REVIEW ARTICLE
Tuberculosis of the

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
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CITE AS:
CONTINUUM (MINNEAP MINN)
2018;24(5, NEUROINFECTIOUS
DISEASE):1422–1438.
Address correspondence to
Dr Joseph R. Zunt, Harborview
Medical Center, 325 Ninth Ave,
Box 359775, Seattle, WA 98104,
jzunt@uw.edu.
RELATIONSHIP DISCLOSURE:
Dr Zunt receives research/grant
support from the National
Institutes of Health (2D43
TW009345-06,
1D43TW009137-01A1,
1D43TW009375-01A1,
1D43TW009763-01).
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Zunt reports no disclosure.
© 2018 American Academy
of Neurology.
1422
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Central Nervous System
By Joseph R. Zunt, MD, MPH
ABSTRACT
PURPOSE OF REVIEW: This article details the epidemiology and clinical
manifestations of central nervous system (CNS) tuberculosis (TB), provides
guidance for diagnostic imaging and CSF testing, and recommends
treatment strategies for tuberculous meningitis and other forms of CNS TB,
illustrating key aspects of diagnosis and management with case
presentations.
RECENT FINDINGS:Although improvements in our understanding of the
pathogenesis and management of CNS TB have occurred over the past
50 years, the emergence of multidrug-resistant and extensively
drug-resistant TB, the advent of acquired immunodeficiency syndrome
(AIDS), and the subsequent availability of highly active antiretroviral
therapy that can produce the immune reconstitution inflammatory
syndrome have complicated the diagnosis and treatment of CNS TB.
Advances in diagnostic assays promise to increase the speed of diagnosis
as well as the percentage of people with a confirmed rather than a
presumptive diagnosis. Advances in precision medicine have identified
polymorphisms in the LTA4H gene that influence the risk for inflammation
in patients with tuberculous meningitis.
SUMMARY: CNS TB continues to be a major cause of morbidity and mortality,
with the majority of people affected living in low-income and middle-
income countries. Newer diagnostic assays promise to increase the speed
of diagnosis and improve appropriate selection of antituberculous therapy
and anti-inflammatory medications. Despite these advances, CNS TB
remains difficult to diagnose, and clinicians should have a low threshold
for initiating empiric therapy in patients with presumptive infection.
INTRODUCTION
A
ccording to the World Health Organization (WHO), seven
countries account for 64% of the world’s tuberculosis (TB)
infections: India, China, Indonesia, Philippines, Pakistan, Nigeria,
and South Africa; this distribution of TB closely mirrors the
distribution of poverty, malnutrition, and low income.1 Risk factors
for acquiring pulmonary TB include malnutrition, human immunodeficiency
virus (HIV) infection, injection drug use, diabetes mellitus, chronic use of
corticosteroids, chronic renal failure/hemodialysis, silicosis, solid organ
transplantation, and carcinoma of the head or neck.2
OCTOBER 2018
 Risk factors for developing central nervous system (CNS) TB include KEY POINTS
malnutrition, alcoholism, concomitant malignancy, use of immunosuppressive
● Although central nervous
medications, HIV infection, recent measles, and measles in childhood.3–8 Studies system tuberculosis (TB)
in developed countries have also identified that individuals born outside of occurs most often as a
developed countries are overrepresented among CNS TB cases.9 Although CNS complication of pulmonary
TB occurs most often as a complication of pulmonary TB, imaging of the lungs TB, imaging of the lungs may
reveal what appears to be
may reveal what appears to be quiescent infection; it is not uncommon to have
quiescent infection; it is not
CNS TB manifest in individuals who were treated for pulmonary TB years or uncommon to have central
even decades previously. nervous system TB manifest
in individuals who were
treated for pulmonary TB
HUMAN IMMUNODEFICIENCY VIRUS COINFECTION years or even decades
More than 50% of people with HIV/TB coinfection develop extrapulmonary previously.
TB, and individuals who are HIV positive are up to 5 times more likely to
● More than 50% of
develop CNS involvement during TB infection than individuals who are people with human
HIV negative.10,11 In addition, paradoxical development of intracranial immunodeficiency virus
tuberculomas has been reported in patients receiving adequate antiretroviral and (HIV)/TB coinfection
antituberculous treatment.12,13 HIV infection also increases the risk for both develop extrapulmonary TB,
and individuals who are HIV
acquiring TB and for progression from latent infection to active disease.14,15 positive are up to 5 times
For patients with advanced HIV infection, highly active antiretroviral therapy more likely to develop
(HAART) decreases the risk for both acquisition and progression of TB as well central nervous system
as the incidence of opportunistic infection and death.16,17 Given the higher involvement during TB
infection than individuals
likelihood of developing TB in the setting of HIV coinfection as well as the who are HIV negative.
association of HIV infection with worse outcome of TB, HIV testing should be
performed in all patients diagnosed with TB.18 ● Given the higher
likelihood of developing TB
in the setting of HIV
TUBERCULOUS MENINGITIS infection as well as the
The most common manifestation of CNS TB is tuberculous meningitis, which association of HIV infection
with worse outcome of TB,
occurs most frequently in young children (especially those younger than 1 year of HIV testing should be
age); at presentation, 75% of children have active pulmonary TB, and performed in all patients
tuberculous meningitis occurs most often within 3 months of primary diagnosed with TB.
infection.19–21 Rich and McCordock22 initially hypothesized that tuberculous
● The most common
meningitis resulted from an extension of infection into the subarachnoid space
symptoms of tuberculous
from a caseating focus in the adjacent cortex (the Rich focus). A later hypothesis meningitis include fever,
agreed with this theory but also suggested that initial hematogenous vomiting, and apathy. Given
dissemination could result in a meningeal or cortical focus that produced the frequent involvement of
immediate or delayed tuberculous meningitis.23 One confirmation of this route the basilar meninges and
ambient cistern in
of dissemination occurred in a man who attempted suicide by injection of viable tuberculous meningitis,
TB bacilli into his antecubital vein and 86 days later developed cranial nerve dysfunction is
tuberculous meningitis.24 frequent. On neuroimaging,
The neurologic manifestations of tuberculous meningitis can develop a common triad of findings
includes basilar meningeal
insidiously or in an abrupt manner similar to bacterial or viral meningitis. The enhancement,
most common symptoms of tuberculous meningitis include fever, vomiting, and hydrocephalus, and
apathy. Given the frequent involvement of the basilar meninges and ambient infarctions in the
cistern in tuberculous meningitis, cranial nerve dysfunction is frequent, with supratentorial brain
parenchyma and brainstem.
cranial nerves VI (abducens), VII (facial), and II (optic) most often affected.25
On neuroimaging, a common triad of findings includes basilar meningeal
enhancement, hydrocephalus, and infarctions in the supratentorial brain
parenchyma and brainstem.26 CASE 8-1 illustrates a typical presentation of a
patient with tuberculous meningitis.

