JECH Online First, published on November 13, 2013 as 10.
1136/jech-2013-202525
Tuberculous meningitis
Thinh Tran Thi Van,1 Jeremy Farrar1,2,3
BURDEN OF DISEASE
Tuberculosis (TB) is one of the most
important infectious diseases and one of
ten most common causes of death glo-
bally,1 with almost 10 million new cases
per year and 1.5 million deaths (WHO
report 2011).2 It is estimated that a third
of the world’s population is infected with
TB of whom approximately 10% will
develop clinically apparent disease. TB is
also in the top 15 of causes of disease
burden worldwide in the rank of
disability-adjusted life years.3 The WHO
estimates that five countries India, China,
South Africa, Indonesia and Pakistan
account for over 70% of the global
burden of disease.2 Southern and eastern
sub-Saharan Africa is the most affected
region by the HIV/AIDS-TB combin-
ation.3 But the reality is that in all low-
income and middle-income countries and
increasingly in high-income countries, TB
remains a major public health problem.
Tuberculous meningitis (TBM) is the
most severe form of TB with a high mor-
tality and many of the survivors are left
with chronic neurological sequelae, which
affect their daily lives and those of their
family and community. The impact of this
disease is even more severe in those coin-
fected with HIV. Patients coinfected with
HIV are at more than 20 times higher risk
of developing TB, compared with non-
infected individuals.2 In a recent studies
from Vietnam, the mortality rate in the
1st year following diagnosis of TBM in
HIV and non-HIV infected adult patients
was approximately 65% and 30%,
respectively, and over 50% of survivors
suffer from long-term disability.4 In coun-
tries with the greatest burden of TB, TBM
is most commonly seen in children while
in lower TB transmission settings, most
cases of TBM occur in adults. It is now
the third most common cause of bacterial
meningitis in the UK. Several aspects of
TBM including the underlying immuno-
pathogenesis, the availability of sensitive
and specific diagnostic tests, optimal
1
Oxford University Clinical Research Unit, Hospital for
Tropical Diseases, Ho Chi Minh City, Vietnam; 2Centre
for Tropical Medicine, University of Oxford, Churchill
Hospital, Oxford, UK; 3Singapore Infectious Disease
Initiative, Singapore
Correspondence to Professor Jeremy Farrar, Oxford
University Clinical Research Unit, Hospital for Tropical
Diseases, Ho Chi Minh City Quan 5, Vietnam;
jfarrar@oucru.org
VanCopyright Article
TTT, et al. J Epidemiol author
Community (orMonth
Health their employer)
2013 Vol 0 No 0
Editorial
treatment regimens and impact of vaccin-
ation require further research if the
unacceptably high mortality and morbid-
ity is to be reduced.
CLINICAL PICTURE
TBM has been traditionally characterised
as a subacute or chronic infection.
However, it can develop and progress in
less than a week from onset of the first
symptoms. In countries with a high
burden of TB, the diagnosis of TBM
should be considered in all patients pre-
senting with meningitis. Early diagnosis
and initiation of effective drugs saves lives
and reduces long-term disability. The clin-
ical symptoms of TBM are broad and can
be analogous to other forms of meningo-
encephalitis. This leads to delays in estab-
lishing a diagnosis. Coinfection with HIV
does not change the neurological presen-
tation of TBM5 even though in indivi-
duals coinfected with HIV there is a
greater range of other potential diagnoses
from opportunistic diseases than in
patients who are not coinfected with HIV.
