REVIEWS

INFECTIONS OF THE CNS

Tuberculous meningitis
Robert J. Wilkinson1–3, Ursula Rohlwink4, Usha Kant Misra5, Reinout van Crevel6,
Nguyen Thi Hoang Mai7, Kelly E. Dooley8, Maxine Caws9, Anthony Figaji4, Rada Savic10,
Regan Solomons11 and Guy E. Thwaites7,12 on behalf of the Tuberculous Meningitis
International Research Consortium
Abstract | Tuberculosis remains a global health problem, with an estimated 10.4 million cases and
1.8 million deaths resulting from the disease in 2015. The most lethal and disabling form of
tuberculosis is tuberculous meningitis (TBM), for which more than 100,000 new cases are
estimated to occur per year. In patients who are co-infected with HIV‑1, TBM has a mortality
approaching 50%. Study of TBM pathogenesis is hampered by a lack of experimental models that
recapitulate all the features of the human disease. Diagnosis of TBM is often delayed by the
insensitive and lengthy culture technique required for disease confirmation. Antibiotic regimens
for TBM are based on those used to treat pulmonary tuberculosis, which probably results in
suboptimal drug levels in the cerebrospinal fluid, owing to poor blood–brain barrier penetrance.
The role of adjunctive anti-inflammatory, host-directed therapies — including corticosteroids,
aspirin and thalidomide — has not been extensively explored. To address this deficit, two expert
meetings were held in 2009 and 2015 to share findings and define research priorities. This Review
summarizes historical and current research into TBM and identifies important gaps in our
knowledge. We will discuss advances in the understanding of inflammation in TBM and its potential
modulation; vascular and hypoxia-mediated tissue injury; the role of intensified antibiotic
treatment; and the importance of rapid and accurate diagnostics and supportive care in TBM.

Extrapulmonary

Tuberculosis occurring outside
the lungs.
7
Oxford University Clinical
Research Unit,
764 Vo Van Kiet, Quan 5,
Ho Chi Minh City, Vietnam.
gthwaites@oucru.org
doi:10.1038/nrneurol.2017.120
Published online 8 Sep 2017
The absolute incidence of tuberculous meningitis
(TBM) and the overall proportion of meningitis cases
that are attributable to TBM vary greatly by location,
and are influenced by the overall incidence of tubercu‑
losis, age structure, and HIV‑1 seroprevalence within a
popu­lation. Population-based estimates of TBM inci‑
dence are infrequently reported, and are challenging to
determine because the diagnosis of TBM is often not
microbiologically confirmed. In 2013, a 7‑year national
study conducted in Germany documented that 422 of
46,349 (0.9%) patients with tuberculosis had meningitis,
with an increased risk of TBM in children younger than
5 years of age (OR 4.90)1. This predisposition towards
TBM in young children is commonly reported2,3. In 2015,
an estimated 10.4 million cases of tuberculosis occurred
­globally, and of 6.1 million incident cases reported, 15%
were extrapulmonary4. A large Brazilian study of 57,217
cases of extrapulmonary tuberculosis estimated that
meningitis accounted for 6% of extrapulmonary pres‑
entations5. A diagnosis of TBM is difficult to ascertain,
so the disease might be underreported, but extrapolation
suggests that the global burden of TBM could be at least
100,000 cases per year. A systematic review of treat‑
ment outcomes in 1,636 children with TBM estimated
a mortality of 19.3%, suggesting that several thousand
very young children die of TBM every year6. The neona‑
tal Bacillus Calmette–Guérin (BCG) vaccine is thought
to be 73% effective in the prevention of TBM, and its use
is estimated to avert 30,000 childhood cases of the dis‑
ease annually3, consistent with the occurrence of around
100,000 cases of TBM per year overall.
In adults, the best-documented risk factor for TBM
is HIV‑1 co‑infection. Among HIV-infected individuals
who live in areas where tuberculosis is highly endemic,
the proportion of HIV‑1‑associated meningitis cases
attributable to Mycobacterium tuberculosis can exceed
50%7. In addition, in an autopsy study conducted in
Kenya, occult, undiagnosed TBM was found in 26%
of individuals with disseminated HIV-tuberculosis8.
Individuals with TBM and a HIV‑1 co‑infection have
a twofold to threefold increase in relative risk of death
from any cause9,10, with overall mortality around 40%,
even in those individuals prescribed antiretroviral ther‑
apy7,10. Drug-resistant TBM in people co‑infected with
HIV‑1 has a particularly poor prognosis, approaching
100% mortality11.
This Review capitalizes on knowledge shared in spe‑
cialist meetings held in 2009 and 2015 to summarize

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Key points
• Tuberculous meningitis (TBM) causes death and disability, with especially high rates of
poor outcomes in children and individuals with an HIV‑1 co‑infection
• Important risk factors for poor outcome are delayed diagnosis, delayed treatment,
advanced disease, and antitubercular drug resistance
• Intracerebral and spinal pathology in TBM is mediated by a dysregulated
inflammatory response that contributes to meningitis, tuberculoma formation,
arteritis, obstruction of cerebrospinal fluid (CSF) flow, and vascular complications
including stroke
• Diagnosis of TBM is insensitive and laborious; clinical scoring algorithms are
imperfect and few rigorous evaluations of diagnostics have been performed
• Multidrug antitubercular antibiotic therapy is the mainstay of treatment; however,
CSF penetration is probably a major limitation of these therapies, and evidence
supporting dosage and treatment combinations is weak
• The supportive management of TBM complications, which include hyponatraemia,
hydrocephalus, hypoxic brain damage and infarction, is poorly understood and
researched, but is vital to outcome
historical and current research into TBM, and identifies
key gaps in our comprehension of the disease. We will
discuss current progress in our understanding of inflam‑
mation in TBM and its potential modulation; vascular
Miliary and hypoxia-mediated tissue injury; the role of intensi‑
Disseminated micronodular
tuberculosis of the lungs.
fied antibiotic treatment; and the importance of rapid
and accurate diagnostics and supportive care in TBM.
Rich focus
The initial intracranial lesion of Pathogenesis
tuberculous meningitis, as
Macroscopic pathology. Transmission of M. tubercu-
described by Arnold Rich.
losis is airborne and, consequently, the first focus of
Tuberculoma infection is the lung. Following initial bacterial replica‑
A clinical manifestation of tion, the infection disseminates to the lymph nodes. For
tuberculosis in which tubercles
miliary and extrapulmonary presentations of the disease,
comglomerate into a firm
lump, and so can mimic cancer
dissemination of tuberculosis bacilli must then occur
tumours of many types in through the blood, either via direct extension of local
medical imaging studies. infection or via lymph nodes. In the 1930s and 1940s, Rich
Author addresses
1
Department of Medicine, Imperial College London, Norfolk Place, London W2 1PG, UK.
2
The Francis Crick Institute, Midland Road, London NW1 2AT, UK.
3
Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious
Disease and Molecular Medicine and Department of Medicine, University of
Cape Town, Republic of South Africa.
4
Division of Neurosurgery, University of Cape Town, Anzio Road, Observatory 7925,
Republic of South Africa.
5
Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences,
Rae Bareli Road, Lucknow, Uttar Pradesh 226014, India.
6
Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen,
The Netherlands.
7
Oxford University Clinical Research Unit, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City,
Vietnam.
8
Johns Hopkins University School of Medicine, The Johns Hopkins Hospital,
1800 Orleans Street, Baltimore, Maryland 21287, USA.
9
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
10
UCSF School of Pharmacy, Department, Bioengineering, 1700 4th Street,
San Francisco, California 94158, UA.
11
Faculty of Health Sciences, Stellenbosch University, Tygerberg Hospital,
Francie van Zijl Drive, Tygerberg 7505, Cape Town, Republic of South Africa.
12
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine,
University of Oxford, Old Road, Oxford OX3 9FZ, UK.
and McCordock produced what are now regarded as the
definitive accounts of the extension of tuberculosis infec‑
tion to the meninges12. They showed that although TBM
might occur as part of disseminated disease, only a single
meningeal or parameningeal granuloma (now termed
the Rich focus) was usually found at autopsy and, thus, the
point of entry of bacilli into the cerebrospinal fluid (CSF)
could be located. Rupture of that focus was postulated to
lead to further extension of inflammation throughout the
meninges, leading to parenchymal t­ uberculoma formation
or to vascular pathology characteristic of the disease.
Ischaemia caused by vascular occlusion owing to inflam‑
mation both within and around vessels is compounded
by raised intracranial pressure and hydrocephalus (espe‑
cially in children, in whom hydrocephalus is nearly invari­
able13), which can, in turn, c­ ompress or cause traction on
already inflamed vessels (FIG. 1).
Historically, the most widely used animal model
of TBM consisted of rabbits infected via intracisternal
inoculation of M. tuberculosis, resulting in histologi‑
cal, pathological and neurological features consistent
with TBM14. However, haematogenous spread cannot
be investigated in this experimental setting and, thus, a
detailed understanding of pathogenesis — which should
include CNS invasion — cannot be achieved using this
model. Zebrafish have also been used to model TBM:
Mycobacterium marinum infection of zebrafish via the
bloodstream resulted in infection of the CNS and devel‑
opment of associated granulomas in 70% of the fish, with
CNS granulomas typically located in close proximity to
blood vessels15. Infection with a mutant M. marinum
lacking the homologue of EsxA, a gene associated with
M. tuberculosis virulence, resulted in substantial changes
in pathology without affecting the ability of the bacte‑
ria to penetrate the blood–brain barrier. High bacterial
loads were observed, but no granulomas developed,
and only small clusters and scattered isolated phago‑
cytes were detected, indicating that EsxA contributes to
pathogenesis in this system.
In the context of disseminated childhood tuberculo‑
sis, the concept of the Rich focus has been re-evaluated16.
Specifically, although TBM can occur when a long-­
standing Rich focus bursts and discharges its contents
into the subarachnoid space, TBM commonly manifests
in the setting of concurrent disseminated infection in
children. TBM associated with HIV‑1 co‑infection also
has distinct pathophysiological features. In 1992, a study
observed that extrapulmonary tuberculosis — and, in
particular, TBM — occurred with greater frequency
in people with tuberculosis who were co‑infected with
HIV‑1 (REF. 17). HIV‑1 co‑infection is associated with an
increased occurrence of occult meningeal disease8 and
additional extrapulmonary tuberculosis9. A positive
M. tuberculosis blood culture was found in up to 40%
patients with newly diagnosed tuberculosis who had
an HIV‑1 co‑infection and severe immunosuppression18.
HIV‑1 infection could, therefore, predispose individuals
to more frequent or multiple seeding of the meninges by
bacilli. Outcome is consistently poor in drug-resistant
patients with TBM who have an HIV‑1 co-infection19,20.
However, the macro­scopic pathology in these individuals

