Tuberculosis 92 (2012) 377e383
Contents lists available at SciVerse ScienceDirect
Tuberculosis
journal homepage: http://intl.elsevierhealth.com/journals/tube
REVIEW
Diagnosis and therapy of tuberculous meningitis in children
Nicola Principi*, Susanna Esposito
Department of Maternal and Pediatric Sciences, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,
Via Commenda 9, 20122 Milan, Italy
a r t i c l e i n f o
s u m m a r y
Article history:
Received 31 March 2012
Received in revised form
22 May 2012
Accepted 29 May 2012
Children are among the subjects most frequently affected by tuberculous meningitis (TBM) due to their
relative inability to contain primary Mycobacterium tuberculosis infection in the lung. TBM is a devastating disease with about 30% mortality among the most severe cases; moreover, 50% of survivors have
neurological sequelae despite an apparently adequate administration of antibiotics. Early diagnosis and
prompt treatment are crucial for reducing the risk of a poor outcome. However, especially in children, the
best and most rapid way to conﬁrm the diagnosis is controversial; the optimal choice, dose, and treatment duration of anti-tuberculosis drugs are not precisely deﬁned, and the actual importance of
adjunctive therapies with steroids and neurosurgery has not been adequately demonstrated. This review
is an effort to discuss present knowledge of the diagnosis and treatment of pediatric TBM in order to offer
the best solution to address this dramatic disease. In conclusion, we stress that new studies in children
are urgently needed because data in the early years of life are more debatable than those collected in
adults. In the meantime, when treating a child with suspected TBM, the most aggressive attitude to
diagnosis and therapy is necessary, because TBM is a devastating disease.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Children
Meningitis
Mycobacterium tuberculosis
Tuberculosis
Tuberculous meningitis
1. Introduction
Tuberculous meningitis (TBM) occurs mainly in developing
countries where tuberculosis (TB) is more common and the wider
incidence of the human immunodeﬁciency virus (HIV) favors the
onset of a great number of cases. However, TBM is also encountered
in industrialized countries, particularly in recent years, as a consequence of the large immigration of infected people1 and the
frequent use of biological agents that favor TB development.2,3
Children are among the subjects who most frequently suffer from
TBM due to their relative inability to contain primary Mycobacterium tuberculosis infection in the lung.1,3 TBM is a devastating
disease with about 30% mortality in the most severe forms;
moreover, 50% of survivors have neurological sequelae despite
apparently adequate administration of antibiotics.4,5 Early diagnosis and prompt treatment are crucial for reducing the risk of
a negative evolution. However, especially in children, the best and
most rapid way to diagnose the disease is controversial; the
optimal choice, dose, and treatment duration of anti-tuberculosis
drugs are not precisely deﬁned, and the actual importance of
adjunctive therapies with steroids and neurosurgery have not been
adequately demonstrated. Consequently, the approach to pediatric
TBM is frequently inadequate. This review is aimed at discussing
* Corresponding author. Tel.: þ39 02 55032203; fax: þ39 02 50320206.
E-mail address: [email protected] (N. Principi).
1472-9792/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tube.2012.05.011
present knowledge on the diagnosis and treatment of pediatric
TBM in order to offer the best solution to address this dramatic
disease.
2. Diagnosis
Although early and rapid identiﬁcation of TBM is crucial for
successful disease management, in most of the cases, diagnosis is
signiﬁcantly delayed. Initial signs and symptoms of disease are
non-speciﬁc and the suspicion of TBM usually arises only some days
or weeks after the disease’s onset and is not different in children
who have or have not been vaccinated with Bacille Calmette-Guerin.6 Fever, headache, anorexia, and vomiting characterize the
prodrome of disease in older children, whereas failure to thrive,
poor appetite, vomiting, and sleep disturbances are more common
in younger ones.7 TBM is more easily suspected when these
symptoms are associated with a history of recent contact with
a case of documented TB or when, after the ﬁrst days of disease,
relevant neurological manifestations, such as cranial nerve palsy,
occur.6,7
2.1. Probable or possible TBM
Diagnosis of probable or possible TBM requires signs and
symptoms of meningitis in association with clinical, CSF and cerebral
imaging ﬁndings suggestive of M. tuberculosis infection. The
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N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383
evidence of TB outside the CNS can further contribute to probable or
possible diagnosis. A score that includes the most common ﬁndings
in children with TBM and in which single ﬁndings are assigned
a point according to the frequency with which they are usually
demonstrated has been created by Marais et al.8 According to these
authors, probable TBM is deﬁned by a score between 10 and 12,
whereas possible TBM is deﬁned by a score higher than 6 (Table 1).