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TUBERCULOSIS OF THE CNS

Hydrocephalus is a common complication of tuberculous meningitis. When

CSF protein is greater than 500 mg/dL, obstruction of CSF flow can occur and
produce subarachnoid block, leading to hydrocephalus.27 Obstruction occurs
most often in the basilar cisterns at the tentorial aperture when septa traversing
this space are occluded by fibrin deposits, producing hydrocephalus that can
cause a falsely low opening pressure with absence of the normal rise of opening
pressure during jugular compression.21

TUBERCULOMA (TUBERCULOUS GRANULOMA)

Ten percent of patients with tuberculous meningitis also have tuberculomas;
with one-third of such patients having multiple tuberculomas.28 The clinical
presentation of CNS tuberculoma varies with the location of the lesion(s) but

CASE 8-1 A 17-year-old boy presented to an outside emergency department with

2 weeks of headache, nausea, and vomiting. His initial evaluation was
unremarkable, and he was discharged home with the diagnosis of a viral
syndrome. He continued to have headaches and fevers; 1 week later, he
was found by his mother at home unresponsive and noncommunicative,
and she called 911.
On arrival, his mother also reported that he had lost 13.6 kg (30 lb) over
the past 3 months. He was born in the Philippines, moved to the United
States at 3 years of age, and had last been in the Philippines 2 years
before presentation. Five months before presentation, he was noted to
have a positive purified protein derivative (PPD) test and had been taking
isoniazid for a planned 9-month course.
On neurologic examination, he was somnolent; he opened his eyes
spontaneously but did not follow commands. His cranial nerve
examination was limited by somnolence, but he had limited lateral gaze
bilaterally. He localized to noxious stimuli in all limbs, and he had a
Babinski sign on the right.
Laboratory evaluation was notable for a serum sodium of 124 mEq/L.
Initial head CT without contrast revealed hydrocephalus with
transependymal flow. CSF was notable for 227 white blood cells/mm3
(60% lymphocytes), protein of 140 mg/dL, and glucose of 29 mg/dL. CT of
the chest, abdomen, and pelvis was unremarkable. Brain MRI showed
leptomeningeal enhancement (including the basilar meninges) and
hydrocephalus (FIGURE 8-1).
He underwent ventriculoperitoneal shunt placement, and, although
his CSF acid-fast bacilli smear and culture as well as Mycobacterium
tuberculosis polymerase chain reaction (PCR) were negative, he was
started on treatment for presumptive tuberculous meningitis with
isoniazid, pyrazinamide, rifampin, ethambutol, and dexamethasone.
He completed 12 months of treatment, and, 15 months after initial
presentation, he had gained 50 pounds, was attending community
college full time, had a part-time job, and had no physical or cognitive
deficits.

