an
ignored epidemiological history. Succi justified the higher
mortality rate based on the profile of these patients: often
very young; transferred from another clinic in which they
were already being treated with various regimens; with poor
outcome; usually in a coma; an absence of information on
the duration and characteristics of the clinical history, which
could be very prolonged; and some cases of institutionalized
children, whose disease symptoms may have been over-
looked.
The authors who have tried to establish a relationship
between contagion and prognosis developed their reasoning
based on bacillary load, which is higher in a household con-
tact. Daily contact with an infected person is more serious
than casual contact and is therefore subject to a greater num-
ber of complications [111, 112]. These descriptions were
prior to an effective chemotherapy for TB, and therefore at a
time when early diagnosis had no prognostic value because
the disease was invariably fatal.
Clinical Staging
In developed countries, patients are usually diagnosed at
less advanced stages of the disease [21]. In 262 patients stud-
ied by Debrè [101], mortality ranged from 27% among chil-
dren admitted while awake to up to 90% for those admitted
in a coma. Berry & Subhedar [113] observed an 87% mortal-
ity rate among patients in a coma.
Rodrigues et al.
While studying 135 adult patients, Gulati et al. [114]
verified that only 14 of 55 who did not exhibit mental prob-
lems on admission died, whereas 50 of 83 who were in a
coma or stupor died. Delage & Dusseaut [65] followed 79
children with 38% lethality and found that in stage III of the
disease, being younger than 4 years, having miliary TB, and
a experiencing a delay in treatment initiation correlated sig-
nificantly with a worse prognosis.
While analyzing 52 patients, Kennedy & Fallon [67]
found that there were no deaths among patients who started
treatment in stage I, but the mortality rate was 46% in pa-
tients in stage III. Three of his patients who died despite hav-
ing started treatment early were at an advanced stage of the
disease at admission. In an analysis of 180 children,
Ramachandran et al. [115] found 9% lethality in the first
stage of the disease, 25% in the second stage, and 73% in the
third stage.
Altunbasak et al. [39] studied 52 children with a mortal-
ity rate of 23% and positively correlated their prognosis with
their clinical stage at admission. In a study of 405 children
with a mortality rate of 16%, Lee [116] concluded that the
most important factor for prognosis is the stage of the dis-
ease at diagnosis and initiation of treatment. Girgis et al. [11]
analyzed 857 patients in Egypt with ages ranging from 5
months to 55 years and found a mortality rate of 57%. Of the
528 patients in stage III of the BMRC, 72% died, compared
with 34% of 292 patients in stage II and only 18% of 37 pa-
tients in stage I. Nunes et al. [60], while evaluating 231 pa-
tients with ages ranging from months to 68 years and 59%
lethality, concluded that the main predictors of mortality are
age 0-4 years, seizures, and coma. In a study in Turkey con-
sisting of 434 patients with 23% mortality including adults
and children, Hosoglu et al. [12] found that a delay or inter-
ruption in treatment was an important predictor of mortality.
They also found that 50% of the patients who were in a coma
at admission died, and those who survived had sequelae.
Studies involving only children are scarcer. Humphries et
al. (1990) [64] evaluated 199 children with 6% mortality and
demonstrated that the age of the patient and stage of the dis-
ease were two independent variables associated with progno-
sis. Misra et al. [37], while studying 49 children with 4%
mortality, concluded that age, disease stage, a focal neuro-
logical deficit, cranial nerve palsies and hydrocephalus were
the most important variables in determining the prognosis.
Mahadevan et al. [117] studied 50 children in India with
10% mortality and found that age, stage of disease, focal
neurological deficits, and papilledema had an adverse effect
on evolution. This latter finding is not emphasized in other
studies.
In an analysis of 123 children in India with 23% mortal-
ity, Karanda et al. [118] found that mortality was related to
coma and an absence of involuntary movement in the hospi-
tal and that the presence of a deep coma was associated with
higher mortality.
In an analysis of 231 patients in Brazil that included chil-
dren and adults, Nunes et al. [60] reported a high mortality
rate (59%), which was justified by the fact that 42% of pa-
tients arrived at the hospital in a coma.
Neurotuberculosis: An Overview Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 4
Also in Brazil, in a study of 358 children admitted to the
Emilio Ribas Hospital - São Paulo with a mortality of 52%,
Succi [23] found that 43% were conscious at admission.
Mortality was significantly lower among children that were
conscious (43%) or only torpid (517%) than among children
who were in a coma (75%). Most (83%) of the children ad-
mitted in a coma were younger than 4 years of age, and in
this age group, the difference in mortality was significant.
Among children 4 years old or older, mortality was higher in
those who were admitted in a coma, but the difference was
not significant. Perhaps the small number of patients in a
coma in this age group (11 children) is the reason for the
lack of significance.
Delage et al. [65] observed a significant increase in mor-
tality in patients in BMRC stage III at the time of admission
that was associated with miliary TB, age under 3 years, and
an interval between admission and initiation of treatment of
more than three days. They concluded that a quick diagnosis
and immediate initiation of treatment are essential to de-
creasing mortality, but they did not mention the factors that
contributed to delays in the initiation of treatment.