2.1.1. Clinical ﬁndings
The low sensitivity and speciﬁcity of most of the relevant
neurologic symptoms has been largely demonstrated by several
clinical trials. Prodromal stage 7 days, optic atrophy on fundal
examination, focal deﬁcit and abnormal movements were found to
be independently predictive of TBM (p < 0.007) in a group of children aged 1 months to 12 years,9 but optic atrophy is usually a late
occurrence and abnormal movements are rare.
2.1.2. Laboratory ﬁndings
CSF modiﬁcations are common in children with TBM. In these
cases, CSF shows a clear appearance, moderate pleocytosis with
Table 1
Diagnostic criteria for classiﬁcation of deﬁnite, probable or possible tuberculous
meningitis.
Criteria
Clinical criteria
Symptom duration of more than 5 days
Systemic symptoms suggestive of TB
(one or more of the following): weight
loss or poor weight gain, night swabs or
persistent cough for more than 2 weeks
History of recent (within the past year)
close contact with an individual
with pulmonary TB or a positive
tuberculin skin test or
interferon-g release assay
Focal neurologic deﬁcit (excluding
facial nerve palsies)
Cranial nerve palsy
Altered consciousness
CSF criteria
Clear appearance
Cells 10e500 per mL
Lymphocytic predominance (>50%)
Protein concentration >1 g/L
CSF to plasma glucose ratio of less than
50% or an absolute CSF glucose
concentration <2.2 mmol/L
Cerebral imaging criteria
Hydrocephalus
Basal meningeal enhancement
Tuberculoma
Infarct
Pre-contrast basal hyperdensity
Evidence of tuberculosis elsewhere
Chest X-ray suggestive of active TB:
signs of TB ¼ 2; miliary TB ¼ 4
CT/MR/ultrasound evidence for TB
outside the CNS
M. tuberculosis cultured from another source
(i.e., sputum, lymph node, gastric lavage,
urine, blood culture)
Positive commercial M. tuberculosis NAAT
from extra-neural specimen
Maximum category
score ¼ 6
4
2
2
1
1
1
Maximum category
score ¼ 4
1
1
1
1
1
Maximum category
score ¼ 6
1
2
2
1
2
Maximum category
score ¼ 4
2/4
2
4
4
CNS, central nervous system; CT, computed tomography; MR, magnetic resonance;
NAAT, nucleic acid ampliﬁcation test; TB, tuberculosis.
From Marais et al.,8 modiﬁed.
a predominance of lymphocytes, an increase in protein content and
a very low glucose concentration. These ﬁndings are different from
those usually reported for typical bacterial meningitis in which CSF
is opaque, pleocytosis is very high, and neutrophils are predominant. Reduction in glucose content is usually less marked in
comparison to purulent bacterial meningitis, where CSF glucose
values below 5 mg/dL will often be found. Clear appearance, white
blood cell count between 50 and 500 per mL with 50% or more
lymphocytes, protein content greater than 1 g/L and a glucose
content less than 2.2 mmol/L are considered to be indicative of
TBM. However, atypical CSF ﬁndings have been repeatedly
described in children with TBM.7
To improve diagnosis of probable or possible TBM, other CSF
tests have been recently studied. Among them, the evaluation of
adenosine deaminase activity (ADA), the measurement of
interferon-gamma (IFN-g) release by lymphocytes, the detection of
M. tuberculosis antigens and antibodies, and the immunocytochemical staining of mycobacterial antigens (ISMA) in the cytoplasm of CSF macrophages are those for which the greatest amount
of data is available. However, none of these seems to have elevated
sensitivity and speciﬁcity, although they can be useful in some
cases to support the diagnosis.
