456

Neurotuberculosis: A Clinical Review

Jerome H. Chin, MD, PhD, MPH1

1 Department of Neurology, NYU Langone Health, New York, New York Address for correspondence Jerome H. Chin, MD, PhD, MPH,
Department of Neurology, NYU Langone Health, 222 East 41st Street,
Semin Neurol 2019;39:456–461. 9th Floor, New York, NY 10017 (e-mail: Jerome.Chin@nyulangone.org).

Abstract In September 2018, the United Nations General Assembly held the first ever meeting to
discuss the global epidemic of tuberculosis (TB) and adopted a political declaration
titled “United to end tuberculosis: an urgent global response to a global epidemic.” The
timing of the meeting was prescient but overdue since Mycobacterium tuberculosis
surpassed the human immunodeficiency virus as the world’s leading infectious killer in
2014. Infection of the central nervous system by Mycobacterium tuberculosis, herein
Keywords referred to as neurotuberculosis, is the most feared and dangerous form of tubercu-
► tuberculosis losis, requiring a high level of suspicion and clinical experience for prompt diagnosis
► meningitis and treatment. Neurologists, infectious disease specialists, orthopedic surgeons,

Downloaded by: University of Utah. Copyrighted material.

► cerebrospinal fluid neurosurgeons, and hospitalists in all countries need to recognize the spectrum of
► HIV neurotuberculosis and be able to integrate clinical information, laboratory data, and
► Xpert radiological findings to make a diagnosis with or without microbiological confirmation.

Tuberculosis (TB) is the oldest microbiologically documented
infectious disease of humans, and likely has killed more
persons in the history of human civilization than any other
infectious disease.1 The distribution of Mycobacterium tuber-
culosis (MTB) complex genotypes varies by region and coun-
try, reflecting, in part, patterns of human migration between
continents.2 Although TB is a disease that initially and
predominantly involves the lungs (i.e., pulmonary TB
[PTB]), extrapulmonary involvement occurs in an estimated
15% of affected individuals.3 Neurological involvement is
considered the most serious and deadly manifestation of
extrapulmonary TB (EPTB) and encompasses tuberculous
meningitis (TBM), brain and spinal tuberculomas, and ver-
tebral infection by MTB with spinal cord compression. Using
a case presentation approach, the diagnostic challenges of
neurotuberculosis are presented in this review in addition to
a comparison of World Health Organization (WHO) and
selected national guidelines for the treatment of TBM.
Epidemiology of TB
TB is a global disease with cases reported in every country.3
However, the quality and completeness of TB surveillance
and reporting varies widely, with some countries having no
reliable data. Annual reports and statistics produced by the
WHO and the Institute for Health Metrics and Evaluation use
different mathematical algorithms to generate estimates
with confidence intervals of incidence rates, incidence,
mortality rates, and mortality for almost all countries in all
regions of the world.4 Estimates from prior years are
adjusted annually based on updated data provided by coun-
tries. In 2017, the WHO estimated 10 million incident cases
of TB globally, with 3.6 million unreported cases.3 The WHO
report includes estimates for EPTB in different regions
(range: 15–18%) without specifying the contributions of
different EPTB subtypes to these estimates.
Reliable estimates of the global incidence of neurotuber-
culosis are lacking. Definitive diagnosis of TBM, brain and
spinal tuberculomas, and vertebral TB requires microbiolo-
gical confirmation, which is not possible in many cases and
not technically feasible in many resource-limited settings.
Underreporting, over-diagnosis, and under-diagnosis make
unadjusted incidence rates obtained from national statutory
reporting registries and vital registration records inadequate
to estimate the incidence of neurotuberculosis. Examination
of multiple overlapping sources, e.g., national registries, vital
registration records, hospital records, and microbiology
laboratory reports, is necessary to provide population-based
estimates of neurotuberculosis incidence. Furthermore, in
countries and regions with limited access to health care or

Issue Theme Neuroinfectious Disease, Copyright © 2019 by Thieme Medical DOI https://doi.org/
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Tel: +1(212) 584-4662.