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Basal exudates
An inflammatory reaction to
tuberculosis in the basal
cisterns of the brain.
Paradoxical worsening
The worsening of a tuberculosis
lesion during otherwise
effective antirtubercular or
antiretroviral therapy.
seems similar to that found in people without an HIV‑1
infection. HIV‑1 co‑infected patients can also experience
TBM-associated immune reconstitution inflammatory
syndrome (TBM-IRIS), which comprises exaggerated
inflammation in response to M. tuberculosis. In these
circumstances, the introduction of antiretroviral ther‑
apy after antituberculous chemotherapy is associated
with the ‘unmasking’ of occult meningeal disease or with
worsening of existing TBM. Inflammatory reactions in
this context can be intense, although their distribution
and features again do not markedly differ from those
described in people without an HIV‑1 infection19,21.
Immune and metabolic factors. Bacterial replication
must occur in the CNS for TBM pathogenesis to pro‑
ceed. However, the bacillary load in the CSF rarely
exceeds 100–1000 bacterial colonies per millilitre, and
viable bacilli are difficult to detect in the majority of
individuals. Early studies in experimental animal m­ odels
showed that the meningitis syndrome and even death
of tuberculin-sensitized animals could be induced by
meningeal inoculation with dead bacilli22. Much of the
tissue damage, therefore, is attributed to a dysregulated
host inflammatory response.
Once bacilli have traversed the blood–brain barrier,
they are taken up by microglia and can also replicate
in these cells, leading to the induction of microglial
cytokine and chemokine production23. Conditioned
media from broth cultures of macrophages infected
with M. tuberculosis induced activation of the NLRP3
(NACHT, LRR and PYD domains-containing protein 3)
inflammasome — composed of NLRP3, apoptosis-
associated speck-like protein and caspase‑1 — in cultured
mouse microglial cells. Furthermore, dexamethasone,
a corticosteroid used as an adjunctive therapy to reduce
inflammation in patients with TBM, decreased inflam‑
masome activation in this culture model through inhib­
ition of reactive oxygen species of mitochondrial origin24.
Elevated levels of reactive oxygen species and malondial‑
dehyde have been suggested to mediate tissue damage in
childhood meningitis25, similarly suggesting that reactive
oxygen could contribute to pathology in TBM.
An 1H-NMR study found an association between
decreased CSF levels of glucose and other energy-
related metabolites and elevated CSF levels of lactate in
TBM26. In addition, low levels of glucose and high levels
of lactate in the CSF were associated with death in an
independent study of prognosis in adults with TBM in
Vietnam27. A 2016 study found a relationship between
hyponatraemia and the presence of basal exudates ,
implicating pituitary involvement in hyponatraemia28.
Indeed, in a systematic investigation of pituitary dys‑
function in TBM that included MRI, 13.3% of 75 cases
had evidence of pituitary abnormality, 42.7% had rela‑
tive or absolute cortisol insufficiency, 30.7% had central
hypothyroidism, and 49.3% had hyperprolactinaemia29.
The occurrence of cortisol deficiency in TBM is
noteworthy given that synthetic corticosteroids are the
best-established adjunctive therapy for this condition.
The beneficial effect of these agents might be partially
metabolic, although most attention has been directed
to the anti-inflammatory effects of these therapies. In
tissue culture, treatment with dexamethasone mark‑
edly suppresses production of cytokines by microglia
and astrocytes30. However, in a clinical trial, although
dexamethasone significantly reduced total protein con‑
centrations in the CSF and marginally reduced CSF
concentrations of IFNγ in patients with TBM, other
cytokines were unaffected31. In a follow‑up study, CSF
concentrations of IL‑6 at presentation of TBM were
independently associated with severe TBM, but elevated
CSF levels of inflammatory cytokines were not associ‑
ated with death or disability in HIV‑1-negative patients
with TBM32. Low CSF concentrations of IFNγ were inde‑
pendently associated with death in HIV‑1 co‑infected
patients with TBM, indicating that IFNγ contributes to
immunity and survival.
Levels of tumour necrosis factor (TNF) correlate with
the extent of pathology in the rabbit model of TBM, and
treatment of this model with antibiotics or thalidomide
(which decreases TNF levels) protects against death33,34.
In children with TBM, CSF levels of TNF and IL‑1β are
elevated35, but no correlation is observed between CSF
levels of TNF and disease stage or response to corti­
costeroid therapy36, and another study reported that
thalidomide therapy was not associated with decreased
mortality37. Yadav and colleagues reported a positive
correlation between CSF levels of proinflammatory
cytokines — including IL‑1β and TNF — and MRI find‑
ings, and fractional anisotropy values and post-contrast
signal intensity collected from cerebral cortical regions
in patients with TBM38. In a small study, levels of IL‑6,
IL‑10, IL‑1β and IL‑8 were found to be elevated in the
CSF of patients with TBM and declined after 3 months
of treatment39. The cytokine levels did not correlate with
stage of meningitis or clinical or radiological outcome,
suggesting that these cytokines cannot be used to infer
severity or predict outcome.
Studies of TBM-IRIS provide further insight into
inflammatory pathology in HIV-associated TBM.
Worsening inflammation in TBM-IRIS is associated
with high CSF neutrophil counts and M. tuberculosis cul‑
ture positivity at TBM presentation40. Multiple cytokines
are elevated in the CSF compared with the blood, but
CSF levels of the neutrophil mediator S100A8/A9 are
most closely associated with clinical deterioration41.
In an unbiased whole-genome analysis of peripheral
blood transcriptomic response, patients with TBM-IRIS
exhibited a substantially increased number of transcripts
associated with canonical and noncanonical inflammas‑
omes after early antiretroviral treatment, compared with
non-IRIS controls. This difference suggests a dominant
role for the innate immune system in the pathogenesis
of TBM-IRIS42. In addition, paradoxical worsening of
TBM after treatment occurs in patients without an HIV
infection who have drug-sensitive TBM. In a study of
34 patients with definite TBM at the time of first treat‑
ment who were followed‑up with cranial MRI at 3 and
6 months after treatment initiation, paradoxical worsen‑
ing was observed in 22 individuals (64.7%), more than
half of whom remained clinically asymptomatic, which
suggests that clinically silent radiographic deterioration

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a Blood
e
Bacteria
Neutrophil
Lymphocyte
Monocyte
Tight
junctions

Basement Endothelial
membrane cells

Astrocyte
Brain Microglial cell

b Uninfected
cells

Diapedesis
of infected
cells
f
Cytokines
Infected
microglial cell

Disrupted
endothelium
and basement
membrane
Diapedesis
of uninfected
cells
Development of
a rich focus with g
a cuff on innate
and specific
B cells and T cells

Cytokines

d Arachnoid mater

White
matter

Grey
matter
CSF
Pia mater
Rupture focus with
spread of infection to
meninges and CSF

Nature Reviews | Neurology

is common43. Furthermore, in a study conducted in
Vietnam, tuberculomas developed in 74% of patients
with TBM during treatment; these tuberculomas were
associated with long-term fever, but not with relapse or
poor clinical outcome44.
These studies suggest that the induction of inflam‑
masomes and activation of an innate cytokine response
leading to influx of phagocytes are key processes in the
pathogenesis of TBM. Nevertheless, an acquired type 1
T-helper cell response to M. tuberculosis antigens, char‑
acterized by IFNγ secretion, occurs in the CSF during
TBM, as documented by studies aimed primarily at
finding diagnostic markers for TBM32,45. Most such diag‑
nostic assays are optimized to detect terminally differ‑
entiated CD4+ T cells, despite the fact that CD8+ T cells
with T-effector memory and terminally differentiated