The ADA activity test is a rapid test that represents the proliferation and differentiation of lymphocytes as a result of the activation of cell-mediated immunity after M. tuberculosis infection.10,11
It has given good results in the diagnosis of the pleural, peritoneal
and pericardial forms of tuberculosis. When applied to patients
with TBM, it was found that ADA activity could not distinguish
between TBM and other types of bacterial meningitis, but that it
could add useful information to suggest TBM once meningitis due
to different pathogens has been ruled out. ADA values from 1 to 4 U/
L (sensitivity >93% and speciﬁcity <80%) can help to exclude TBM
and values >8 U/L (sensitivity <59% and speciﬁcity >96%) can
improve the diagnosis of TBM (p < 0.001). However, values
between 4 and 8 U/L are insufﬁcient to conﬁrm or exclude the
diagnosis of TBM (p ¼ 0.07).10 Moreover, false positive results can
be found in HIV-infected patients.11
Measurement of IFN-g release by lymphocytes stimulated by
M. tuberculosis antigens has been demonstrated to be more accurate than skin testing for the diagnosis of latent TB and to be useful
in the diagnosis of extrapulmonary TB. However, sensitivity and
speciﬁcity of the test varied markedly according to the disease
site.12 When adapted to TBM, collected data vary sharply from study
to study. Liao et al. found that the test was 100% sensitive and 100%
speciﬁc,12 whereas other authors reported a very poor value of the
test in diagnosing TBM.13 It has been suggested that the failure of
the test in some studies could be ascribed to the fact that
lymphocytes die rapidly when stimulated with M. tuberculosis
antigens ex vivo so that the test can be negative even if TBM is
actually present.14
Detection of various M. tuberculosis antigen markers, such as
lipoarabinomannan, puriﬁed protein derivatives, heat shock
protein of 62Kd and 14Kd, GroE, Ag 85 complex and 38Kd antigen,
have been tried to conﬁrm TBM diagnosis.15e17 However, their
presence remains questionable and many of these antigens are
reported in blood only, but not in the CSF and this questions their
veracity for the diagnosis of TBM. The same seems true for speciﬁc
antibody detection.18
Use of ISMA in the cytoplasm of CSF macrophages is based on
the assumption that, during the initial stage of infection, ingestion
of the bacilli by macrophages takes place and that during the
second stage bacilli grow logarithmically within newly recruited
macrophages.19 Consequently, the positivity of the test indicates
that viable M. tuberculosis isolates are present in CSF. A recent study
in which this test was evaluated in 393 patients, among whom
N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383
some with deﬁnite TBM, has demonstrated that it has a sensitivity
of 73.5% and speciﬁcity of 90.7% with positive and negative
predictive values of 52.9% and 96.0% respectively.20 This means that
this test can be useful, in actual fact, to exclude TBM, but that its
sensitivity is too low to diagnose deﬁnite TBM.
2.1.3. Imaging
Similarly to clinical and laboratory ﬁndings, cerebral imaging
can also contribute to diagnosing probable or possible TBM.
However, discrimination between TBM and another cerebral
disease is frequently very difﬁcult. The most common brain
computed tomography (CT) or magnetic resonance (MR) features in
children with TBM are hydrocephalus, which can be demonstrated
in about 80% of cases,21 and basal meningeal enhancement, found
in 75% of young patients.22 Infarction, as a result of ongoing
vasculitis, particularly of the basal ganglia and of the areas of the
medial striates and thalamoperforating arteries, and tuberculoma
can be found in a smaller number of TBM pediatric cases.23,24 MR
has a higher sensitivity than CT in the identiﬁcation of CNS modiﬁcation, although it does not seem to offer more help in distinguishing TBM from other CNS diseases such as viral encephalitis,
cryptococcal meningitis or cerebral lymphomas that can have
similar cerebral imaging.25 However, a combination of basal
meningeal enhancement, infarction and hydrocephalus was found
to have a high speciﬁcity for the diagnosis of TBM, whereas basal
meningeal enhancement was reported as the most sensitive
feature.22 Recently, it was reported that border zone necrosis (BZN)
of the brain parenchyma in areas adjacent to meningeal inﬂammation can occur in 50% of children with TBM.26 Detection and
conﬁrmation of cytotoxic edema associated with BZN using
diffusion-weighted MR can offer further support to probable or
possible TBM diagnosis. However, it has to be highlighted that in
stage 1 TBM imaging ﬁndings may be normal, yet it is at that stage
that treatment should be started in order to prevent brain damage.