Moreover, in many countries access to
healthcare for HIV-positive individuals
remains less good than HIV-negative indi-
viduals and this can lead to delays in
health-seeking behaviour. Patients with
and without HIV present with fever,
altered mental status, meningism and
focal neurological signs, particularly
cranial nerve lesions and hemiparesis are
common. The characteristic cerebrospinal
fluid (CSF) features in TBM are straw col-
oured CSF, leucocytosis with a predomin-
ant lymphocytosis, low CSF:blood
glucose ratio, moderately raised lactate
and increased protein level. However, par-
ticularly in those who present early,
within 7 days, and in those who are
HIV-positive with low CD4 counts, the
CSF may show a polymorphonuclear
leucocytosis and the CSF glucose can be
normal or only very slightly reduced on
admission. In these patients, the diagnosis
can be extremely difficult and consider-
ation should be given to treating with
broad-spectrum antibiotics and to repeat-
ing the CSF investigation if the patient
does not improve within 48–72 h. The
insensitive ZN test for acid-fast bacilli in
the CSF and the time for mycobacterial
culture add to the difficultly in establish-
ing a diagnosis. A chest X-ray can help in
the diagnosis if miliary TB is seen or the
2013. Produced by BMJ Publishing Group Ltd under licence.
characteristic features of pulmonary TB
are present. Brain imaging, with CT or
MRI, may help in suggesting a diagnosis
of TBM with hydrocephalus, tubercu-
loma, basilar meningeal enhancement and
basal ganglial infarction, all suggestive but
not specific for TBM. A prior history of
TB or known close contacts with patients
with TB should be ascertained in the
history in all patients.
IMPACT ON THE PATIENTS
Early diagnosis of TBM plays a crucial
role in saving lives and reducing disability
because the prognosis is dependent on the
patient’s severity at the time that effective
antibiotics and steroids are started. Sadly
in practice, many patients are initially
treated for pyogenic meningitis and when
not improving, the diagnosis of TBM is
considered, often after many days. This
then may involve a transfer to a tertiary
medical centre, which further adds to the
delays in diagnosis and treatment. TBM
must be considered a medical emergency
as with all forms of brain infections, and
clinicians need to appreciate the import-
ance of early treatment.
CURRENT TREATMENT
Anti-TB chemotherapy should be started as
soon as possible in all patients with
suspected TBM without waiting for the
microbiological confirmation. The optimal
treatment for TBM has not been definitely
established. It is recommended by WHO
that patients with drug sensitive TBM
should receive anti-TB treatment for 9–12
months with the combination of four drugs
(rifampicin, isoniazid, pyrazinamide and
streptomycin) for the intensive phase, and
two drugs (rifampicin, isoniazid) for the
continuation phase.6 The British Infection
Society guideline recommends 12 months
of anti-TB drugs for TBM.7 A recent study
assessed the use of high dose intravenous
rifampicin (600 mg, approximately 13 mg/
kg), and either oral moxifloxacin 400 mg,
moxifloxacin 800 mg or ethambutol
750 mg for 2 weeks compared with stand-
ard therapy. Sixty patients were randomised
and the investigators reported a reduction
in mortality from 65% to 35% in the inten-
sive treatment group.8 The results from this
combined clinical and pharmacological
study could be of huge importance in redu-
cing the mortality in TBM. The results of
an ongoing large randomised clinical trial
of high dose rifampicin 15 mg/kg/day and
levofloxacin 20 mg/kg/day in 750 patients is
eagerly awaited (ISRCTN61649292).9
Adjunctive corticosteroids (dexametha-
sone) are recommended for all patients
with TBM regardless of the severity of
1
 Editorial
disease. Corticosteroids are believed to
reduce the intracranial inflammatory
response leading to improved outcome,
and two pivotal trials in Vietnamese
adults and in South African children
showed that it saves lives.4 10
In HIV-infected adults with TBM, dexa-
methasone has not been demonstrated to
reduce the risk of death. However, it is
recommended that they are used as there is
a non-significant trend for a reduction in
mortality rates and no evidence of an
increase in adverse events with corticoster-
oid. In HIV-positive ARV naïve patients,
concurrent management of the HIV infec-
tion and TB is a huge challenge due to
pharmacological interactions between the
HIV and the TB drugs and the potential for
worsening of the clinical status caused by
an Immune Reconstitution Syndrome.