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◀ Figure 1 | Pathogenesis of tuberculous meningitis. a | Bacilli could reach brain blood
capillaries within cells or as extracellular bacilli; the precise mechanism is unknown.
b | The endothelium itself can be infected, or infected cells can adhere and undergo
diapedesis. Both processes result in breakdown of tight endothelial junctions and the
basement membrane. c | Microglial cells can become infected, and these cells, together
with infiltrating cells, produce inflammatory chemoattractants that result in further
breakdown of the blood–brain barrier and influx of uninfected cells, including innate and
specific T and B lymphocytes. d | The nascent granuloma might rupture via necrosis,
leading to meningeal and intracerebral dissemination of infection. e | Confocal
microscopy of a lymph node from an individual infected with HIV‑1, showing localization
of Mycobacterium tuberculosis (green) in or near endothelial cells and in infected cells
(nucleus blue) within a blood vessel (lining red). f | Consequences of meningeal
dissemination of infection. Endoscopic third ventriculostomy in a child illustrates the
cistern of the subarachnoid space beneath the third ventricle, showing no visible normal
anatomy, with the basilar artery, perforators and brainstem covered by tuberculous
exudate. g | T1 contrast MRI, showing multiple parenchymal granulomas in the basal
ganglia and cortex — one of the consequences of intracerebral dissemination. CSF,
cerebrospinal fluid. Part e republished with permission of American Society for Clinical
Investigation, from Lerner, T. R. et al. Lymphatic endothelial cells are a replicative niche
for Mycobacterium tuberculosis J. Clin. Invest. 126, 1093–1108 (2016). Permission
conveyed through Copyright Clearance Center, Inc.
phenotypes46, as well as mycobacterial antigen-reactive
Vγ9–Vδ2 T cells that secrete interferon and TNF, are
also found in the CSF of patients with TBM47. A relation‑
ship between high levels of IFNγ and the formation of
intracerebral tuberculomas has been suggested48. C‑X‑C
motif chemokine  10 (also known as 10 kDa IFNγ-
induced protein, or IP‑10) and C‑X‑C motif chemo­
kine 9 (also known as monokine induced by IFNγ, or
MIG) are compartmentalized at the site of disease and
decrease after treatment49. However, substantial immune
activation and blood–brain barrier abnormalities are still
apparent after 60 days of treatment27.
Although cytokines can mediate inflammatory
­reactions, these molecules do not directly cause tissue
damage. Proteolytic matrix metalloproteinases (MMP)
have attracted interest as potential mediators of this
damage. The kinetics of CSF MMPs and their endoge‑
nous tissue inhibitors were studied in 37 HIV-uninfected
adults with TBM in Vietnam who were recruited to a ran‑
domized controlled trial of adjuvant dexamethasone50.
This therapy resulted in a substantially reduced CSF
concentration of MMP‑9 after 5 days of follow‑up. The
MMP‑9 concentration correlated with the CSF neutro­phil
count. Paradoxically, suppression of microglial secretion
of 72 kDa type IV collagenase (also known as MMP‑2)
by signalling pathways activated by tuberculosis-­infected
monocytes involves the proinflammatory mediators TNF,
MAP kinase 14 and nuclear factor‑κB, in addition to a
novel caspase-8‑dependent pathway51.
Evidence also indicates a contribution from growth
factors — particularly those involved in angiogenesis
— in the vascular pathology observed in TBM. A study
of serum and CSF from 56 children with and 55 chil‑
dren without TBM found that increased levels of
vascular endothelial growth factor (VEGF) were char‑
acteristic of TBM52. In a study examining patients with
meningitis in Japan, serum and CSF levels of VEGF
were substantially higher in TBM than in other forms
of meningitis. Decreases in CSF levels of VEGF paral­
leled clinical improvement in patients with TBM53.
Immunohistochemical staining of brain tissue from
patients who had TBM demonstrated the presence of
VEGF in the inflammatory mononuclear cells of the
dense fibroconnective tissue in the subarachnoid space
and surrounding vasculitic lesions. In addition, CSF
levels of VEGF were found to be associated with the
presence of TBM and MRI evidence of infarction, but
not with death54. Furthermore, CSF levels of hepatocyte
growth factor (HGF) are higher in patients with TBM
than in those with bacterial meningitis, suggesting that
other growth factors contribute to pathogenesis55.
Bacillary and host genetic factors. M. tuberculosis can
be divided into seven lineages classified as ‘ancient’ (lin­
eages 1, 5, 6 and 7) or ‘modern’ (lineages 2, 3 and 4)56.
One hypothesis is that some lineages might more fre‑
quently cause or affect the severity of meningeal infec‑
tion. In children with TBM in China, lineage 2 was twice
as common as other prevalent lineages2, and in Vietnam,
the Thr597Cys polymorphism in the Toll-like receptor 2
(TLR2) gene was associated with a slightly elevated risk
of tuberculosis caused by lineage 2 strains57. In a sub‑
group of 122 patients in Vietnam who were co‑infected
with HIV‑1 and TBM, patients infected with lineage 2
strains had lower mortality than those infected with
lineage 1 strains11. However, in Thailand, no differences
in mortality were found between lineages 1, 3 and 4
among 184 patients with CSF isolates of M. tuberculo-
sis58. In children living in Cape Town, South Africa, lin‑
eages 2 and 4 showed comparable propensity to cause
extra­pulmonary disease in general, and TBM in par‑
ticular59. In children with tuberculosis in China, a single
nucleotide polymorphism in the PE_PGRS33 gene of
M. tuberculosis was associated with an increased risk
of developing TBM, suggesting that even minor bacillary
variation can influence pathogenesis60.
Many immune response genes are under poly­
morphic genetic influence. Several studies conducted
over the past 10 years indicate that polymorphisms
in host response genes (such as TLR9, SIGIRR, SPN,
TIRAP, TLR2 and MRC1) can influence the immune
response and, thus, predispose an individual to TBM
(TABLE 1). Consistent with data from cytokine studies,
many of the reports document that polymorphism in
innate immune response receptors or signalling path‑
ways influences the susceptibility of an individual to
TBM itself, or the form in which it manifests. A strik‑
ing example is a single nucleotide polymorphism in the
leukotriene A4 hydrolase (LTA4H) promoter, which
alters the transcriptional activity of this gene and, thus,
influences the balance between proinflammatory leuko­
triene B4 and immuno­suppressive lipoxin A4. In TBM,
this polymorphism is associated with inflammatory cell
recruitment, patient survival and response to adjunctive
anti-inflammatory therapy61.
These intriguing findings, which introduce the pos‑
sibility of personalised anti-inflammatory TBM treat‑
ment, were replicated in a cohort of adults with TBM
in Vietnam62. All participants received corticosteroids in
accordance with current clinical guidelines. The LTA4H
genotype influenced the pretreatment intracerebral

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Table 1 | Genetic polymorphisms associated with TBM

Gene Function Location Polymorphisms Association Refs
SPN Surface glycoprotein (CD43) Vietnam rs17842268 rs17842268 associated with decreased 171
involved in Mycobacterium rs12596308 survival from TBM. Both polymorphisms
tuberculosis adhesion and associated with focal neurological deficit at
proinflammatory cytokine TBM presentation
induction
MBL2 Lectin involved in recognition South Africa Gly54Asp allele Protection from TBM 172
and uptake of M. tuberculosis
TLR2 Innate pattern recognition India Arg753Gln and No association 173
receptor Pro631His
China rs3804099 (597T>C) Associated with pulmonary tuberculosis but 174
not meningitis
Vietnam rs3804099 (597T>C) Associated with TBM caused by lineage 2 57,175
strains
TLR9 Innate pattern recognition Vietnam rs352142 TBM rather than PTB 176
receptor
TIRAP Toll adaptor protein Vietnam and 558C>T allele Associated with TBM 177,178
South Africa
PKP3–SIGIRR–ANO9 Negative regulator of Toll-like Vietnam rs10902158 TBM and PTB 179
gene region receptor/IL‑1R signalling rs7105848
rs7111432
VDR Vitamin D receptor India ApaI and TaqI Heterozygous (TC) and mutant (CC) 173
restriction sites genotypes of Taq1 VDR SNP significantly
associated with TBM
LTA4H Leucotriene A4 hydrolase Vietnam rs17525495 High (TT) and low (CC) inflammatory 61
homozygous forms associated with death
from TBM; dexamethasone protects from
death in TT but not CC genotype
Indonesia rs17525495 No significant association with CSF 63
leukocytes or patient survival
CCL2 Chemokine China rs4586 C/T TT genotype associated with lower CSF 180
mononuclear leukocyte counts in TBM
PTB, pulmonary tuberculosis; SNP, single nucleotide polymorphism; TBM, tuberculous meningitis.

inflammatory phenotype and was independently associ‑
ated with survival in 446 individuals with TBM who did
not have an HIV infection. By contrast, LTA4H geno­type
did not influence the inflammatory phenotype or sur‑
vival in 326 adults with TBM and an HIV ­co‑infection,
with the possible exception of those with peripheral
blood CD4+ cell counts >150 × 106/μl.
In an Indonesian study, LTA4H genotype was not
associ­ated with survival in 427 HIV-negative patients with
TBM, all of whom received corticosteroids, and did not
influence patient survival in sensitivity analyses63. Thus,
uncertainty remains as to whether the LTA4H geno­type
determines TBM inflammatory pathophysiology in
all populations.
Clinical features
Effects of age and HIV‑1 co‑infection. TBM has a non‑
specific prodrome that gradually evolves to include
more-recognizable symptoms and signs of meningitis,
such as headache, fever, vomiting and neck stiffness64.
Without treatment, meningitic symptoms become pro‑
gressively more dominant, consciousness falls, and focal
neurological deficits occur, with cranial nerve palsies —
largely in the fifth and third cranial nerves — in around
50% of patients and limb weakness (either hemiplegia or
paraplegia) in around 10% of patients. Death is nearly
certain unless antitubercular treatment is provided.
The clinical features of TBM are influenced by the
immune response against M. tuberculosis. Very young
children (<1 year of age) and those with advanced HIV‑1
co‑infection are highly susceptible to M. tuberculosis,
which frequently leads to uncontrolled extrapulmonary
dissemination and meningitis. In these groups, the pres‑
entation of TBM can be abrupt, and can rapidly progress
to severe coma and prostration with high mortality;
furthermore, these individuals have an increased risk of
active tuberculosis in other organs9,65.
Age and HIV‑1 co‑infection also influence the lab‑
oratory features of TBM66. The CSF of individuals with
TBM typically has 150–1000 leukocytes per μl, with a
mixed population of neutrophils and lymphocytes
(although lymphocytes usually predominate), elevated
protein (0.8–2.0 g/dl), and CSF:plasma glucose ratios
of <0.5 in 90% of individuals. HIV‑1 co‑infection can
alter the CSF inflammatory profile, with either no
leukocytes present, or large numbers (>1000 cells per
μl) of n
­ eutrophils mimicking acute pyogenic bacterial
meningitis67.
The outcomes of TBM are better the earlier treat‑
ment is started. The Medical Research Council (MRC)

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Box 1 | The Medical Research Council tuberculous meningitis severity grade
In 1948, Medical Research Council investigators in the UK graded tuberculous
meningitis for the first trial of streptomycin as:
• Early — no clinical signs of meningitis or focal neurology and fully conscious
• Medium — patient’s condition falls between early and advanced
• Advanced — extremely ill, in a deep coma
With the introduction of the Glasgow Coma Scale (GCS) in 1974, this classification was
modified to:
• Grade I (GCS score 15; no focal neurological signs)
• Grade II (GCS score 11–14, or 15 with focal neurological signs)
• Grade III (GCS score ≤10)
50% of patients with TBM77. A normal magnetic reso‑
nance angiography result at disease p­ resentation strongly
predicts an infarct-free disease course78.
Spinal cord disease is common in people with TBM
and often goes undetected: one imaging study of chil‑
dren with TBM and hydrocephalus found that 76% had
spinal disease79. Definition of the full extent of the CNS
disease is important for treatment and prognosis in peo‑
ple with TBM, and the detection of extraneural disease
— for example, in the lymph nodes — could offer alter‑
native diagnostic sampling opportunities in those with
diagnostic uncertainty.