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typically includes headache, seizures, focal neurologic deficits, and
papilledema.29 Tuberculomas can develop in the brain; spinal cord; or
subarachnoid, subdural, or epidural space and are often accompanied by
surrounding edema and ring enhancement.26 On neuroimaging, tuberculomas
are typically space-occupying lesions; as the center of the tuberculoma caseates
and becomes liquefied, neuroimaging characteristics on T2-weighted and
fluid-attenuated inversion recovery (FLAIR) MRI sequences change from
hypointense to isointense to hyperintense.30 The neuroimaging characteristics of
CNS tuberculoma change according to the age of the lesions and none are
pathognomonic for CNS tuberculoma.31,32 While in adults, tuberculomas are
typically supratentorial, in children, lesions are often infratentorial.33 The
CSF of patients with tuberculomas is typically unremarkable, while the

FIGURE 8-1
Imaging of the patient in CASE 8-1. A, Coronal postcontrast T1-weighted MRI shows diffuse
enhancement of the leptomeninges (more prominent on the right), including the basilar
meninges, as well as ventriculomegaly. B, Axial postcontrast T1-weighted MRI shows diffuse
enhancement adjacent to the ambient cistern as well as enlargement of the temporal horns
of the lateral ventricles.

This case illustrates how tuberculous meningitis can present with subacute COMMENT
onset of symptoms and the benefits of starting anti-TB treatment even
when CSF testing does not confirm the diagnosis. The patient’s clinical
presentation with recent weight loss, diffuse meningitis on MRI,
hyponatremia, and recent conversion to a positive PPD raised the suspicion
for tuberculous meningitis.

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TUBERCULOSIS OF THE CNS

tuberculin skin test is positive in up to 85% and chest radiography is abnormal

in 30% to 80%.34

TUBERCULOUS ABSCESS
Tuberculous abscess occurs in less than 10% of patients with CNS TB and
likely represents a later stage of tuberculoma that occurs after granulation; an
abscess contains many more bacilli than a granuloma.36 The clinical symptoms
produced by a tuberculous abscess typically include fever, headache, and focal
neurologic deficits.29 Differentiation between tuberculoma and tuberculous
abscess can be difficult by neuroimaging, but an abscess wall tends to be
thicker, can be multiloculated, and typically has robust contrast

CASE 8-2 A 43-year-old man presented for a second neurologic opinion. Seven
months prior he had presented to an outside emergency department
because of expressive dysphasia and progressive somnolence, and MRI
showed a left frontal brain mass with heterogeneous gadolinium
enhancement with mild surrounding edema (FIGURE 8-2A). The presumptive
diagnosis was glioma, and he underwent biopsy, which was
nondiagnostic. His speech continued to worsen, and 1 month later he
developed a right hemiparesis. Reevaluation disclosed a 5 cm by 7 cm
heterogeneously enhancing left frontal mass. He underwent complete
resection of the mass. Neuropathology revealed no evidence of glial or
lymphoid neoplasm; Gram stain, Gomori methenamine-silver stain, and
acid-fast stains did not reveal microorganisms.

FIGURE 8-2
Axial postcontrast T1-weighted MRIs of the patient in CASE 8-2. A, Heterogeneous gadolinium
enhancement with mild surrounding edema is seen. B, After resection, and after 3 months
of treatment for central nervous system tuberculous abscess, the heterogeneous
enhancement has transitioned to ring enhancement. Perilesional edema is still present. C,
After 12 months of antituberculous therapy, resolution of enhancement and edema is seen.
Residual encephalomalacia is present.

