JECH Online First, published on November 13, 2013 as 10.

1136/jech-2013-202525
Editorial

Tuberculous meningitis characteristic features of pulmonary TB

are present. Brain imaging, with CT or
MRI, may help in suggesting a diagnosis
Thinh Tran Thi Van,1 Jeremy Farrar1,2,3 of TBM with hydrocephalus, tubercu-
loma, basilar meningeal enhancement and
basal ganglial infarction, all suggestive but
BURDEN OF DISEASE treatment regimens and impact of vaccin- not specific for TBM. A prior history of
Tuberculosis (TB) is one of the most ation require further research if the TB or known close contacts with patients
important infectious diseases and one of unacceptably high mortality and morbid- with TB should be ascertained in the
ten most common causes of death glo- ity is to be reduced. history in all patients.
bally,1 with almost 10 million new cases
per year and 1.5 million deaths (WHO CLINICAL PICTURE IMPACT ON THE PATIENTS
report 2011).2 It is estimated that a third TBM has been traditionally characterised Early diagnosis of TBM plays a crucial
of the world’s population is infected with as a subacute or chronic infection. role in saving lives and reducing disability
TB of whom approximately 10% will However, it can develop and progress in because the prognosis is dependent on the
develop clinically apparent disease. TB is less than a week from onset of the first patient’s severity at the time that effective
also in the top 15 of causes of disease symptoms. In countries with a high antibiotics and steroids are started. Sadly
burden worldwide in the rank of burden of TB, the diagnosis of TBM in practice, many patients are initially
disability-adjusted life years.3 The WHO should be considered in all patients pre- treated for pyogenic meningitis and when
estimates that five countries India, China, senting with meningitis. Early diagnosis not improving, the diagnosis of TBM is
South Africa, Indonesia and Pakistan and initiation of effective drugs saves lives considered, often after many days. This
account for over 70% of the global and reduces long-term disability. The clin- then may involve a transfer to a tertiary
burden of disease.2 Southern and eastern ical symptoms of TBM are broad and can medical centre, which further adds to the
sub-Saharan Africa is the most affected be analogous to other forms of meningo- delays in diagnosis and treatment. TBM
region by the HIV/AIDS-TB combin- encephalitis. This leads to delays in estab- must be considered a medical emergency
ation.3 But the reality is that in all low- lishing a diagnosis. Coinfection with HIV as with all forms of brain infections, and
income and middle-income countries and does not change the neurological presen- clinicians need to appreciate the import-
increasingly in high-income countries, TB tation of TBM5 even though in indivi- ance of early treatment.
remains a major public health problem. duals coinfected with HIV there is a
Tuberculous meningitis (TBM) is the greater range of other potential diagnoses CURRENT TREATMENT
most severe form of TB with a high mor- from opportunistic diseases than in Anti-TB chemotherapy should be started as
tality and many of the survivors are left patients who are not coinfected with HIV. soon as possible in all patients with
with chronic neurological sequelae, which Moreover, in many countries access to suspected TBM without waiting for the
affect their daily lives and those of their healthcare for HIV-positive individuals microbiological confirmation. The optimal
family and community. The impact of this remains less good than HIV-negative indi- treatment for TBM has not been definitely
disease is even more severe in those coin- viduals and this can lead to delays in established. It is recommended by WHO
fected with HIV. Patients coinfected with health-seeking behaviour. Patients with that patients with drug sensitive TBM
HIV are at more than 20 times higher risk and without HIV present with fever, should receive anti-TB treatment for 9–12
of developing TB, compared with non- altered mental status, meningism and months with the combination of four drugs
infected individuals.2 In a recent studies focal neurological signs, particularly (rifampicin, isoniazid, pyrazinamide and
from Vietnam, the mortality rate in the cranial nerve lesions and hemiparesis are streptomycin) for the intensive phase, and
1st year following diagnosis of TBM in common. The characteristic cerebrospinal two drugs (rifampicin, isoniazid) for the
HIV and non-HIV infected adult patients fluid (CSF) features in TBM are straw col- continuation phase.6 The British Infection
was approximately 65% and 30%, oured CSF, leucocytosis with a predomin- Society guideline recommends 12 months
respectively, and over 50% of survivors ant lymphocytosis, low CSF:blood of anti-TB drugs for TBM.7 A recent study
suffer from long-term disability.4 In coun- glucose ratio, moderately raised lactate assessed the use of high dose intravenous
tries with the greatest burden of TB, TBM and increased protein level. However, par- rifampicin (600 mg, approximately 13 mg/
is most commonly seen in children while ticularly in those who present early, kg), and either oral moxifloxacin 400 mg,
in lower TB transmission settings, most within 7 days, and in those who are moxifloxacin 800 mg or ethambutol
cases of TBM occur in adults. It is now HIV-positive with low CD4 counts, the 750 mg for 2 weeks compared with stand-
the third most common cause of bacterial CSF may show a polymorphonuclear ard therapy. Sixty patients were randomised
meningitis in the UK. Several aspects of leucocytosis and the CSF glucose can be and the investigators reported a reduction
TBM including the underlying immuno- normal or only very slightly reduced on in mortality from 65% to 35% in the inten-
pathogenesis, the availability of sensitive admission. In these patients, the diagnosis sive treatment group.8 The results from this
and specific diagnostic tests, optimal can be extremely difficult and consider- combined clinical and pharmacological
ation should be given to treating with study could be of huge importance in redu-
1
Oxford University Clinical Research Unit, Hospital for broad-spectrum antibiotics and to repeat- cing the mortality in TBM. The results of
Tropical Diseases, Ho Chi Minh City, Vietnam; 2Centre ing the CSF investigation if the patient an ongoing large randomised clinical trial
for Tropical Medicine, University of Oxford, Churchill does not improve within 48–72 h. The of high dose rifampicin 15 mg/kg/day and
Hospital, Oxford, UK; 3Singapore Infectious Disease insensitive ZN test for acid-fast bacilli in levofloxacin 20 mg/kg/day in 750 patients is
Initiative, Singapore
the CSF and the time for mycobacterial eagerly awaited (ISRCTN61649292).9
Correspondence to Professor Jeremy Farrar, Oxford
University Clinical Research Unit, Hospital for Tropical
culture add to the difficultly in establish- Adjunctive corticosteroids (dexametha-
Diseases, Ho Chi Minh City Quan 5, Vietnam; ing a diagnosis. A chest X-ray can help in sone) are recommended for all patients
jfarrar@oucru.org the diagnosis if miliary TB is seen or the with TBM regardless of the severity of