Ziehl–Neelsen staining
A technique to visualize
Mycobacterium tuberculosis
directly by microscopy in
pathological samples.
Paucibacillary
Disease associated with very
low numbers of bacteria in
clinical specimens.
disease severity grade remains the most widely used
method to define TBM disease severity68 (BOX 1), and
strongly predicts outcome6,69,70. The rate of death or
severe neurological disability in MRC grades I, II, and
III are approximately 15%, 30% and 50%, respectively,
in HIV-1-negative individuals, rising to 25%, 50%, and
80%, respectively, in people co‑infected with HIV‑1. The
widespread availability of antiretroviral treatment has
improved outcomes in HIV‑1 co‑infected individuals
with TBM; however, outcomes remain poor.
Disease caused by multidrug-resistant M. tuberculosis
— that is, resistant to at least rifampicin and isoniazid
— confers a major risk of death11,71. Before the introduc‑
tion of rapid molecular tests that can identify rifampicin
resistance at TBM disease presentation, almost all
patients died before the results of a conventional drug
susceptibility test were returned and second-line treat‑
ment could be initiated. Other important risk factors for
death from TBM include extremes of age, and interrup‑
tions to first-line antitubercular treatment (for example,
because of drug-induced adverse events)72.
Radiographic appearance. Basal meningeal exudates,
infarcts, tuberculomas and hydrocephalus are all com‑
mon features of TBM73. These features can occur in
isolation or in combination, and might not be detected
radiographically until the disease becomes advanced.
CT and MRI are widely used for detection of these
signs, although the latter has superior resolution,
especially for the detection and definition of infarcts
and tuberculomas.
New imaging modalities can assist in TBM diagnosis
and management. Diffusion-weighted MRI can detect
the early changes of cerebral ischaemia and border‑
zone necrosis, and is more sensitive than conventional
MRI for the detection and localization of ischaemia and
infarcts74,75.
The importance of infarction to long-term outcomes
has led to much interest in cranial vessel ima­ging. CT
angiography has been used to define lesions in the ante‑
rior and posterior cerebral circulation, and has demon‑
strated that the supraclinoid portion of the internal
carotid artery and proximal portions of the anterior cer‑
ebral and middle cerebral arteries are most commonly
affected in TBM76. Magnetic resonance angiography
has demonstrated vascular lesions, which are related to
hydrocephalus, infarction and poor outcome, in around
Diagnosis
Microbiological diagnosis. The use of microscopy and
Ziehl–Neelsen staining to detect of acid-fast bacilli in fluids
or tissues from affected organs has long been the main‑
stay for the rapid diagnosis of tuberculosis. However, the
detection of <10,000 bacteria per ml remains consistently
difficult owing to the low numbers of bacilli present and
time required to find them by microscopy. This impedi‑
ment renders microscopy around 50% sensitive for tuber‑
culosis associated with high bacterial burdens (such as
cavitory pulmonary tuberculosis in adults) and 10–20%
sensitive in paucibacillary disease (such as meningitis).
The sensitivity of CSF microscopy can be increased
from 10–20% to >50% by simple measures80. A large vol‑
ume of CSF (~10 ml), centrifuged at 3,000 g and exam‑
ined for 30 min by an experienced microscopist, can lead
to the detection of bacteria in >80% of TBM cases81, and
also increases the yield of culture. However, these meth‑
ods are rarely practical where they are most needed in
resource-poor settings, and rapid diagnostic methods for
TBM with improved accuracy are required.
Culture of M. tuberculosis from patient specimens is
more sensitive than microscopy for diagnosis, but takes
at least 10 days in liquid media and up to 8 weeks on solid
media, and ideally requires a biosafety level 3 laboratory.
Clinical decision-making, especially for TBM, cannot
wait this long, and few centres have the required facilities.
Innovative methods for the early detection of M. tuber-
culosis in liquid culture media have been developed, but
only the microscopic observation drug susceptibility
(MODS) assay has been investigated for the diagnosis of
TBM82. This method uses microscopy to detect the early
M. tuberculosis-specific ‘cords’ of bacterial growth and
was found to provide results in a median of 6 days when
used on CSF, with a sensitivity of around 65%.
Molecular assays. The insensitivity, slow speed and
expense of conventional bacteriology have provided the
impetus to develop tests based on nucleic acid ampli‑
fication to detect M. tuberculosis-specific molecules.
Aplethora of in‑house nucleic acid amplification tests
have been developed and tested, but few have been sub‑
ject to repeated or well-designed validation83. GeneXpert
MTB/RIF (manufactured by Cepheid) is a commercial,
real-time PCR-based assay for the detection of M. tuber-
culosis in clinical specimens, and also detects mutations
associated with rifampicin resistance. This assay was
endorsed by the WHO in 2010, and is being adopted

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globally as a front-line diagnostic test. Three studies have
investigated the role of GeneXpert in the diagnosis of
TBM84–86, and found the assay to be around 60% sen‑
sitive and nearly 100% specific. Testing of centrifuged
CSF deposit from a large volume of CSF enhances sen‑
sitivity. The WHO has recommended GeneXpert as an
essential diagnostic test in people with suspected TBM,
but the results must be interpreted with caution87,88, and
it should be used as a ‘rule‑in’ rather than a ‘rule-out’
test. Further investigations searching for additional evi‑
dence of TBM should always be sought, and antitubercu‑
lar treatment should be started without microbiological
proof in individuals clinically suspected of having TBM.
A second generation GeneXpert test (Ultra) is available
that relies on detection and amplification of a multicopy
gene target, and a 2017 WHO report suggested 95%
­sensitivity for TBM89.
The limitations of nucleic acid amplification have led
to investigation of the M. tuberculosis glycolipid lipoara‑
binomannan as a diagnostic marker in CSF. A compar‑
ison of lipoarabinomannan detection by lateral flow
assay (LFA) or ELISA with GeneXpert in CSF from an
autopsy cohort of 91 adults with confirmed TBM and
an HIV co‑infection found the sensitivity of lipoara‑
binomannan LFA to be 75%, compared with 43% for
ELISA and 100% for Gene Xpert MTB/RIF, suggesting
that lipoarabinomannan LFA could be a useful test90.
However, others have found lipoarabinomannan LFA
to be substantially less sensitive in practice than was
suggested by this study, especially in those without an
HIV‑1 infection91. In HIV co‑infected individuals, per‑
formance could be enhanced by combining the test with
a clinical diagnostic prediction rule92.
Diagnosis based on the host response. The difficulty
of detecting M.  tuberculosis in the CSF has driven
interest in whether specific immune responses can
aid TBM diagnosis. IFNγ release assays depend on the
ability of T lymphocytes from M. tuberculosis-infected
individuals to produce IFNγ when stimulated with
M. tuberculosis-specific antigens. A 2016 systematic
review and meta-analysis found that the overall sensi‑
tivities of blood and CSF IFNγ release assays were 78%
and 77% respectively, with 61% and 88% specificity93.
These data suggest that these assays have only moderate
a b c and diffusion-weighted MRI improves the detection
Figure 2 | MRI scans from a patient with stage II tuberculous meningitis. The patient
Nature Reviews | Neurology
had presented with fever for 15 days and altered sensorium for 1 day. a | Granuloma in T1
contrast axial section. b | Anterior cerebral artery territory infarction in diffusion-weighted
sequence. c | Narrowing right anterior cerebral artery and occlusion of left anterior
communicating artery.
accuracy. Specificity is enhanced when the assays are
used on CSF, but large volumes are required (>2 ml) and
indeterminate results are common (up to 15%).
Two systematic reviews and meta-analyses have
examined the diagnostic accuracy of CSF levels of
adeno­s ine deaminase in TBM 94,95. For adenosine
de­aminase values from 1–4 U/l, the sensitivity and
speci­ficity were >93% and <80%, respectively, compared
with >96% and <59% for values >8 U/l. None of the
cut-off values could reliably discriminate between TBM
and bacterial meningitis. The different methods used to
measure adeno­sine deaminase and the heterogeneity of
data limit standardization of this test in routine practice.
Diagnostic imaging. Brain imaging has long been part of
the diagnostic assessment of TBM. Numerous case series
have described the common radiographic appearances
of basal meningeal exudates, hydrocephalus, infarcts and
tuberculomas (FIG. 2). However, few studies have defined
the diagnostic performance of these features.
Early studies suggested that basal meningeal exu‑
dates, identified by contrast-enhanced CT imaging,
were specific for TBM and predicted poor outcome96.
Subsequent investigators reported that post-contrast
basal exudates detected by CT imaging were both
sensitive (~90%) and specific (~95%) for the diagno‑
sis of TBM in children97. Pre-contrast hyperdensity
in the basal cisterns might be an even more accurate
predictor of TBM97, but further research is needed
to validate this finding. Various objective criteria for
post-contrast CT basal enhancement have been pro‑
posed, most of which are specific but lack sensitivity98.
A study evaluating these criteria in adults again
found high specificity (90–100%) but low sensitivity
(0–30%)99. Furthermore, inter-reader variability was
high, limiting clinical utility.
Infarcts and hydrocephalus revealed by CT brain
imaging lack diagnostic specificity for TBM, as other
infectious and noninfectious diseases can cause simi‑
lar features. An increased specificity (95–100%) can be
achieved via detection of the combination of hydro‑
cephalus, basal enhancement and infarction; however,
these features can be absent in early disease, which
reduces diagnostic sensitivity to around 40%. MRI can
provide additional diagnostic information100; for exam‑
ple, gadolinium-enhanced MRI is superior to CT for the
visualization of small leptomeningeal tuberculomas101,
of small areas of ischaemia or early infarction74. In one
study102, MRI revealed 55 cases of stroke — 54 ischaemic
and one haemorrhagic — in 122 patients with TBM.
Infarcts were present in the basal ganglia (n = 30), the
thalamus (n = 9), the brainstem (n = 10), the cerebral
cortex (n = 27) and the cerebellum (n = 4). 29 patients
experienced multiple strokes. 38 had infarcts in the
anterior circulation, seven had infarcts in the poste‑
rior circulation and the remaining ten had infarcts in
both areas102. However, the diagnostic sensitivity and
specificity of these features for TBM are undefined.
The main limitation of both imaging modalities is
that around 30% of individuals at an early stage in the