financial barriers to seeking health care, patients with neu-
rotuberculosis, particularly TBM, may die without contact
with the health system and therefore go uncounted. Identi-
fying these cases would require administration of a validated
verbal autopsy to a representative sample of communities in
a country.
Limited national and subnational surveillance data are
available from certain upper-middle income and high-
income countries. The Canadian Tuberculosis Reporting Sys-
tem reported an incidence rate in 2016 of all new active and
retreatment TB cases of 4.8/100,000, and an incidence rate of
“central nervous system” (CNS) TB of 0.1/100,000 (2.1% of all
reported cases).5 An analysis of surveillance data for 2001 to
2010 for the State of Catarina in Brazil obtained from the
Information System on Disease Notification of the Ministry
of Health reported an annual incidence rate of TBM of 0.2/
100,000.6 TBM was confirmed microbiologically (culture,
bacterioscopy, polymerase chain reaction [PCR], and
necropsy) in less than 15% of cases. In the United Kingdom,
9.2 cases of TB/100,000 were reported to the Enhanced TB
Surveillance System in 2017.7 Seventy-one percent of cases
were non-United Kingdom born individuals, and 31% of cases
were not confirmed by any laboratory method. “CNS-menin-
gitis” and “CNS-other” each accounted for 2.2 and 2.1% of
total cases, respectively, giving a combined incidence of 0.4/
100,000.
Tuberculous Meningitis
Case 1
A 20-year-old male nursing student, human immunodefi-
ciency virus (HIV)-negative, was admitted to a regional hospi-
tal in Uganda with 3 weeks of fever, chest pain, cough, weight
loss, and reduced appetite. Chest X-ray revealed a large right
pleural effusion (►Fig. 1A) which was aspirated and a chest
tube was inserted. Two sputum specimens tested negative by
Ziehl–Neelsen (ZN) staining and direct microscopy for acid-
fast bacilli. Anti-tuberculosis therapy (ATT) with standard
Fig. 1 Case 1, tuberculous meningitis (see text for descriptions): (A) chest X-ray; (B) coronal contrast-enhanced brain CT image; (C) axial
contrast-enhanced brain CT image. CT, computed tomography.
Neurotuberculosis: A Clinical Review Chin 457
doses of isoniazid (H), rifampicin (R), pyrazinamide (Z), and
ethambutol (E) (HRZE) was started for presumed PTB. The
patient developed headaches and a progressive decrease in
level of consciousness over the next week and was transferred
to the national referral hospital. On admission, he was afebrile,
hypoxic, and stuporous with a stiff neck. Cerebrospinal fluid
(CSF) was obtained by lumbar puncture (10 days after initia-
tion of ATT) and revealed the following: 25 white blood cells/
mm3 (80% lymphocytes), protein 109 mg/dL, and glucose 0.4
mmol/L (7.2 mg/dL) with serum glucose 6.7 mmol/L (121 mg/
dL). ZN stain, Gram stain, and India ink preparation of CSF were
all negative. Contrast-enhanced brain computed tomography
(CT) revealed intense enhancement of the basal meninges,
Sylvian fissures, and cerebral meninges, hydrocephalus, and
subcortical and basal ganglia infarcts (►Fig.1B, C). Xpert MTB/
RIF testing of uncentrifuged CSF was negative. Xpert MTB/RIF
Ultra testing of uncentrifuged CSF was trace positive (rifampi-
cin resistance indeterminate). ATT was continued and intra-
venous dexamethasone was added at a dose of 8 mg every
8 hours. Automated liquid culture (BD BACTEC MGIT) showed
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positive growth at day 17. Phenotypic drug susceptibility
testing showed sensitivity to HRZE. The patient died 2 weeks
after admission and prior to the positive MGIT culture.
TBM develops as a result of hematogenous seeding of the
meninges or brain parenchyma with MTB. Patients with TBM
may or may not have clinical symptoms or radiological signs
on chest X-ray of PTB. CSF analyses in cases of TBM typically
show a modest predominantly lymphocytic pleocytosis
(10–300 cells/mm3) and elevated protein levels (50–
400 mg/dL).8,9 CSF glucose levels are often but not always
reduced below 2.2 mmol/L. In highly immunosuppressed
patients with HIV infection, CSF may be acellular (<5 cells/
mm3).10 Liquid and solid media cultures for MTB are the
current gold standard for premortem diagnosis of TBM, but
the earliest time to positive growth is usually 2 weeks. The
true sensitivity of culture for the detection of MTB in CSF is
not known. A study of 374 patients with a clinical diagnosis
of TBM (definite, probable, and possible) according to
Seminars in Neurology Vol. 39 No. 4/2019
458 Neurotuberculosis: A Clinical Review Chin
uniform case definitions for research11,12 reported positive
liquid cultures for MTB in the CSF of 119 patients (31.8%).
Direct microscopy using ZN staining to identify mycobac-
teria in CSF requires experienced microscopists, and
reported sensitivities are variable but generally low.12,13
Several immunological and biomarker assays of CSF have
been developed and evaluated to assist in the diagnostic
confirmation of TBM, including measurements of adenosine
deaminase levels, lactate levels, and gamma interferon
release.13–15 However, these assays have not demonstrated
sufficient specificity to distinguish nonmycobacterial bac-
terial meningitis from mycobacterial meningitis.
Rapid microbiological identification of MTB in CSF is now
possible with commercial and in-house PCR-based assays
using different hybridization targets. Xpert MTB/RIF is a fully
automated PCR-based assay that was approved by the WHO
in 2010 for the diagnosis of PTB and EPTB, and distributed
globally to high-burden countries at a deeply discounted