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enhancement.37 CASE 8-2 illustrates an insidious presentation of CNS
tuberculous abscess. On diffusion-weighted imaging (DWI) sequences, MRI
may demonstrate restricted diffusion in tuberculomas or abscesses with
liquefied caseation but, typically, this is absent in lesions that have only
solid caseation.38

RADICULOMYELITIS
Tuberculous radiculomyelitis is an uncommon complication of TB infection
that can occur as an initial manifestation of CNS TB, as an extension of TB
infection of an adjacent vertebra, or as a complication of tuberculous
meningitis.39 Tuberculous radiculomyelitis typically produces a subacute,

Seven months after initial presentation, he was referred to the author’s

neurology clinic. The patient was born in Korea and had moved to the
United States 2 years before presentation. He reported having pulmonary
tuberculosis (TB) approximately 10 years previously, which was treated
with oral medications for 1 year. He denied having fevers, chills, or cough
but endorsed mild weight loss.
On examination, he had frequent difficulty with word finding and was
unable to name a straw or paper clip. He had a right lower facial droop,
and hearing was reduced in his left ear. He had a mild right hemiparesis
and asymmetry of deep tendon reflexes (right greater than left). Pinprick
sensation was reduced over the right body.
CT of the chest revealed calcified lung granulomas and mediastinal
lymph nodes, consistent with prior granulomatous disease. Examination
of a paraffin block of brain tissue from the initial biopsy was resubmitted
to the molecular microbiology laboratory for mycobacterial polymerase
chain reaction (PCR) and revealed mycobacterial DNA sequences
consistent with central nervous system TB. A follow-up MRI after
3 months of four-drug anti-TB treatment showed the heterogeneous
enhancement had transitioned to ring enhancement. Perilesional edema
was still present (FIGURE 8-2B).
After 18 months of anti-TB therapy, his neurologic examination
improved to normal motor strength in all limbs without pronator drift and
halting but fluent speech. MRI of his brain continued to show
improvement, with mild persistent enhancement. After 12 months of
anti-TB therapy, MRI showed resolution of enhancement and edema, with
residual encephalomalacia still present (FIGURE 8-2C).

This case illustrates the difficulty of recognizing tuberculous abscess COMMENT

through neuroimaging, the frequent delay between prior pulmonary TB and
the development of central nervous system TB, and the utility of advanced
diagnostics, in this case mycobacterial PCR, to make the diagnosis of TB
granuloma. The majority of cases of TB in the United States occur in people
who are born outside the United States.35

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TUBERCULOSIS OF THE CNS

gradually progressive, lower limb weakness with bladder dysfunction,

paresthesia, radicular pain, and muscle wasting. Neuroimaging of tuberculous
radiculomyelitis often reveals obliteration of the spinal subarachnoid space,
loss of spinal cord landmarks, clumping of nerve roots, and nodular
intradural enhancement.40 Despite the absence of a randomized controlled
trial of steroid treatment for tuberculous radiculomyelitis, most experts
recommend concomitant administration of steroids to accompany
antituberculous therapy.39,41

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME

The immune reconstitution inflammatory syndrome (IRIS) is an inflammatory
response to a prior or undiagnosed infection that can develop in patients with
HIV infection shortly after starting HAART.42–44 IRIS produces two distinct
clinical syndromes: unmasking and paradoxical. Both syndromes respond
favorably to steroids, but unmasking IRIS requires treatment of the underlying
infection as well.45–48
Unmasking IRIS occurs when an occult infection that had previously not
produced signs or symptoms is recognized by the host immune system that
is recovering within the first months of HAART treatment. Paradoxical IRIS is
the recurrence of inflammation against a previously treated infection that is
driven by host recognition of antigens by an immune system that is recovering
through HAART treatment; this can occur in the setting of few or no viable
organisms, and cultures are typically negative. IRIS most frequently occurs in
adults, with 17% to 32% of adults developing IRIS after initiating HAART.44,46,49,50
Approximately 18% of patients with TB who are HIV infected and initiate
HAART will develop IRIS. Mycobacterium tuberculosis–associated IRIS most
often manifests as fever with clinical deterioration of preexisting
lymphadenopathy (in 70%) or respiratory disease (in 30%).51 Mycobacterial
infection associated with IRIS typically occurs in patients with a median CD4+
count of less than 50 cells/mm3 and a median of 4 weeks after starting
HAART.52 In addition to Mycobacterium species, a variety of other pathogens
have been associated with IRIS; those of interest to neurologists include
cytomegalovirus, Cryptococcus neoformans, varicella-zoster virus, and
Toxoplasma gondii.