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TBM disease course (MRC grade I) have normal brain
CT scans, and around 15% have normal brain MRI scans.
Furthermore, age and HIV‑1 co‑infection status influ‑
ence the appearance of the brain on imaging. Children
with TBM are more likely to exhibit hydrocephalus
than are adults with TBM, and basal enhancement is
often less prominent in people co-infected with HIV‑1,
especially those with very low CD4+ cell counts103.
Follow‑up imaging during treatment can pro‑
vide additional useful diagnostic information, as well
as important evidence concerning complications104.
Imaging of organs other than the brain can also yield
important diagnostic information. Concomitant tuber‑
culosis of the spinal cord can occur in more than half of
individuals with TBM, and is commonly overlooked79
unless MRI or PET–CT scans are performed105. Plain
chest radiography is normal in around 50% of people
with TBM, and the remaining individuals have a spec‑
trum of changes suggestive of previous or currently
active tuberculosis 106. Only the chest radiographic
appearance of miliary tuberculosis indicates dissemi‑
nated tuberculosis and the strong likelihood of TBM.
Radiographic evidence of tuberculosis at other sites,
acquired by conventional or PET–CT of the chest,
abdomen and pelvis, can provide supportive diagnostic
information and offers low-risk opportunities to biopsy
the affected tissues.
Clinical scoring systems. Several studies have described
the clinical features that are most predictive of TBM,
leading to the development of diagnostic scoring sys‑
tems (TABLE  2). The findings vary according to the
population in which they were derived, with age and
HIV status accounting for much of this variation.
Nevertheless, these scoring systems serve to highlight
the key distinguishing features of TBM: long-term
symptoms (>5 days), lower numbers of CSF leukocytes
(<1000 cells per mm3) than are typically observed in
other forms of bacterial mening itis, CSF leukocytes
comprised of <90% neutrophils, elevated CSF protein
(>100 mg/dl), and a low CSF:blood glucose ratio (<0.5)
compared with uninfected individuals.
A major limitation of these clinical diagnostic rules
is that their performance is variable in different popu‑
lations and settings, and few of these scoring systems
have been externally validated. A diagnostic rule devel‑
oped in Vietnam is currently the only one to be been
tested in different populations. This rule was originally
described to be 86% sensitive and 79% specific for
TBM diagnosis in Vietnamese adults107, and subsequent
studies in Turkey108, Vietnam109, India110, China111 and
Colombia112 reported sensitivities >90% and specificities
ranging from 50–90%. However, a serious limitation of
the Vietnam rule was exposed by a study in Malawi of
86 HIV‑1 co‑infected adults with meningitis113. In this
popu­lation, the rule was only 78% sensitive and 43% spe‑
cific, with cryptococcal meningitis accounting for most
of the false-positive results.
A consensus case definition for TBM has been pub‑
lished to help standardize clinical TBM research and
enable direct comparison of studies114. However, the
case definition was not designed to be used as a clinical
diagnostic tool, and was shown to perform poorly when
used in this manner115.
Management
Antimicrobial therapy. Antitubercular treatment before
the onset of coma is the strongest predictor of survival
from TBM. However, the best combinations, doses, fre‑
quencies and durations of these drugs have not been
determined, despite their importance to a successful out‑
come. The treatment of drug-susceptible TBM is based
on the regimens used against pulmonary tuberculosis.
The WHO recommends the same regimen of 2 months
of rifampicin, isoniazid, pyrazinamide and ethambutol
followed by 10 months of rifampicin and isoniazid, for
all patients. The recommended doses and frequencies for
TBM treatment are the same as for pulmonary tubercu‑
losis, despite concerns that rifampicin — in p ­ articular
— does not penetrate the blood–brain barrier well, and
concentrations of this agent in the CSF are 10–20% of
those achieved in plasma116,117 (TABLE 3). In addition, eth‑
ambutol does not cross the blood–brain barrier, even
when it is inflamed. Children generally require higher
doses per kg of body weight than do adults to achieve
similar exposures to antituberculosis drugs, and this dif‑
ference is reflected in the current paediatric tuberculo‑
sis treatment guidelines118,119. Paediatric TBM treatment
guidelines mirror those of adults in terms of regimen
composition and treatment duration. In practice,
paediatric treatment regimens vary, as no clinical trials
data are available to guide drug combination and dose
selection in paediatric TBM.
Whether rifampicin — the key sterilizing drug
in tuberculosis treatment — should be used at doses
>10 mg/kg for the treatment of TBM is controversial.
Paediatricians in Cape Town have long used a hyper­
intensive regimen, consisting of 20 mg/kg rifampicin,
isoniazid and ethionamide, with 40 mg/kg pyrazinamide,
all given for 6 months. They report few adverse events and
excellent outcomes120. Pharmacokinetic modelling studies
have suggested that in childhood TBM, rifampicin doses
of at least 30 mg/kg orally, or 15 mg/kg intravenously,
could be required to achieve sufficient CSF drug expo‑
sure and bacterial killing to reduce mortality121. Whether
the same applies to adults is currently uncertain. A trial
conducted in 60 adults with TBM in Indonesia found
that mortality was nearly halved if rifampicin was given
at a dose of 600 mg intravenously, compared with the
standard dose of 450 mg orally, resulting from a three‑
fold increase in systemic rifampicin exposure for the first
2 weeks of combination antituberculosis treatment122.
A strong concentration–effect relationship was found,
with higher rifampicin exposure being associated with
better TBM survival. Minimum rifampicin target values
were derived from exposure–response curves, and only
38% of patients receiving 600 mg intravenously reached
these target rifampicin exposures, suggesting that even
higher doses are required to optimize rifampicin dosing.
However, a subsequent a trial in 817 adults with TBM
in Vietnam failed to show any survival benefit of using
increased doses of rifampicin (15 mg/kg given orally

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Table 2 | Published clinical diagnostic rules for the diagnosis of TBM

Publication Population from which
rule derived
Kumar et al.181 Children from India
Thwaites et al.107 Adults from Vietnam
Youssef et al.182 Children and adults from
Egypt
Cohen et al.183 Adults from Malawi (77%
HIV-infected)
Patel et al.92 Adults from South Africa
(84% HIV-infected)
Hristea et al.184 Adults from Turkey
Vibha et al.110 Adults from India
Dendane et al.185 Adults from Morocco
Zhang et al.186 Adults from China (all
HIV-uninfected)
Qamar et al.187 Children from Pakistan
CSF, cerebrospinal fluid; MRC, Medical Research Council; TBM, tuberculous meningitis.
Case comparison Predictors of TBM
TBM versus other meningitis • Symptoms ≥7 days
• Optic atrophy
• Focal neurological deficit
• Extrapyramidal movements
• CSF leukocytes <50% neutrophils
TBM versus bacterial meningitis • Age <36 years
• Blood leukocytes <15 × 109/l
• Symptoms ≥6 days
• CSF leukocytes <750/mm3
• CSF neutrophils <90%
TBM versus bacterial meningitis • Symptoms >5 days
• CSF leukocytes <1000/mm3
• Clear CSF
• CSF lymphocytes >30%
• CSF protein >100 mg/l
TBM versus cryptococcal • Low CSF opening pressure
meningitis • Neck stiffness
• Raised CSF leukocytes
• Low Glasgow Coma Scale score
• High fever
TBM versus other meningitis • CSF:blood glucose ratio ≤0.2
• CSF lymphocytes >200/mm3
• CD4+ cell count <200 × 106/l
• Negative cryptococcal antigen test
TBM versus viral meningitis • Symptoms ≥5 days
• MRC grade II or III
• CSF:blood glucose ratio <0.5
• CSF protein >100 mg/dl
TBM versus bacterial meningitis • Living in a rural area
• Symptoms ≥6 days
• Cranial nerve palsy
• Hemiplegia
• Clear CSF
• CSF neutrophils <75%
TBM versus bacterial meningitis • Female sex
• Symptoms ≥10 days
• Focal neurological deficits
• Blood leukocytes <15 × 109/l
• Plasma sodium <130 mmol/l
• CSF leukocytes <400/mm3
TBM versus cryptococcal • Female sex
meningitis • Reduced consciousness
• No visual or hearing loss
• Evidence of extraneural
tuberculosis
• CSF leukocytes ≥68/mm3
• CSF protein >0.91 mg/dl
TBM versus bacterial meningitis • Hydrocephalus on brain CT
• CSF leukocytes <800/mm3
• CSF protein:glucose ratio ≥2