price.16 Xpert MTB/RIF amplifies and detects copies of the
rpoB gene and mutations that confer resistance to rifampicin.
The majority of MTB strains that are resistant to rifampicin
are resistant to isoniazid.9,17,18 Therefore, a positive Xpert
MTB/RIF assay allows rapid identification of multidrug resis-
tant TB. A recent Cochrane review of published studies of
Xpert MTB/RIF for the detection of TBM reported a pooled
sensitivity of 71.1% when compared with MTB culture.19
Xpert MTB/RIF Ultra is a next-generation assay that was
launched in 2017 to replace Xpert MTB/RIF. Xpert MTB/RIF
Ultra employs three hybridization targets (rpoB, IS6110, and
IS1081) and a larger PCR reaction chamber that improves the
analytical limit of detection of MTB to 15.6 colony-forming
units/mL compared with 112.6 colony-forming units/mL for
Xpert MTB/RIF.20,21 The only published study of Xpert MTB/
RIF Ultra for the detection of TBM in CSF reported sensitiv-
ities of 70% for Xpert MTB/RIF Ultra, 43% for Xpert MTB/RIF,
and 43% for MGIT culture for 23 HIV-infected participants
with probable or definite TBM defined by a uniform case
definition.22 Eight CSF samples were only positive by Xpert
MTB/RIF Ultra. Xpert MTB/RIF Ultra includes a “trace” level of
detection of MTB which does not allow determination of
rifampicin resistance. Although Xpert MTB/RIF Ultra is a
major advance for the rapid point-of-care diagnosis of all
forms of TB, neither Xpert MTB/RIF nor Xpert MTB/RIF Ultra
should be used to exclude a diagnosis of TBM.23
For the HIV-infected patient, it is critical to distinguish
between TBM and cryptococcal meningitis (CCM). Clinical
presentation and neurological signs are overlapping, including
subacute course of meningitis symptoms, cranial nerve pal-
sies, fever, confusion, and seizures. In a single-center retro-
spective comparison of TBM and CCM from Malawi, higher
temperature, neck stiffness, and lower Glasgow Coma Scale
score were associated with TBM.24 Routine CSF profiles can be
similar with lymphocytic pleocytosis, elevated protein, and
low glucose. HIV-infected patients with unknown CD4 levels
or current CD4 levels less than 200 cells/mm3 should have
testing for cryptococcal antigen in CSF (or serum if CSF cannot
be obtained) in addition to testing for TBM (nucleus acid
testing and/or culture). Cases of concurrent TBM and CCM
Seminars in Neurology Vol. 39 No. 4/2019
have been reported.25 In both immunocompromised and
immunocompetent patients presenting with subacute menin-
gitis, other fungal etiologies (e.g., Aspergillus) need to be
considered. In a review of 93 cases of Aspergillus meningitis,
20 of 56 cases with CSF glucose measurements had values less
than 25 mg/dL. Median CSF white blood cell counts (678/mm3)
and median CSF protein levels (1007 mg/dL) were higher than
typically seen in cases of TBM.26
Hydrocephalus, communicating or obstructive, is found
on brain imaging in approximately 50% of TBM cases and can
be the sole neurological complication.27 The frequency and
severity of hydrocephalus may be higher in children and
require early intervention with ventriculoperitoneal shunt-
ing.28,29 Inflammatory involvement of cerebral vessels in
TBM results in infarcts seen on brain magnetic resonance
imaging (MRI) in approximately 25% of cases.27 Unilateral or
bilateral basal ganglia infarcts are most common due to
involvement of lenticulostriate arteries. In an autopsy series
of 51 TBM cases from India, infarcts were found in 37 cases—
27 with macroscopic infarcts and 10 with microscopic
infarcts.30 Arterial aneurysms were found in two cases,
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and dural or cortical venous thrombosis in nine cases. TBM
should be considered in the differential diagnosis of subar-
achnoid hemorrhage and cerebral venous thrombosis. Tuber-
culomas, single or multiple, can be found in the cerebrum,
brainstem, cerebellum, and/or spinal cord.27
Isolated Tuberculoma
Case 2
A 36-year-old female in Uganda presented with complaints
of progressive headaches, ataxia, and diplopia for 3 months.
She was on antiretroviral therapy (ART) with a CD4 cell count
of 491 cells/mm3. On examination, she was alert and
oriented, with normal mentation. A complete left abducens
nerve palsy was noted in addition to mild gait ataxia. Neck
was supple. CSF analysis demonstrated <5 white blood cells/
mm3, protein 55 mg/dL, and glucose 4.0 mmol/L (72 mg/dL)
with serum glucose 4.9 mmol/L (88 mg/dL). ZN stain, Gram
stain, India ink preparation, and cryptococcal antigen test of
CSF were all negative. CSF Xpert MTB/RIF was negative.
Contrast-enhanced brain CT revealed multiple round lesions
(pons, left temporal lobe, left parietal lobe, right frontal lobe)
appearing isodense or hypodense to gray matter and demon-
strating robust ring-like enhancement. The lesion in the pons
(►Fig. 2A) had a lobulated appearance. The following blood
tests were negative: treponemal antibody, anti-Toxoplasmo-
sis IgG and IgM, and anti-Taenia solium IgG. The patient was
started on ATT with standard doses of HRZE and dexametha-
sone (6-week tapering regimen). MGIT culture of CSF was
negative at 6 weeks. Repeat contrast-enhanced brain CT after
6 months of ATT demonstrated complete resolution of all of
the ring-enhancing lesions and no new abnormalities
(►Fig. 2B). The patient’s abducens nerve recovered to com-
pletely normal function. ATT was continued for a total
treatment duration of 12 months.
The clinical presentation of isolated tuberculomas
depends on the number, size, and location of the
 Neurotuberculosis: A Clinical Review Chin 459