There is no evidence supporting the imme-
diate initiation of ARV in patients present-
ing with TBM. A trial in HIV co-infected
patients with pulmonary TB demonstrates
that starting ART 2 weeks after starting TB
treatment improves survival, comparing
with starting after 8 weeks.11 However, the
evidence in TBM found that immediate
ARV treatment did not improve the
outcome but was associated with increase
in severe adverse events,12 and starting
ARV tends to be deferred until the TB treat-
ment has been initiated and the patients are
stable on their TB drugs. The optimal time
for initiation of ARV has not been defined,
and there are different recommendations
between international guidelines on when
to start ARV in patients with TBM.
FUTURE RESEARCH+CHALLENGES
There is an urgent need to develop and
implement sensitive and specific diagnostic
tests that can improve the early diagnosis of
TBM. The GenXpert MTB/RIF (Cepheid,
Sunnyvale, USA) has recently been assessed
and introduced in many parts of the world. It
is a rapid test for detecting Mycobacterium
tuberculosis and rifampicin resistance, and is
the first diagnostic test to have been endorsed
by the WHO. This is a very promising test
for early TB diagnosis and can produce
results in approximately 2 h, compared with
approximately 2 months for culture by trad-
itional methods. However, this method is cur-
rently recommended by WHO for sputum
samples, and not yet for extrapulmonary spe-
cimens. If this test can be proven to work in
TBM it could revolutionise the management
of TBM. This is an absolute priority.
The other priorities for the future are
continued education of clinicians to
encourage earlier consideration of a diag-
nosis of TBM, improving near bedside
diagnostics and faster laboratory
2 Van TTT, et al. J Epidemiol Community Health Month 2013 Vol 0 No 0
confirmation of resistance patterns, and
the clinical trials involving the reassessing
of existing treatment regimens and devel-
opment of new anti-TB drugs with
improved penetration into CSF.
The BCG vaccine was demonstrated to
protect against TBM, particularly in children,
and has been used widely for more than
50 years.13 BCG is the only licensed vaccine
for TB and remains in use globally although
it is an imperfect vaccine. There is an urgent
need for an effective and affordable vaccine,
which can be used in all patients including
children and adults and in those individuals
who are immunocompromised. In the last
decade, there has been development of many
new vaccine candidates aimed at preventing
active TB or even to one day eradicating M
tuberculosis infection. In 2012, 12 potential
TB vaccines were in clinical trials. This is a
potentially wonderful pipeline however the
great challenges faced by vaccine developers
was highlighted with the recent results from
a Phase II trial in South Africa.14 Even in the
most optimistic scenario, a new vaccine is
unlikely to be available and implemented
before 2020.15 In the meantime, enhanced
case detection through enhanced screening,
improved diagnostics and better treatment
remain our most potent weapons against TB,
including TBM.
CONCLUSION
TB meningitis is an ancient scourge,
which remains a major public health chal-
lenge in the 21st century. Diagnostics has
remained largely unchanged for 100 years
and treatment is based on extrapolations
from pulmonary TB drugs assessed in
studies almost 50 years ago. Saving lives
and reducing disability in patients with
TBM requires continued education of
clinicians to consider the diagnosis earlier,
enhancing diagnostics and improving
treatment. We can make a real difference
today by implementing what we already
know. Further improvements will depend
on challenging existing dogma on treat-
ment and development of new drugs with
greater activity against MTB and better
penetration into the CSF. We are in an
extraordinary scientific age with new tech-
nologies opening up exciting possibilities
for saving lives. TB remains of the great
global challenges. We need to ensure we
move these advances into the clinic as
quickly as possible, establish an evidence
base for their utility and do not allow
unnecessary regulations to delay their
assessment and implementation.
Contributors JF had the idea, TTTV wrote the first
draft, both authors contributed to the editing.
Competing interests None.
Provenance and peer review Commissioned;
externally peer reviewed.
To cite Van TTT, Farrar J. J Epidemiol Community
Health Published Online First: [ please include Day
Month Year] doi:10.1136/jech-2013-202525
Received 18 February 2013
Revised 9 October 2013
Accepted 9 October 2013
J Epidemiol Community Health 2013;0:1–2.
doi:10.1136/jech-2013-202525
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