2.2. Evidence of TB outside the CNS
The evidence of TB infection or disease outside the CNS can
signiﬁcantly increase the probability or possibility that a child with
cerebral signs and symptoms can have TBM. However, a great
number of patients, especially when HIV negative, will present
with normal chest radiography or negative tuberculin skin
testing.27 Moreover, particularly in high TB prevalence areas,
a positive skin test with an unrelated illness has been frequently
documented. Taking samples from sites of frequent TB infection
such as lymph nodes, lung and gastric ﬂuid can increase the likelihood of a positive culture. Gastric aspiration was positive in 68% of
children with TBM.28
In conclusion, considering the need for a rapid diagnosis of TBM,
all possible efforts to demonstrate the probable or possible presence of this disease must be pursued using all available laboratory
tests and imaging techniques. Moreover, the potential severity of
TBM calls for the immediate treatment of all the doubtful cases.
2.3. Conﬁrmed diagnosis of TBM
Independently from the characteristics and duration of the
prodromal stage, a deﬁnite diagnosis of TBM can be made only
when, after a lumbar puncture (LP) in a patient with signs and
symptoms of central nervous system (CNS) disease, acid-fast bacilli
(AFB) are seen and/or M. tuberculosis is detected by molecular
methods and/or cultured in cerebrospinal ﬂuid (CSF). The same
conclusion can be drawn from autopsy when M. tuberculosis is
identiﬁed in histological lesions of the CNS. This is in line with what
has been deﬁned by most of the authors who have made the
379
attempt to standardize clinical case deﬁnition of TBM for use in
clinical research.5, 29e34
However, all the methods for the conﬁrmation of the diagnosis
of TBM risk further delay in diagnosis and initiation of therapy.35e37
Culture requires >2e3 weeks to give results. Moreover, both
microscopic AFB detection and culture isolation have low sensitivity, particularly in children in whom these allow for identiﬁcation of only about 20% of cases. Finally, modern molecular methods
can have, at the same time, both low sensitivity and low speciﬁcity.
Sensitivity of traditional microbiological tests seems to be strictly
dependent on the amount of CSF that is sampled, the frequency of
LPs, the time devoted to the microscopic search for the organism,
and the moment in which the CSF is drawn. The minimum volume
of CSF to obtain reliable results seems to be 6 mL,35 an amount
difﬁcult to be safely obtained in younger children that have a low
total volume of CSF.36 In comparison with a single LP, four LPs can
increase sensitivity of microscopy examination and culture from
37% and 52% to 87% and 83%, respectively.37 However, in pediatrics
several lumbar punctures are not easily performed, mainly because
of the aversion of parents to let their children undergo repeated
invasive procedures. Thirty minutes are considered the minimum
time needed for a correct evaluation of CSF by microscopy36 and in
a busy laboratory this may not be possible. Finally, antibiotic
administration rapidly reduces the number of pathogens in the CSF.
Anti-tuberculosis drugs are usually started immediately after TBM
is suspected and consequently LPs are negative even in children
actually suffering from the disease.
Accuracy of nucleic acid-based ampliﬁcation (NAA) tests,
though better than that of conventional microscopic methods,38
was not considered completely satisfactory for many years
because their sensitivity and speciﬁcity in identifying
M. tuberculosis, in comparison with culture, ranged from 2% to 100%
and from 75% to 100%, respectively.39 The most important reason
for the low sensitivity of some of the ﬁrst polymerase chain reaction (PCR)-based methods was the use of a single target for
ampliﬁcation. Most studies have used the IS6110 gene of
M. tuberculosis that is usually present in multiple copies in the
bacterial genome assuring high sensitivity. Unfortunately, this gene
is absent in a signiﬁcant number of isolates, so that a false negative
result was regularly found when patients infected by these isolates
were studied.40,41 More reliable results have been obtained in more
recent years when ampliﬁcation of multiple gene targets from CSF
samples was performed. Kusum et al. evaluated a multiplex PCR
using protein b, MPB64 and IS6110 primers and found that this
method had a sensitivity of 94.4% and a speciﬁcity of 100% in
culture-conﬁrmed cases.42 Recently, molecular methods capable of
simultaneously identifying both M. tuberculosis and resistance of
the strain to antibiotics have been developed. Among these, the
Xpert M. tuberculosis/RIF assay seems to be the most promising,
although no data regarding its use in extrapulmonary TB are
available.43 Finally, preliminary studies have suggested that
molecular methods could be used to quantify the bacterial load in
CSF and consequently to evaluate treatment response.44
In conclusion, making a deﬁnite diagnosis of TBM is still
a problem. In many cases, diagnosis remains probable or possible
and treatment is initiated without the demonstration of the presence of M. tuberculosis in CSF.