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Fig. 2 Case 2, isolated tuberculomas (see text for descriptions): (A) axial contrast-enhanced brain CT image before treatment; (B) axial contrast-
enhanced brain CT image after 6 months of ATT. ATT, anti-tuberculosis therapy; CT, computed tomography.

tuberculomas. Symptoms can include headaches, seizures,
confusion, visual symptoms, hemiparesis, paraparesis, and
ataxia. Tuberculomas are typically isointense or hypointense
to gray matter on CT and MRI imaging (both T1- and T2-
weighted sequences) and demonstrate homogenous or ring-
like enhancement with contrast administration.31,32 A lobu-
lated appearance or multiple conglomerated rings are com-
mon and may suggest tuberculoma over neoplasm.
Variable degrees of perilesional edema and mass effect are
observed. Single large tuberculomas can mimic primary
brain neoplasms.32 Differentiating tuberculomas from
metastases and other infectious etiologies of ring-enhancing
brain and spinal cord lesions can be challenging,33 especially
in the absence of TBM or other forms of EPTB. In highly
immunosuppressed patients, testing of serum for Toxo-
plasma gondii antibodies and serum and CSF for cryptococcal
antigen is essential. If biopsy confirmation is not possible,
empiric treatment of suspected tuberculomas with ATT is
justified in a high-prevalence TB setting.
Vertebral Tuberculosis
Case 3
A 53-year-old female in Uganda experienced nontraumatic
upper back pain radiating to the anterior chest. Four weeks
later, she developed bilateral lower extremity weakness
progressing to complete paralysis over 6 days with sensory
loss and urinary retention. The patient was on first-line ART
for 3 years and compliant with her treatment. She was an
urban dweller with no contact with livestock. MRI of the
spine revealed disc space loss at T3-T4 with abscess forma-
tion surrounding the vertebrae and extending into the ante-
rior epidural space (►Fig. 3A, B). Chest X-ray (CXR) showed
hilar enlargement and right lung infiltrates suggestive of TB

Fig. 3 Case 3, vertebral tuberculosis (see text for descriptions): (A) sagittal T2-weighted MRI image of upper thoracic spine, (B) axial T2-
weighted MRI image of spine at T4 vertebral level, (C) chest X-ray. MRI, magnetic resonance imaging.