The literature agrees that the stage of disease is the main
prognostic factor, and a progressive increase in mortality at
each successive stage of the disease has been present since
the start of chemotherapy for TB.
Prevention
Vaccination with the Calmette-Guerin (BCG) Bacillus
The purpose of vaccination is to replace natural pre-
infection by virulent TB with an artificial pre-infection by
non-virulent TB. This simultaneously increases the resis-
tance of the individual in the face of subsequent infection by
virulent bacilli and prevents the most serious manifestations
of the disease [25, 119].
It is likely that no other vaccine that is so widely used
remains as controversial as the BCG vaccine [107]. Although
the association of BCG vaccination with TB in children is
very controversial, it is postulated that the vaccine protects
children against more severe forms of the disease, i.e., mil-
iary TB, bone TB, and neurotuberculosis [23, 25, 110, 120,
121].
Studies before 1955 reported that the effectiveness of
BCG ranged from 56% to 80% [122]. Since 1975, however,
case-control studies using different BCG strains have re-
ported efficacy ranging from 0% to 80% [123].
A meta-analysis of published studies on the effectiveness
of BCG suggests that the protective effect of BCG in the
prevention of miliary TB and neurotuberculosis is 75% to
86% [120].
Thus, although a history of immunization with BCG is
not sufficient to exclude the diagnosis of neurotuberculosis,
it can reduce the chance that an infection of the CNS is of
tuberculous etiology [23, 124].
Al-Abbasi [109], while studying 224 cases of tuberculous
meningoencephalitis, showed that in 80 vaccinated patients,
there was a mortality rate of 13%, whereas in the remaining
144 patients, without vaccination, the mortality rate was
257
26%. A decrease in the severity of disease in vaccinated
children in Singapore was also reported [125].
Delage et al. [65] conducted a retrospective study of 79
children in Canada and concluded that there was no decrease
in the severity of the disease in the 25 children that reported
being vaccinated. However, they admitted that because there
was no record of the scar caused by the vaccination, failure
to immunize some of the children may have occurred.
Succi [23] reported that only 35 of the 358 children stud-
ied had evidence of prior immunization with BCG (10%) and
that this small number of vaccinated children indirectly
shows the protective efficacy of the vaccine, particularly in
severe forms of TB, as is the case with meningoencephalitis.
Analysis of the cases revealed, however, that a previous vac-
cination was not effective at protect these children from a
fatal outcome because mortality did not differ significantly
between vaccinated and unvaccinated children.
Paganini et al. [107], in a retrospective study with 40
children with neurotuberculosis in which 67% had been im-
munized with BCG, found no effect of the vaccine on prog-
nosis.
Mahadevan et al. [117] studied 50 children in India with
neurotuberculosis and found no association between a his-
tory of BCG vaccination and disease prognosis. They con-
cluded that immunization with BCG can prevent the most
serious forms of TB, but it has no role in predicting whether
the patient has developed the most severe form.
What we should learn based on these data is that in the
presence of suspicious cases of CNS infection, a tuberculosis
etiology should be considered even when a child has been
vaccinated, especially because delaying the diagnosis will
surely worsen the prognosis.
DRUG THERAPY
The World Health Organization recommends that pulmo-
nary and extrapulmonary disease should be treated using the
same regimens [126].
Unless drug resistance is suspected, adjuvant corticoster-
oid treatment is recommended for TB meningitis.
The treatment regimen is divided into two phases: an
intensive phase treatment, which consists of two months
with a combination of four drugs, including isoniazid, rifam-
picin, streptomycin, and pyrazinamide. The continuation
phase is a regimen with isoniazid and rifampicin, which is
given for at least four months. Some experts recommend 9-
12 months of treatment for TB meningitis [127, 128], given
the serious risk of disability and mortality.
The second-line groups of drugs are fluoroquinolones,
oral bacteriostatics, injectable agents, and agents with an
unclear role. Their ability to penetrate the CNS varies [129].
Ethionamide, which is an oral bacteriostatic, penetrates the
CSF well [130, 131]. Cycloserine, another bacteriostatic,
penetrates equally well, although its considerable neurotoxic-
ity generally precludes its use in infections of the CNS. Of
the fluoroquinolones, ofloxacin is the most able to penetrate
the blood-brain barrier, with CSF concentrations of 70% or
more of the serum concentration in patients with meningitis
[132].
258 Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 4
The prevalence of multidrug resistance (MDR) in previ-
ously treated patients is five times higher than in drug-naive
patients. For previously treated patients, it is recommended
that drug susceptibility testing (DST) be performed for at
least isoniazid and rifampicin. In settings where DST is not
rapidly available, MDR treatment based on second-line
agents should be considered. Additionally, if there is a his-
tory of contact with a patient with MDR pulmonary tubercu-
losis or a poor clinical response, MDR schemes should be
considered [126].
Despite numerous scientific and technological advances,
diagnosing tuberculous meningoencephalitis remains a chal-
lenge. Even doctors with extensive experience in treating this
disease have experienced the frustration of starting treatment
at a late stage of the disease in patients who were under their
care and had a diagnosis that was suspected but not con-
firmed. Thus, one must always remember that the main fac-
tor for successful treatment is early treatment initiation and
that a high degree of suspicion of the disease is the most im-
portant factor for diagnosis.
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