3. Treatment
Treatment of TBM is based on three different components:
administration of anti-infective drugs active against M. tuberculosis,
modulation of the destructive elements of the immune response,
and management of increased intracranial pressure.
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3.1. Anti-infective therapy
Contrary to what applies to pulmonary tuberculosis, recommendations for anti-infective therapy in TBM are, in general, not
based on well-conducted clinical trials. Few data, particularly in
children, are available to guide the clinician who derives the
schemes for treatment of TBM from those used for pulmonary TB.
This explains why most experts recommend that the treatment of
TBM follows the model of short-course chemotherapy with an
intensive phase of treatment with several drugs followed by
a continuation phase in which only two drugs are
administered.45,46
Table 2 summarizes the main guidelines for treatment of pediatric TBM and Table 3 shows second-line drugs that could be used
in case of resistant strains taking in account that very few data of
their real efﬁcacy, safety and tolerability in children are available.
Before the emergence of multidrug-resistant M. tuberculosis, three
drugs were considered adequate for the ﬁrst phase. More recently,
in order to address the problem of resistance, four antibiotics for
the initial months of treatment are preferred. However, there is no
agreement on the duration of each of the two phases and on the
total length of therapy. The intensive phase can range from 2 to 6
months and total treatment from 6 months to one year.47 Unfortunately, studies comparing the different schemes of antibiotic
administration in children are not available.48,49 Studies regarding
the outcome of 6-month regimens have demonstrated that the
relapse rate was not signiﬁcantly different from that reported when
longer periods of antibiotic administration were used.48 This seems
to speak in favor of the shortest therapy. However, because most of
these data have been collected in adults, no deﬁnitive conclusions
can be drawn when children with TBM have to be treated.
According to Donald, in situations where the directly observed
treatment and follow-up after treatment completion is impeccable,
a 6-month treatment duration is probably satisfactory.47 When
treatment supervision and/or follow-up are questionable, it may be
better practice to prolong length of treatment.47
For several years now, the drugs considered essential by the
World Health Organization (WHO) to treat pulmonary TB in children are isoniazid (INH), rifampicin (RMP),pyrazinamide (PZA), and
ethambutol (EMB).50 Other drugs, such as streptomycin (SM) or
other aminoglycosides, ethionamide (ETH) and cycloserine are
Table 2
Main guidelines for the treatment of tuberculous meningitis in infants and children.
British Infection Society
Isoniazid 10e20 mg/kg/24 h (max 500 mg) orally for 12 months
Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 12 months
Pyrazinamide 30e35 mg/kg/24 h (max 2 g) orally for 2 months
Ethambutol 15e20 mg/kg/24 h (max 1 g) orally for 2 months
Prednisolone 4 mg/kg/24 h orally for 4 weeks, followed by a
reducing course over 4 weeks
American Thoracic Society, CDC, and Infectious Diseases Society of America
Isoniazid 10e15 mg/kg/24 h (max 300 mg) orally for 9e12 months
Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 9e12 months
Pyrazinamide 15e30 mg/kg/24 h (max 2 g) orally for 2 months
Ethambutol 15e20 mg/kg/24 h (max 1 g) orally for 2 months
Dexamethasone 8 mg/day/24 h orally for children weighing less than 25 kg
and 12 mg/day for children weighing 25 kg or more for 3 weeks,
followed by a reducing course over 3 weeks
World Health Organization
Isoniazid 10e15 mg/kg/24 h (max 300 mg) orally for 6 months
Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 6 months
Pyrazinamide 15e30 mg/kg/24 h (max 2 g) orally for 2 months
Streptomycin 20e40 mg/kg (max 1 g) i.m. or i.v. for 2 months
Prednisone 2 mg/kg/24 h orally for 4 weeks, followed by a
reducing course over 1e2 weeks
Table 3
Recommended daily dosages of second-line anti-tuberculous drugs for treatment of
tuberculous meningitis in infants and children.