Seminars in Neurology Vol. 39 No. 4/2019

460 Neurotuberculosis: A Clinical Review Chin
(►Fig. 3C). Examination demonstrated paraplegia with loss
of sensation below the mid-chest level. Standard dose ATT
with HRZE and dexamethasone (6-week tapering regimen)
was initiated for presumed TB with a prescribed duration of
treatment of 12 months.
TB of the spine, commonly known as “Pott’s disease,’
begins with MTB seeding through the arterial supply of the
vertebrae which arises from the vertebral, intercostal,
lumbar, or sacral arteries. Involvement of adjacent verteb-
rae and discs is common due to extensive anastomoses of
the segmental arterial supply along the anterolateral sur-
faces of the vertebral bodies.34 Progressive subacute infec-
tion leads to development of characteristic TB abscesses
around the vertebrae and eventual collapse of the vertebral
elements leading to angular deformity of the spine. Para-
paresis and paraplegia occur due to mechanical compres-
sion of the spinal cord. Less commonly, paraplegia can
occur without vertebral involvement as a result of TBM
with vasculitic thrombosis of the arterial supply to the
spinal cord or intramedullary tuberculomas. In resource-
limited settings, plain X-rays are often adequate to demon-
strate the typical abnormalities for making a presumptive
diagnosis of TB of the spine. CT or MRI studies should be
obtained, if available, when X-rays are nondiagnostic and
clinical suspicion is high.
Treatment Guidelines
Evidence-based guidelines for the treatment of neurotuber-
culosis are lacking. Recommended ATT regimes for TBM only
are provided by the WHO and national TB programs, and use
the standard four drugs for drug-sensitive PTB (HRZE). The
WHO recommends 2 months of intensive treatment with
HRZE followed by 7 to 10 months of HR. Initial adjuvant
corticosteroids (dexamethasone or prednisolone) are
recommended with tapering over 6 to 8 weeks.35–37 National
guidelines of India for treatment of TBM recommend
2 months of HRZE followed by a minimum 7 months of
HRE or HRZ in addition to corticosteroids for at least
4 weeks.38 National guidelines of South Africa for treatment
of TBM recommend 2 months of HRZE followed by 7 months
of HR in addition to corticosteroids for 2 to 4 weeks and
“taper off gradually over several weeks depending on clinical
progress.”39 A Cochrane review of nine trials of adjuvant
corticosteroids for treatment of TBM found a mortality
benefit of corticosteroids but no reduction in the number
of survivors with disabling neurological deficits.40 Pyridox-
ine 25 mg daily should be added to all regimens to prevent
peripheral neuropathy caused by isoniazid. There is inade-
quate published data to make recommendations regarding
initiation of ART in patients with TBM and HIV coinfection.
One randomized, double-blind, placebo-controlled study
from Vietnam found no difference in outcomes between
immediate ART and delayed ART (2 months).41 Finally,
specific recommendations for treatment of drug-resistant
TBM are not available and discussion of drug-resistant TB is
beyond the scope of this review. The reader is referred to the
excellent review by Dheda et al.42
Seminars in Neurology Vol. 39 No. 4/2019
Conclusions
TB is a curable disease. Reducing the mortality and morbidity
from neurotuberculosis will require greater global invest-
ments in research and clinical capacity to improve access to
diagnostic technologies, identify drug resistance, develop
more effective and shorter treatment regimens, and provide
patient support to ensure treatment success. Early diagnosis
and initiation of ATT is the best intervention to reduce the
risk of death and neurological complications of neurotuber-
culosis. Genotype analyses of MTB complex isolates from
patients with TBM may identify lineages and strains with a
higher fitness for causing TBM, potentially leading to
improved therapeutics. Finally, a validated clinical algorithm
for the presumptive diagnosis of TBM and initiation of
treatment in resource-limited settings with only basic
laboratory facilities, particularly in rural areas, is urgently
needed to reduce the global burden of neurotuberculosis.
Conflict of Interest
Downloaded by: University of Utah. Copyrighted material.
None
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