DIAGNOSIS
Because of the paucity of TB organisms in the CSF, diagnosis of CNS TB can
be difficult. A wide range of diagnostic assays are available; this article
discusses the categories of assays and provides an approach to making the
diagnosis of CNS TB infection. Hyponatremia is present in nearly 45% of
patients with tuberculous meningitis and is most often due to cerebral
salt wasting.53

Test Sensitivity and Specificity

The diagnostic sensitivity of a test for a CNS infection is defined as the
proportion of persons with a CNS infection who have a positive test result, while
specificity is the proportion of persons without a CNS infection who have a
negative test result. Although the optimal CSF test would confirm CNS infection
in all persons with an infection and exclude infection in all persons without the
disease (100% sensitivity and 100% specificity), most tests are either highly

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sensitive or highly specific but not both. If the diagnostic sensitivity is low, a high KEY POINTS
proportion of tests will not detect an infection when one is present (many false
● On neuroimaging,
negatives), while if the specificity is low, a high proportion of tests will report an tuberculomas are typically
infection when one is not present (many false positives). As most CNS infections space-occupying lesions;
are serious and many are treatable, it is often more important that a CSF test be as the center of the
highly sensitive so the diagnosis of CNS infection is not missed. tuberculoma caseates
and becomes liquefied,
neuroimaging
Cerebrospinal Fluid characteristics change
One of the first descriptions of lumbar puncture was provided by Wynter54 in from hypointense to
1891 when he used a trocar to relieve hydrocephalus associated with tuberculous isointense to hyperintense.
meningitis in four patients. Compared to other CNS infections, tuberculous
● The immune
meningitis typically produces a mild pleocytosis similar to that caused by viral or reconstitution inflammatory
fungal meningitis but with a protein level higher than most other forms of CNS syndrome is an inflammatory
infection. In a study of 84 patients with tuberculous meningitis, CSF white blood response to previous or
cell count in 253 samples ranged from 5 cells/mm3 to 2021 cells/mm3, with 85% of undiagnosed infection that
can develop in patients with
samples between 50 cells/mm3 and 500 cells/mm3.27 CSF protein is frequently HIV infection shortly after
elevated during tuberculous meningitis, and if CSF is allowed to stand at room starting highly active
temperature for 6 to 12 hours, the protein may spontaneously form into a fine antiretroviral therapy.
fibrin clot (also called a pellicle or spiderweb).27 Longitudinal studies of CSF
● Hyponatremia is present
abnormalities have demonstrated delayed normalization of protein level and cell
in almost half of patients
count; in only two (4%) of 45 patients was the protein level normal at 6 months, with tuberculous meningitis
and in six (13%) normalization took more than 1 year.55 The median time to CSF and should alert the
protein normalization was 8 months. For CSF cell count, although the count had practitioner to not only the
possible diagnosis of
dropped by 50% after 1 month for 96% of patients, 36% had abnormal CSF cell
tuberculous meningitis but
counts at 6 months and 16% at 24 months. Normalization of CSF glucose occurred also the need for addressing
much faster, with 58% returned to normal after 1 month and 88% normal after hyponatremia to avoid
2 months. potential complications.

● Compared to other
Adenosine Deaminase central nervous system
Adenosine deaminase (ADA) is an enzyme in purine metabolism associated with infections, tuberculous
proliferation and differentiation of lymphocytes. ADA is produced by the meningitis typically
cerebral cortex and lymphoid tissue, with elevated levels reflecting nonspecific produces a mild pleocytosis
similar to that caused by
CNS damage and increased permeability of the blood-brain barrier. Elevated viral or fungal meningitis
ADA in the CSF accompanies most forms of meningitis and is closely correlated but with a protein level
with levels of CSF protein.56 In many parts of the world, CSF mycobacterial higher than most other
culture and PCR are not available, and the ADA assay is often used to help forms of central nervous
system infection.
distinguish between meningitis due to M. tuberculosis and meningitis caused
by bacteria or viruses. Although elevated ADA levels are not specific for ● CSF culture typically
tuberculous meningitis, elevated levels have been associated with poor takes 2 to 4 weeks to
prognosis of tuberculous meningitis in children.57 In one meta-analysis, ADA become positive, so when
values greater than 8 U/L improved the diagnosis of tuberculous meningitis central nervous system TB
is suspected, empiric
(sensitivity <59% and specificity >96%), but most experts agree that other treatment for presumptive
pathogens, especially bacterial, should be ruled out before attributing the central nervous system
infection to M. tuberculosis.58 TB should be initiated
before confirmation.
Acid-fast Bacilli Stain and Culture
CNS TB is difficult to diagnose using traditional Ziehl-Neelsen (acid-fast
bacilli) stain and mycobacterial culture and has the highest yield when
performed by an experienced technician. When only one CSF examination is
performed, the sensitivity of smear and culture are 37% and 52%, respectively,