Drug
Dosage
Ethionamide
20 mg/kg/24 h (max 1 g/day) orally as a
single daily dose
10e15 mg/kg/24 h (max 1 g/day) orally
as a single daily dose
20e40 mg/kg/24 h (max 1 g/day) i.m.
or i.v. as a single daily dose
200e300 mg/kg/24 h orally in 2e4 doses
15e30 mg/kg/24 h (max 1000 mg) orally
as a single daily dose
15e30 mg/kg/24 h (max 1 g/day) i.m.
or i.v. as a single daily dose
15e20 mg/kg/24 h (max 800 mg) orally
as a single daily dose
7.5e10 mg/kg/24 h (max 500 mg) orally
as a single daily dose
7.5e10 mg/kg/24 h (max 500 mg) orally
as a single daily dose
20e30 mg/kg/24 h (max 1.5 g) orally
as a single daily dose
Cycloserine
Steptomycin
Para-amino-salicylic acid
Capreomycin
Amikacin and Kanamycin
Oﬂoxacin
Levoﬂoxacin
Moxiﬂoxacin
Ciproﬂoxacin
considered second-line drugs because of their toxicity.50 However,
when TBM has to be treated ETH and cycloserine that have
a reasonable CSF penetration, even better of that of EBM can be
considered where they are available.51,52 Newer anti-tuberculosis
drugs, such as ﬂuoroquinolones, have been scarcely used in pediatric TBM and are off-label in children, although for both penetration in CSF and in-vitro efﬁcacy against M. tuberculosis, they are
considered promising therapeutic options.50
Independently from the drugs prescribed, the scheme of administration used, and the total duration of therapy, INH remains the drug
most widely prescribed in children for initial TBM treatment.50 The
choice of INH is based on several positive factors: the good absorption
by the gastrointestinal tract, the rapid diffusion in body compartments including CSF and the low toxicity. Moreover, it rapidly kills
most of the replicating M. tuberculosis and, consequently, protects
companion drugs against the development of resistance, reduces the
risk of infecting contacts and leads to a more rapid mitigation of
disease symptoms. In children, INH is recommended at the dose of
10 mg/kg/day (range: 6e15 mg/kg/day, maximum 500 mg), generally
useful to reach in CSF concentrations that are high enough to eliminate fully sensitive M. tuberculosis or resistant mutants with a relatively low minimum inhibitory concentration (MIC) even in patients
who are fast acetylators.53,54 When M. tuberculosis resistance is suspected or demonstrated, the highest doses have to be administered,
striking the right balance between toxicity and optimal efﬁcacy.
RMP has the advantage of killing low or non-replicating
M. tuberculosis, thus complementing INH activity and allowing
the sterilization of lesions. Unfortunately, it has several limits
because its concentrations in CSF do not exceed 10% of those in
plasma,55 its absorption is negatively inﬂuenced by food and
antacids56 and it has a relevant protein binding action that can
signiﬁcantly reduce its clinical efﬁcacy.57 RMP is ofﬁcially recommended at the dose of 10e20 mg/kg/day45,46 but, considering the
MIC of susceptible M. tuberculosis and the concentrations reached
in CSF of children,58 it has been recommended to administer the
highest dosage in young children and infants <10 kg and at least
15 mg/kg/day in older patients weighing between 10 and 20 kg.47
The dose of 10 mg/kg/day could lead to CSF levels <1.0 mg/mL,
which is ineffective against most M. tuberculosis, particularly when
strains with increased MIC are present. However, raising the dose
has no effect on highly resistant mutants as their MIC is far too high.
For the early phase of therapy, PZA and any of the second-line
drugs are usually administered. PZA has a good penetration in
CSF and, despite a very low early bactericidal activity in the ﬁrst
N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383
days of treatment, it is important because in the course of time it
becomes as effective as INH and RMP.59,60 Moreover, together with
RMP, it makes an essential contribution to the sterilization of
lesions and has an important role in reducing the risk of recurrence.61 PZA is recommended at the dose of 30e35 mg/kg/daily
with the highest dosage for younger children. With these regimens,
CSF concentration in excess of 20 mg/mL higher than the MIC of PZA
is reached in most children.62
The fourth drug to complete the antibiotic regimen in the early
phase of TBM therapy is usually chosen from EMB or SM. Both have
limited CSF penetration, low bactericidal activity and do not
contribute to the sterilization of lesions and reduction of the risk of
relapse. Their contribution to the treatment of TBM is probably
minor, although they protect companion drugs against the emergence of resistance.47
The growing emergence of resistant strains has raised the
question of the importance of resistance to TBM outcome. Available
data clearly indicate that resistance to both INH and RMP signiﬁcantly worsen the ﬁnal outcome.45 The effect of resistance to
a single drug is more controversial. Regarding INH, some studies
indicate that INH resistance does not inﬂuence TBM outcome,63,64
whereas other studies seem to associate INH resistance to a significant higher risk of death.65 These different ﬁndings may be due to
different doses of INH used and different resistant mutants.