VanCopyright Article
TTT, et al. J Epidemiol author
Community (orMonth
Health their employer)
2013 Vol 0 No 0 2013. Produced by BMJ Publishing Group Ltd under licence. 1
 Editorial

disease. Corticosteroids are believed to confirmation of resistance patterns, and Provenance and peer review Commissioned;
reduce the intracranial inflammatory the clinical trials involving the reassessing externally peer reviewed.
response leading to improved outcome, of existing treatment regimens and devel- To cite Van TTT, Farrar J. J Epidemiol Community
and two pivotal trials in Vietnamese opment of new anti-TB drugs with Health Published Online First: [ please include Day
Month Year] doi:10.1136/jech-2013-202525
adults and in South African children improved penetration into CSF.
showed that it saves lives.4 10 The BCG vaccine was demonstrated to Received 18 February 2013
Revised 9 October 2013
In HIV-infected adults with TBM, dexa- protect against TBM, particularly in children, Accepted 9 October 2013
methasone has not been demonstrated to and has been used widely for more than
J Epidemiol Community Health 2013;0:1–2.
reduce the risk of death. However, it is 50 years.13 BCG is the only licensed vaccine doi:10.1136/jech-2013-202525
recommended that they are used as there is for TB and remains in use globally although
a non-significant trend for a reduction in it is an imperfect vaccine. There is an urgent
mortality rates and no evidence of an need for an effective and affordable vaccine,
increase in adverse events with corticoster- which can be used in all patients including REFERENCES
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2 Van TTT, et al. J Epidemiol Community Health Month 2013 Vol 0 No 0