versus 10 mg/kg given orally in the control arm) with the
addition of levofloxacin for the first 2 months of treat‑
ment10. A probable explanation is that the rifampicin dose
was too low to substantially improve CSF drug exposure
and bacterial killing, and higher doses might yet prove
beneficial. Much higher doses of rifampicin (35 mg/kg)
have now been tested in clinical trials for the treatment of
pulmonary tuberculosis, and resulted in increased rates
of sputum culture conversion by 2 months of treatment123.
The problem of poor blood–brain barrier penetra‑
tion of antitubercular drugs is particularly pertinent
when choosing the fourth drug of a regimen for drug-­
sensitive TBM or for constructing a multidrug regimen
for drug-resistant TBM (TABLE 3). The addition of a fourth
drug (usually ethambutol) to the intensive phase of pul‑
monary tuberculosis treatment is primarily to overcome
the possibility of isoniazid resistance; if the bacteria are
susceptible to isoniazid then the addition of ethambutol

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Table 3 | Antituberculosis drugs used in TBM treatment

Drug WHO recommended daily dose WHO CSF penetration Important adverse effects
recommended (CSF/plasma
Children Adults duration concentration)
First-line drugs for the treatment of drug-sensitive TBM
Rifampicin 15 mg/kg (range 10 mg/kg (range 12 months 10–20% Hepatotoxicity, orange urine, many drug
10–20 mg/kg); 8–12 mg/kg); interactions
max. 600 mg max. 600 mg
Isoniazid 10 mg/kg (range 5 mg/kg (range 12 months 80–90% Hepatotoxicity, peripheral neuropathy,
7–15 mg/kg; 4–6 mg/kg); max. lupus-like syndrome, confusion, seizures
max. 300 mg 300 mg
Pyrazinamide 35 mg/kg (range 25 mg/kg (range First 2 months 90–100% Hepatotoxicity, arthralgia, gout
30–40 mg/kg) 20–30 mg/kg)
Ethambutol 20 mg/kg (range 15 mg/kg (range First 2 months 20–30% Dose-related retrobulbar neuritis, more
15–25 mg/kg) 15–20 mg/kg) common in renal impairment
Streptomycin* 15–30 mg/kg; 15 mg/kg (range First 2 months 10–20% Monitor plasma concentrations when possible;
max. 1 g IV or IM 12–18 mg/kg); causes nephrotoxicity and ototoxicity
max. 1 g
Core second-line drugs for the treatment of MDR-TBM‡
Levofloxacin <5 years: 10–15 mg/kg Throughout 70–80% Nausea, headache, tremor, confusion, tendon
15–20 mg/kg treatment rupture (rare)
≥5 years:
10–15 mg/kg
Moxifloxacin 10–20 mg/kg: 400 mg Throughout 70–80% Nausea, headache, tremor, confusion, tendon
max. 400 mg treatment rupture (rare)
Not well
established
Amikacin 15–30 mg/kg; 15 mg/kg; max. Intensive phase 10–20% Monitor plasma concentrations when possible;
max. 1 g IV or IM 1 g IV or IM only causes nephrotoxicity and ototoxicity
Kanamycin 15–30 mg/kg; 15 mg/kg; max. Intensive phase 10–20% Monitor plasma concentrations when possible;
max. 1 g IV or IM 1 g IV or IM only causes nephrotoxicity and ototoxicity
Capreomycin 15–30 mg/kg; 15 mg/kg; max. Intensive phase No data (probably Monitor plasma concentrations when possible;
max. 1 g IV or IM 1 g IV or IM only very low) causes nephrotoxicity and ototoxicity
Ethionamide or 15–20 mg/kg; 15–20 mg/kg; Throughout 80–90% Anorexia, nausea, vomiting, gynaecomastia,
prothionamide max. 1 g max. 1 g treatment hypothyroidism, confusion, seizures
Cycloserine 10–20 mg/kg; 10–15 mg/kg; Throughout 80–90% CNS toxicity: depression, seizures,
max. 1 g max. 1 g treatment neuropathy; co‑administration with pyridoxine
recommended
Linezolid 10 mg/kg; max. 600 mg Throughout 30–70% Myelosuppression, optic neuropathy;
600 mg treatment co‑administration with pyridoxine
recommended
Other drugs used to treat MDR tuberculosis, but of uncertain benefit in TBM
Clofazimine 1 mg/kg 100–200 mg No recommended Limited data Can discolour skin orange/red;
duration (probably low) photosensitivity
Para-aminosalicylic 200–300 mg/kg 8–12 g No recommended No data (probably Vomiting, diarrhoea, reversible hypothyroidism
acid duration very low) (increased risk with ethionamide)
Bedaquiline Not determined 400 mg for New drug; limited Probably very low Nausea, vomiting, arthralgia, QT prolongation;
2 weeks, then availability (but data from metabolized through CYP3A4; rifampicin
200 mg thrice one patient only) halves concentrations
weekly
Delamanid Not determined 200 mg New drug; limited No data Nausea, vomiting, dizziness rarely; QT
availability prolongation
*Streptomycin is no longer recommended in the standard regimen for drug-susceptible tuberculosis. ‡WHO recommend an initial regimen with at least five
effective drugs, including pyrazinamide and four second-line drugs. An injectable agent should be used in the intensive phase, the duration of which is uncertain,
but 2011 WHO guidelines recommend at least 8 months. Total duration of treatment for MDR-TBM is uncertain, but should probably be at least 18 months.
CSF, cerebrospinal fluid; IM, intramuscular; IV, intravenous; MDR, multidrug-resistant; TBM, tuberculous meningitis.

does not enhance bacterial killing or improve outcomes. the poor penetration of rifampicin into the brain and
By contrast, in TBM treatment, the rationale for adding CSF, addition of a fourth drug in TBM might also have
a fourth drug is that it should overcome the potential a larger role in overall bacterial killing and increased
adverse effects of isoniazid resistance. However, given patient survival.

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No comparative controlled trials have been con‑
ducted that define the optimal fourth drug for TBM.
Ethambutol is widely recommended, but concentrations
in the CSF are <20% of those in the plasma owing to its
poor penetration of the blood–brain barrier, and its con‑
tribution to outcome is potentially limited, even in the
presence of isoniazid resistance117. Historically, strepto­
mycin has been used widely, but it also penetrates the
blood–brain barrier poorly — especially once inflamma‑
tion has subsided — and this property, combined with
frequent vestibular toxicity (30%) and a high prevalence
of resistance, limits its use. Ethionamide passes across
the blood–brain barrier more effectively than ethambu‑
tol or streptomycin, enabling high CSF concentrations
to be achieved, and has become part of standard TBM
therapy at some centres120. The fluoroquinolones moxi‑
floxacin and levofloxacin both have good CSF penetra‑
tion, and high activity against drug-susceptible bacteria
as well as many drug-resistant bacteria124,125. In a 2016
trial of intensified antituberculosis therapy in Vietnam10,
levofloxacin failed to improve survival when used as a
fifth drug alongside high-dose rifampicin and ethambu‑
tol. However, if the disease was caused by bacteria resist‑
ant to isoniazid, intensified treatment was associated with
significantly increased survival.
Current evidence suggests that the choice of fourth
drug in antituberculosis treatment has little influence on
outcome if the disease is caused by bacteria susceptible
to all first-line drugs, although the limited available data
mandate caution in forming conclusions. However, in dis‑
ease caused by isoniazid-resistant bacteria, clinical trial
data indicate that a high dose (minimum 15 mg/kg) of
rifampicin and the addition of levofloxacin as a fifth agent
improve survival. Observational data also indicate that
the negative effect of isoniazid resistance on survival could
be reduced by prescribing pyrazinamide throughout
treatment (9–12 months)20.
The effect of multidrug resistance to rifampicin and
isoniazid on TBM outcome is catastrophic, with mor‑
tality >80%20,71,126. This finding is a particular concern
given the global rise in multidrug-resistant tuberculosis,
which now stands at 480,000 cases annually4. The main
reason for mortality is the inability for drug resistance
to be detected sufficiently quickly to enable changes
to be made to the antitubercular treatment regimen.
GeneXpert MTB/RIF has enabled same-day detection
of rifampicin-resistant bacteria, which can facilitate
the timely switch to second-line agents in some cases.
However, even in settings in which GeneXpert is avail‑
able, outcomes remain poor owing to the limited sensi‑
tivity of this assay in CSF samples (50–60%), the lack of
timely susceptibility information on companion drugs,
and the unknown brain penetration and efficacy of
second-line drugs for TBM.
The best regimen for the treatment of multidrug-
resistant TBM is unknown, but until additional data
become available, the regimens advised by the WHO for
the treatment of multidrug-resistant pulmonary tuber‑
culosis should be used (TABLE 3). Notably, the second-line
drugs known to have good penetration into the CSF
include fluoroquinolones, ethionamide, cycloserine and
linezolid; pyrazinamide and high-dose isoniazid, which
are often added to second-line treatment, also have good
penetration into the CSF.
Adjunctive host-directed therapies. Intracerebral
inflammation has long been recognized as an impor‑
tant determinant of TBM outcome. The hypothesis that
adjunctive corticosteroids reduce inflammation and
thereby improve outcome from TBM was first postu‑
lated in the early 1950s127, but it took nearly 50 years for
sufficient randomized controlled trial evidence to accu‑
mulate before this treatment was widely recommended
in guidelines. A 2016 Cochrane systematic review and
meta-analysis of all relevant published trials concluded
that corticosteroids increase survival in HIV-1-negative
children and adults with TBM, but that the benefit of
corticosteroids was uncertain in individuals co‑infected
with HIV‑1, and was not found to reduce long-term
neurological disability in any group128.
Inflammatory complications can occur weeks or even
months after the start of antituberculosis chemotherapy
for TBM, when initial corticosteroid treatment has
been reduced or stopped129,130. These events are termed
‘paradoxical reactions’, or IRIS in individuals started
on antiretroviral therapy for HIV co‑infection within
the past month. Symptoms include fever, progressively
worsening headache, and sometimes seizures and reduced
consciousness. Brain imaging is important to deter‑
mine whether the cause is hydrocephalus, infarction or
tuberculoma formation.
Tuberculomas are the best described paradoxical
reactions to TBM treatment, and most are treated with
high-dose adjunctive corticosteroids, despite the absence
of controlled trial evidence supporting this approach.
Anecdotal evidence suggests that corticosteroids reduce
symptoms and inflammation in around 50% of patients
with TBM. However, in some cases corticosteroids have
no effect, and symptoms of TBM will persist or worsen.
In these circumstances, alternative anti-inflammatory
agents have been tried, particularly when the tubercu‑
loma involves the optic chiasm or when optochiasmatic
arachnoiditis threatens vision. Some case series suggest
that thalidomide could help to alleviate these problems,
especially when corticosteroids are ineffective131,132. Other
studies have reported success with anti-TNF biological
agents (such as infliximab)133 and IFNγ treatment134.
Brain infarction is the most common cause of long-
term neurological disability owing to TBM, and is not
prevented by corticosteroid treatment44. Two small trials
have suggested that treatment with aspirin is safe when
added to dexamethasone, and might improve outcome
from TBM by reducing the incidence of brain infarc‑
tion135,136. One of these studies, conducted in India,
randomly assigned 118 adults with TBM to standard
antituberculosis chemotherapy, with or without aspi‑
rin (150 mg daily), and found a trend towards reduced
stroke incidence with aspirin (24%, compared with 43%
in the control group) and a significant reduction in mor‑
tality (21.7% versus 43.0%, P = 0.02)135. A second study in
South Africa randomly assigned 146 children with TBM
to standard antituberculosis chemotherapy plus placebo