However, in order to minimize risks, it has been suggested that
duration of treatment for TBM caused by INH-resistant organisms
should be extended and always include PZA as well as a new antiM. tuberculosis antibiotic.47
381
the severity of increased intracranial pressure.71e74 Shunting is
preferred by most experts when hydrocephalus is noncommunicating or when medical treatment fails even if it is not
known which kind of shunting is the best.74 In communicating
hydrocephalus, diuretics are generally effective in reducing the risk
of long-term neurologic impairment. Endoscopic third ventriculostomy is considered a possible option, particularly in patients
who have experienced multiple episodes of shunt dysfunction.75
4. Conclusions
Despite undeniable advances in the identiﬁcation of markers of
deﬁnite, probable or possible TBM have been made in recent years,
most of the problems that pediatricians and neurologists have to
face in TBM are still unsolved. The most important difﬁculty regards
early diagnosis because in those patients in whom TBM is suspected early enough present treatment is sufﬁcient to bring about
complete cure in the majority of cases, at least when pathogens are
fully drug susceptible and treatment is complied with. More difﬁculties in achieving cure can arise when treatment is delayed and
when multidrug-resistant pathogens are the cause of the disease. In
this case prognosis is poor, particularly in children because it is not
deﬁnitively clear what has to be done when resistance of
M. tuberculosis to one or more antibiotics is present, which duration
of treatment is to be recommended and what is the actual role of
adjunctive therapy. New studies in children are urgently needed. In
the meantime, when treating a child with suspected TBM, the most
aggressive attitude is to be used both for diagnosis and for therapy,
because TBM is an extremely devastating disease.
3.2. Adjunctive steroids
In meningitis, most of the damage derives from the immune
response elicited by the presence of bacterial pathogens in the
CNS.66 This leads to a very relevant inﬂammatory process with
signiﬁcant inﬁltrative, proliferative and necrotizing vessel pathologies.67 Anti-tuberculous chemotherapy and the administration of
thalidomide and salicylates appear to be relatively ineffective in
preventing vascular complications that remain the major unresolved problem related to TBM. Corticosteroids have been used in
TBM for over 50 years, although the real importance of these drugs
in this disease is not completely deﬁned. A meta-analysis recently
carried out that comprised 7 randomized controlled trials involving
a total number of 1140 participants, both children and adults, has
demonstrated that in HIV-negative subjects prednisolone or
dexamethasone signiﬁcantly reduced the risk of death (relative risk
[RR], 0.78; 95% conﬁdence interval [CI], 0.67e0.91) or disabling
residual neurological deﬁcit (RR 0.82; 95% CI, 0.70e0.97) with mild
and treatable adverse events.68 On the contrary, no effect was
reported in HIV-infected patients. The positive effect on HIVnegative subjects was found independently from the severity of
the disease, thus suggesting that this therapy should be added to
anti-infective therapy in all children with TBM.69,70
The best steroid and the most effective scheme of administration are not known because no data comparing different regimens
are available at the moment. Moreover data collected in children
are few. According to the suggestions of some American and
European Scientiﬁc Societies,45,46 it could be suggested the use of
oral compounds for 3 or 4 weeks with subsequent reduction in few
days.
3.3. Management of increased intracranial pressure
Hydrocephalus is common in children with TBM. Its management is debated. Diuretics, repeated LPs or CSF diversion through
ventriculoperitoneal or atrial shunting can be used, according to
Funding:
This study was supported by a grant from the Italian
Ministry of Health (Bando Giovani Ricercatori 2007).
Competing interests:
to declare.
The authors have no conﬂict of interest
Ethical approval:
This review was approved by the Ethical
Committee of Fondazione IRCCS Ca’ Granda Ospedale Maggiore
Policlinico, Milan, Italy and all the papers included in this review
have been approved by local Ethical Committees.
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