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TUBERCULOSIS OF THE CNS

while if three CSF samples are examined, the yield increases to 87% and 83%.59
Unfortunately, CSF culture typically takes 2 to 4 weeks to become positive,
so when CNS TB is suspected, empiric treatment for presumptive CNS TB
should be initiated before confirmation.59 HIV status should be ascertained at
the time of diagnosis as coinfection decreases both the sensitivity and
specificity of TB testing as well as the differential diagnosis of CNS lesions,
especially solitary CNS lesions.

Tuberculosis Polymerase Chain Reaction

Most PCR assays for M. tuberculosis detection amplify the MPB64 gene or
IS6110, an insertion element with multiple copies in the genome of M.
tuberculosis. The sensitivity and specificity of PCR assays for M. tuberculosis are
highly dependent upon the diagnostic criteria used, the amount of CSF
sampled, and whether antituberculous therapy was administered before the
collection of CSF.60–63 Two PCR assays for detection of M. tuberculosis
have been approved in the United States for testing of respiratory specimens:
the Amplified MTB Direct Test and the Amplicor MTB assay. These tests
can be performed on CSF samples. The PCR assays can be more sensitive
than CSF culture, but diagnosis of tuberculous meningitis cannot be excluded
on the basis of a negative PCR result. Where laboratory facilities are
available, TB PCR assays can provide a valuable additional tool for
detecting infection.

CARTRIDGE-BASED NUCLEIC ACID AMPLIFICATION TEST. A cartridge-based

nucleic acid amplification test that can detect M. tuberculosis in clinical
specimens as well as mutations associated with rifampin resistance is available;
this same-day detection of rifampin-resistant bacteria can influence the
decision to switch to second-line agents. In 2013, the WHO endorsed the Xpert
MTB/RIF assay as the preferred initial test to investigate tuberculous
meningitis.64
Since the WHO endorsement, an improved assay from the same manufacturer
has been released, with initial studies suggesting this assay is more sensitive and
specific for the diagnosis of tuberculous meningitis. The advanced assay uses a
larger chamber for DNA amplification and two additional molecular targets to
detect TB. In a prospective cohort of 129 patients with HIV infection and
suspected tuberculous meningitis, the assay had greater sensitivity for diagnosis
of tuberculous meningitis than culture or the earlier assay, with 95% sensitivity,
compared with 45% sensitivity using the previous assay or mycobacteria growth
indicator tube culture.65 Of 21 cases detected by the advanced assay, eight (38%)
had not been detected by previous tests. Although the yield of CSF testing has
increased with these tests, neither has reached 100% sensitivity, so the clinician
with a high index of suspicion for CNS TB (eg, a patient with meningitis in the
setting of hyponatremia and pulmonary adenopathy) should still consider
initiating empiric antituberculous treatment.

Biopsy
Biopsy can be a useful ancillary test for patients with solitary enhancing lesions or
chronic meningitis with persistently negative cultures. Although the sensitivity
of biopsy is unknown, in theory, examination of infected tissue with Ziehl-
Neelsen (acid-fast bacilli) staining, culture, and PCR assays should increase the

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diagnostic yield. For instances when CNS TB was not suspected at the time of KEY POINT
biopsy, the health care provider should consider sending formalin-fixed or
● Given the multiple
paraffin-embedded tissue for PCR assays despite the lower sensitivity than for potential interactions and
fresh tissue. complications of
medications used for the
treatment of tuberculous
TREATMENT meningitis and HIV
For treatment of tuberculous meningitis, the WHO recommends the same infections, consultation with
combination and duration of medications as for pulmonary TB: 2 months of an infectious diseases
specialist is recommended
rifampin, isoniazid, pyrazinamide, and ethambutol, followed by 10 months of to provide expert
rifampin and isoniazid.66 Empiric treatment should be started if CNS TB is management of these
suspected rather than waiting for confirmation, with treatment based on HIV treatments.
status and presumed susceptibility of the TB organism. Unfortunately,
determining susceptibility requires either a nucleic acid assay that can detect M.
tuberculosis as well as gene mutations associated with resistance, such as the
rpoB gene mutations associated with rifampin resistance, or traditional culture
of the organism (the latter of which is typically not available for weeks or
months after treatment has been started). Of the available antituberculous
medications, isoniazid and pyrazinamide have the best penetration into the
subarachnoid space67:

u Isoniazid: CSF/serum concentration ratio is 40% with normal meninges, and the CSF level
equals the serum level when the meninges are inflamed. Dosage is 10 mg/kg/d orally
for adults (administer with 50 mg/d to 100 mg/d oral pyridoxine).
u Rifampin: CSF/serum concentration ratio is poor with normal meninges and 20% with
inflamed meninges (less than minimal inhibitory concentration for pan-sensitive
M. tuberculosis). Dosage is 15 mg/kg/d orally for adults.
u Ethambutol: CSF/serum concentration ratio is poor without meningeal inflammation
but reaches adequate minimal inhibitory concentration levels in the presence of
meningeal inflammation. Dosage is typically 15 mg/kg/d orally; higher dosage of 25 mg/kg/d
to 35 mg/kg/d orally achieves better minimal inhibitory concentration but increases the
incidence of optic neuritis (2% at 25 mg/kg/d orally).
u Pyrazinamide: CSF/serum concentration ratio is similar to isoniazid with dosage of 30 mg/kg/d
to 35 mg/kg/d orally.
u Streptomycin: CSF/serum concentration ratio is nearly zero without meningeal inflammation
and poor even when meningeal inflammation is present. Dosage is 1g/d IM in adults.

Tuberculosis Resistance
The treatment of all forms of TB has been complicated by the emergence
of drug resistance. Multidrug-resistant TB is defined as TB resistant to
isoniazid and rifampin. Although multidrug-resistant TB can be transmitted,
it most often develops when a patient with fully sensitive TB does not
complete treatment, is not adherent to recommended treatment, or receives
inappropriate treatment.68 Extensively drug-resistant TB is defined as
TB resistant to isoniazid, rifampin, an antibiotic in the quinolone family,
and at least one of the second-line injectable treatments kanamycin,
capreomycin, or amikacin.69 Both multidrug-resistant TB and extensively
drug-resistant TB have been detected in all regions of the world.70 The
WHO recommends all patients with multidrug-resistant TB or extensively
drug-resistant TB receive a directly observed treatment strategy plus a
second-line anti-TB medication.

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TUBERCULOSIS OF THE CNS

Treatment With Human Immunodeficiency Virus Coinfection

For patients newly diagnosed with HIV and TB infections, if the CD4+ T-cell
count is less than 50 cells/mm3, early initiation of antiretroviral therapy (ART)
reduces mortality and the risk of opportunistic infections; for those with
CD4+ T-cell counts of 50 cells/mm3 or higher, HAART should be started 2 to
12 weeks after TB treatment has been started. Some antituberculous medications,
such as the rifamycins, can decrease serum concentrations of protease inhibitors
and some non-nucleoside reverse transcriptase inhibitors, potentially making
them ineffective.71
In 2017, the WHO reconfirmed its recommendations regarding HIV
therapy in patients with TB coinfection: (1) HIV treatment should be started
regardless of CD4+ T-cell count; (2) TB treatment should be initiated first,
followed by ART as soon as possible within the first 8 weeks of treatment; and
(3) patients with profound immunosuppression (eg, CD4+ T-cell counts less
than 50 cells/mm3) should receive ART within the first 2 weeks of initiating
TB treatment.66

Paradoxical Expansion
Paradoxical expansion is defined as the increase in size of an existing tuberculoma
or development of a new tuberculoma despite appropriate antituberculous
treatment; this expansion typically occurs within 3 months of starting treatment
and is associated with neurologic deterioration. Paradoxical expansion in patients
who are HIV infected and receiving HAART suggests that immune reconstitution
may contribute to paradoxical expansion.72 In a report of 23 patients with
paradoxical expansion, one patient died, approximately 25% had residual neurologic
symptoms, and less than one-third required surgical intervention.73 Although no
randomized trial of corticosteroid treatment for paradoxical expansion has been
conducted, most experts believe corticosteroids improve neurologic symptoms
and outcome and that antituberculous treatment should be extended to 12 to
18 months.