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(n = 50), low-dose aspirin (75 mg per 24 h; n = 47), or
high-dose aspirin (100 mg/kg per 24 h; n = 49). In this
trial, aspirin had no significant effect on patient survival,
but on‑treatment new hemiplegia was less common in
the high-dose aspirin group136.
Aside from corticosteroids, antiretroviral drugs
are the only adjunctive agents with proven benefit in
the treatment of TBM. Before the advent of antiretro­
viral therapy, 9‑month mortality in patients with HIV-
associated TBM in Vietnam was around 65%72; with
antiretroviral treatment, mortality is now <40%10. The
one remaining area of uncertainty is whether, in anti­
retroviral therapy-naive patients, this therapy should
be started concurrently with antituberculosis drugs
or delayed until the tuberculosis has been partially or
completely treated. The balance of risks lies between
reducing the incidence of other potentially fatal oppor‑
tunistic infections that can result from early initiation
of anti­retro­viral treatment and reducing the risk of IRIS
reactions that could result from delayed antiretroviral
therapy and complicate treatment. Trials in pulmonary
tuberculosis have shown that early antiretroviral ther‑
apy is associated with increased survival, especially in
patients with very low CD4+ T‑cell counts137,138; con‑
versely, a single trial in adults with TBM comparing early
with 2‑month delayed antiretroviral therapy showed no
difference in survival139. Grade 4 adverse events were
more frequent in patients given early antiretroviral ther‑
apy, suggesting that the deferral of antiretroviral ­therapy
for up to 2 months could be advantageous in the man‑
agement of TBM with an HIV co‑infection. No data
are currently available that can inform decisions about
antiretroviral therapy use in children with HIV and
TBM, and the risk:benefit analysis is different from that
in adults owing to the high mortality related to untreated
HIV in young children.
Supportive management. Raised intracranial pressure
(ICP), cerebral ischaemia, hydrocephalus, hyponatrae‑
mia and seizures all contribute to poor outcome in
patients with TBM, and should be actively tested for
and treated. However, the evidence defining optimal
management of these complications is scant, and physi‑
cians often overlook this important component of TBM
care140. Unfortunately, no standardized protocols exist,
and practice varies substantially between centres.
Cerebral perfusion and oxygenation can be com‑
promised globally by hypovolaemia and hypoxia, or
locally by raised ICP and infection-related vasculitis and
infarction. Hydrocephalus is the most common cause
of raised ICP, but ICP can also be elevated by cerebral
vasogenic or cytotoxic oedema, a loss of cerebral pres‑
sure autoregulation and vascular reactivity, hypercapnia
or hypocapnia, hyponatraemia, and high temperature.
Thus, clinical management should be directed at the
careful and continuous monitoring and correction of
abnormalities in gas exchange and tissue oxygenation,
through mechanical ventilation (if necessary), metic‑
ulous fluid and electrolyte management, control and
monitoring (when possible) of intracranial pressure,
and rigorous temperature control140,141.
Vascular compromise is a common complication of
TBM, and leads to ischaemia, infarction and raised ICP.
The techniques available for real-time monitoring of vas‑
cular abnormalities and their effects on cerebral haemo‑
dynamics, ischaemia and ICP are limited, and are mostly
unavailable outside large, well-resourced centres. The
most studied technique is transcranial Doppler ultra‑
sonography, which can provide accurate non­­invasive
information on intracranial blood flow velocities and
identifies areas of intracranial stenosis in the major ves‑
sels in the circle of Willis. Transcranial Doppler can be
performed at the bedside, making it a potentially valu‑
able tool in critically ill and ventilated patients. To date,
studies have suggested that transcranial Doppler can
reliably diagnose and track TBM-related intracranial
vasculopathy142,143, but is not a reliable indicator of raised
ICP in children with tuberculous hydrocephalus144.
Published data regarding invasive monitoring of
brain tissue oxygenation and ICP are limited. Some
centres advocate immediate external ventricular drains
with pressure monitoring in children who have severe
TBM with hydrocephalus, and parenchymal ICP moni‑
toring in those without hydrocephalus140, but the role of
these techniques in treatment decision-making remains
uncertain. One study used a cerebral oxygenation tissue
probe in two children with severe TBM who demon‑
strated delayed and worsening cerebral ischaemia
despite full conventional therapy and controlled ICP145.
These data confirm that the vascular involvement in
TBM is potentially progressive. Cerebral oxygenation
monitoring successfully reversed a precipitous decline
in oxygen readings in one patient, which might have
prevented infarction, indicating a possible benefit for
this intervention in selected patients with severe disease.
Mannitol has been the long-standing treatment for
raised ICP in traumatic brain injury, although evidence
from the past decade suggests that hypertonic saline is
equally effective and safer, especially if ICP monitoring
is unavailable146,147. Furthermore, hypertonic saline might
be effective in treating TBM-associated ­hyponatraemia,
a common complication of severe disease.
Hyponatraemia (plasma sodium <135 mmol/l)
occurs in around 40–50% of patients with TBM 28.
Management difficulties stem from the incompletely
characterized pathogenesis of hyponatraemia, com‑
bined with few data detailing its optimal treatment.
SIADH (syndrome of inappropriate antidiuretic hor‑
mone secretion) and cerebral salt wasting, which possi‑
bly occur owing to atrial natriuretic peptide secretion148,
are conventionally thought to be the causes of hypo­
natraemia in TBM, with results from a 2016 study con‑
ducted in India suggesting that cerebral salt wasting
is the most common cause28. However, distinguishing
between these two conditions can be difficult. By con‑
vention, SIADH is managed by fluid restriction, and
cerebral salt wasting by fluid administration. Some
have argued that both conditions can be treated with
hypertonic saline149, whereas others have argued that
fluid restriction, the traditional treatment for SIADH,
has little benefit in meningitis and might result in
worsening hypovolaemia and harm150.

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Hydrocephalus is the most common cause of raised
ICP. In the majority (80%) of patients with TBM, com‑
municating hydrocephalus is observed, caused by
exudates in the basal cisterns and resulting in disrup‑
tion of CSF flow. Reasonable evidence suggests that
hydrocephalus in TBM can be treated medically with
diuretics and with repeated lumbar punctures151,152.
Noncommunicating hydrocephalus, caused by obstruc‑
tion at the level of the cerebral aqueduct and/or the out‑
let foramina of the fourth ventricle, is less common in
this population, and should be treated with ventriculo­
peritoneal shunting (VPS) or endoscopic third ventricu‑
lostomy (ETV)153. Conventional CT imaging cannot
reliably determine the physical position of the CSF
block154, and air encephalography has been suggested as
a gold standard155. Air encephalography is carried out at
the time of lumbar puncture, with the patient in the sit‑
ting position: 10 ml of air are injected into the subarach‑
noid space, and its journey to the ventricles is shown by
plain skull radiographs 30 min later. Air trapped below
the ventricles indicates the presence of noncommuni‑
cating hydrocephalus140. However, air encephalography
involves a lumbar puncture and carries the risk of cere‑
bral herniation; therefore, further exploration of alterna‑
tive approaches, such as thin-sliced CT of the posterior
fossa or MRI CSF-flow studies, is desirable, although
access to such imaging can be limited in many TBM
prevalent settings.
A 2017 systematic review of VPS in TBM concluded
that the outcome depends on the clinical severity of
TBM. Patients with an HIV‑1 co‑infection have a worse
prognosis than HIV negative patients156. The main chal‑
lenge for surgeons is the selection of patients for VPS
insertion or ETV157,158. One randomized controlled trial
comparing VPS with ETV in 48 children with TBM and
hydrocephalus suggested that the risk of early recur‑
rence of hydrocephalus was higher with ETV, but ETV
had fewer long-term complications than VPS159. Many
studies attest to the high complication rate of VPS160,
especially in individuals co‑infected with HIV 161.
However, whether EVT offers a meaningful advantage
remains controversial. ETV in TBM hydrocephalus
can be technically very difficult, especially in the acute
stage of disease, owing to the presence of an inflamed,
thick and opaque third ventricle floor162,163. Others
have opined that ETV should be reserved for early-stage
TBM with aqueductal stenosis, whereas chronic
burnt-out cases or cases with communicating hydro‑
cephalus should be managed by ventriculoperitoneal
shunting164.
Prevention
The role of BCG in reducing the incidence of dissemi‑
nated tuberculosis, including TBM, is widely accepted.
Childhood disease can also be prevented by giving
isoniazid, or other preventive therapy regimes, to chil‑
dren exposed to infectious adults. Improvements in
worldwide tuberculosis control through increased
and more-rapid detection of infection would improve
preven­tion. Antiretroviral therapy is the most effective
pre­ventive strategy against tuberculosis in people with
HIV, substantially reducing the risk of TBM irrespective
of baseline CD4+ T-cell count, tuberculin skin test status,
and antimycobacterial drug resistance165.
Conclusions
Progress has been made in understanding the patho‑
genesis of TBM, but has not yet translated into outcome
benefits in patients. Inconsistency between studies
has reduced their generalizability and comparability.
A standardized definition of TBM, which has been pro‑
posed for use in research studies114, and standardized
methods for enhanced quality and comparability of
TBM studies166 will help to increase generalizability and
comparability of studies.
High-resolution MRI or CT imaging combined with
imaging techniques to assess TBM disease activity, as
demonstrated in other forms of tuberculosis167, could
provide a more detailed clinical phenotype for TBM
than is currently available. This assessment could also
be extended to include monitoring of parameters such
as brain oxygenation and CSF pressure. Unbiased appli‑
cation of ‘omics’ technologies (particularly transcrip‑
tomics) has also provided important insight into human
tuberculosis168. Analysis of cells and fluid arising from
the site of disease is likely to be particularly valuable.
One small autopsy study compared gene transcripts
in brain biopsy samples from patients with TBM and
patients with traumatic brain injury, and showed that
genes encoding proteins involved in metabolism, cell
growth, transport, immune response, cell communica‑
tion and signal transduction are differentially expressed
in these patient populations169. In addition, previous
work has shown that longitudinal sampling of blood or
CSF during observational studies or randomized con‑
trolled trials is highly informative regarding the dynam‑
ics of the disease, such as disease progression and drug
response31.
Delayed diagnosis and treatment is associated with a
poor prognosis in TBM. Thus, new tests that can be used
at the point of care are crucially needed, particularly for
drug-resistant TBM, which has a dismal outcome. Next-
generation nucleic amplification tests might address this
issue. High quality, well-designed head‑to‑head compar‑
isons that are compliant with Consolidated Standards
of Reporting Trials (CONSORT) and Standards for
Reporting of Diagnostic Accuracy (STARD) are
required, as small-scale studies without validation are
insufficient to establish a new diagnostic test. The use
of the absolute gold standard of microbiological confir‑
mation is likely to lead to overestimates of diagnostic
sensitivity: further use of composite gold standards and
latent class analysis, as well as rational decision trees that
combine diagnostic information with clinical outcome
data, should also form part of the evaluation. In addi‑
tion, improved diagnosis has the potential to improve
national and international surveillance of numbers of
cases and trends in incidence.
Few studies have rigorously evaluated antibiotic
treatment regimens in TBM. Culture positivity was
associated with worse TBM outcome in a large cohort
of HIV-negative patients and in patients with TBM-IRIS

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in South Africa40; consequently, more-rapid reduction Of 17 clinical trials registered on ClinicalTrials.gov

of bacillary load represents an intuitive approach.
Disappointingly, however, the largest trial of an intensi‑
fied treatment regimen showed no benefit10. This finding
emphasizes the need for further detailed pharmaco­
dynamic and pharmacokinetic studies in TBM trials
so that site‑of‑action pharmacokinetics and exposure–
response relationships can be explored and regimens
can be built, with ineffective drugs and doses confi‑
dently discarded. No high-quality studies on the treat‑
ment of drug-resistant TBM are currently available, but
the urgent need for these studies can now be addressed
with the increasing application of molecular diagnostics
such as Gene Xpert MTB/RIF testing.
under the terms ‘tuberculosis’ or ‘tuberculous’ and
‘meningitis’, only two (both of aspirin or corticos‑
teroid adjunctive therapies) have clinical end points.
This observation emphasizes the need for biomarkers
of clinical response that might facilitate shorter trials.
TBM would also be a potential target for multi-arm
multistage clinical trial designs, given the frequently
poor outcome of the disease170. Multinational collabo‑
rating consortia might go some way towards increasing
advocacy for TBM and enabling high-quality studies
to be undertaken. Further high-quality studies into
optimal supportive treatment for TBM would also
be desirable.

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Acknowledgements
Tuberculous Meningitis International Research Consortium
members include: Rob Aarnoutse, Reinout Van Crevel,
Aarjan van Laarhoven, Sofiati Dian (Radboud University
Nijmegen Medical Center, Nijmegen, The Netherlands);
Nathan C. Bahr (University of Kansas Medical Center,
Kansas City, USA); David R. Boulware (University of
Minnesota, Minneapolis, USA); Maxine Caws (Liverpool
School of Tropical Medicine, Liverpool, UK); Mark R. Cronan,
David Tobin (Duke University School of Medicine, Durham,
USA); Kelly Dooley (Johns Hopkins University School
of Medicine, Baltimore, USA); Sarah Dunstan (University of
Melbourne, Melbourne, Australia); Guo-dong Feng, Xiaodan
Shi, Ting Wang (Fourth Military Medical University, Xi’an,
People’s Republic of China); Anthony Figaji, Suzaan Marais,
Helen McIlleron, Graeme Meintjes, Ursula Rohlwink
(University of Cape Town, Cape Town, South Africa); Ahmad
Rizal, Rovina Ruslami (Padjadjaran University, Bandung,
Indonesia); Ravindra K. Garg (King George Medical
University, Lucknow, India); Mudit Gupta, Rakesh K. Gupta
(Fortis Memorial Research Institute, Gurgaon, India); Sneha
Gupta, Rada Savic (University of California, San Francisco,
USA); Anna D. Heemskerk, Thuong Thuy Thuong Nguyễn,
Mai Thi Hoàng Nguyễn, Vijay Srinivasan, Guy Thwaites,
Trâm Thi Bích Trân, Thinh Thi Vân Trân, Anh Thi Ngoc Trân,
Trang Hồng Yêng Võ, Marcel Wolbers (Oxford University
Clinical Research Unit, Ho Chi Minh City, Vietnam); Jayantee
Kalita, Usha K. Misra (Sanjay Gandhi Postgraduate Institute
of Medical Sciences, Lucknow, India); Rachel Lai (The Francis
Crick Institute, London, UK); Ben J. Marais, Mai Quỳnh Trinh
(University of Sydney, Sydney, Australia); Bằng Đức Nguyễn,
Yến Bích Nguyễn (Pham Ngoc Thach Hospital for
Tuberculosis & Lung Diseases, Ho Chi Minh City, Vietnam);
Vinod Patel (University of KwaZulu-Natal, Durban, South
Africa); Thomas Pouplin (Mahidol-Oxford Tropical Medicine
Research Unit, Bangkok, Thailand); Lalita Ramakrishnan
(University of Cambridge, Cambridge, UK); Johan F.
Schoeman, Regan Solomons, Ronald Van Toorn (University
of Stellenbosch, Cape Town, South Africa); James Seddon
(Imperial College, London, UK); Javeed Shah (University of
Washington, Washington, USA); Jaya S. Tyagi (All India

NATURE REVIEWS | NEUROLOGY VOLUME 13 | OCTOBER 2017 | 597

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Institute of Medical Sciences, New Delhi, India); Douwe H.
Visser (VU University Medical Center, Amsterdam, The
Netherlands); Robert J. Wilkinson (Imperial College and
The Francis Crick Institute, London, UK and University of
Cape Town, South Africa). R.J.W. is supported by the Francis
Crick Institute, which receives its core funding from Cancer
Research UK (FC00110218), the UK Medical Research
C o u n c i l ( F C 0 0110 21 8 ) , a n d t h e We l l c o m e Tr u s t
(FC00110218). He also receives support from the Wellcome
Trust (104803, 203135) and the National Research
Foundation Of South Africa (96841). G.T. is supported by
the Wellcome Trust through a Major Overseas Programme
grant (106680/Z/14/Z) and an Investigator Award
(110179/Z/15/Z).
Author contributions
R.J.W, U.R., U.K.M., R.v.C., N.T.H.M., K.E.D., M.C., A.F., and
G.T. researched data for the article, R.J.W, U.R., U.K.M.,
R.v.C., K.E.D., M.C., A.F., R. Savic, R. Solomons, and G.T
made a substantial contribution to discussion of content,
R.J.W., U.R., U.K.M., R.v.C., wrote the article, and all authors
contributed to the review and editing of the manuscript
before submission.
Competing interests statement
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

598 | OCTOBER 2017 | VOLUME 13 www.nature.com/nrneurol

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