Corticosteroids
The use of corticosteroids has become increasingly accepted and recommended
as concomitant treatment of CNS TB (CASE 8-3), especially for patients with
tuberculous meningitis. A meta-analysis that examined seven randomized
controlled trials comparing antituberculous treatment with or without
corticosteroids concluded that “Corticosteroids reduce mortality from tuberculous
meningitis, at least in the short term.”74 In the 2017 Guidelines for Treatment of
Drug-Susceptible Tuberculosis and Patient Care, the WHO recommends initial
adjuvant corticosteroid therapy with dexamethasone or prednisolone tapered
over 6 to 8 weeks for all patients with tuberculous meningitis.66
In animal models, corticosteroids reduce intracranial pressure and decrease
inflammation in the subarachnoid space, cerebrum, spinal cord, and small
blood vessels.75 The theoretical harm of corticosteroids results from reducing
meningeal inflammation, thus potentially decreasing penetration of
antituberculous medications; from suppressing the immune system, which
could lead to bacterial superinfection; or from worsening of TB or from other
complications associated with corticosteroid use, such as gastrointestinal
bleeding. Recent research suggests polymorphisms in the leukotriene A4
hydrolase (LTA4H) gene, which encodes a protein affecting the production of

1432 OCTOBER 2018

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leukotriene B4 (an inflammatory eicosanoid), affects the risk for inflammation KEY POINTS
in patients with tuberculous meningitis; the polymorphism rs17525495 CT
● In 2017, the World Health
determines inflammation, with patients who possess the homozygous TT Organization reconfirmed its
genotype having the highest level of inflammation.76 recommendations regarding
If corticosteroids are administered, dexamethasone is most often used at a HIV therapy in patients with
TB coinfection: (1) HIV
dosage of 12 mg/d to 16 mg/d for 3 weeks, then tapered off over 3 weeks. For
treatment should be started
patients who experience worsening during or after tapering, corticosteroids can regardless of CD4+ T-cell
be extended for a longer period. Serial neuroimaging of patients with tuberculous count; (2) TB treatment
meningitis has demonstrated that patients receiving dexamethasone had fewer should be initiated first,
complications of hydrocephalus and cerebral infarction.77 followed by antiretroviral
therapy as soon as possible
within the first 8 weeks
OUTCOME of treatment; and (3)
In the era of streptomycin and isoniazid, 32% of children with tuberculous patients with profound
meningitis died and 24% of survivors had neurologic disability, including immunosuppression should
receive antiretroviral
hemiparesis, spastic quadriplegia, ataxia, or cognitive impairment21; 58% therapy within the first
had hearing impairment, but all had received streptomycin, a known 2 weeks of initiating
ototoxic aminoglycoside. TB treatment.
Currently, the outcome of tuberculous meningitis is correlated with neurologic
● Paradoxical expansion of
status at presentation.59 The British Medical Research Council has defined three
tuberculomas despite
stages of tuberculous meningitis. Stage 1 includes patients who are conscious and adequate therapy is
without evidence of neurologic deficits or hydrocephalus; meningismus may be uncommon but can produce
present. Stage 2 includes patients who are confused and have focal neurologic marked worsening of
deficits. Stage 3 includes patients who are obtunded or comatose with hemiplegia symptoms; it typically
responds well to continuing
or paraplegia. All patients at stage 1 at the time of diagnosis survived with few steroid treatment.
neurologic disabilities, while nearly 25% of those at stage 2 or stage 3 died or had
severe neurologic disabilities.78 Intracranial vasculopathy is common during ● The World Health
tuberculous meningitis, and stroke can occur as a complication of vasospasm, Organization recommends
initial adjuvant
thrombosis, vasculitis, or hemorrhagic infarction.79 The most commonly affected corticosteroid therapy with
arteries are the middle cerebral arteries and their branches. The outcome of dexamethasone or
tuberculoma when treated with appropriate antituberculous therapy is good, with prednisolone tapered over 6
mortality of less than 10%.29 to 8 weeks for all patients
with tuberculous meningitis.

● The most common

CONCLUSION complications of
CNS TB is a common complication of pulmonary TB. It occurs most commonly tuberculosis treatment
include hearing impairment
in countries with high rates of poverty, malnutrition, and low income and can be
(streptomycin) and vision
difficult to diagnose. Diagnosis is most efficiently made through combining loss (ethambutol).
CSF examination with traditional methods of diagnosis, eg, Ziehl-Neelsen
(acid-fast bacilli) stain and mycobacterial culture, and with newer technologies.
As the diagnosis of TB is frequently delayed by weeks, empiric treatment
should be started when CNS TB is suspected. When possible, TB infection
should be confirmed through culture of CSF or other tissue and drug
susceptibility determined, as antituberculous treatment should be adjusted
if multidrug-resistant TB or extensively drug-resistant TB is detected.
Concomitant treatment with steroids should be administered to all patients
with tuberculous meningitis and strongly considered for other forms of CNS
TB that are accompanied by edema. Although HIV coinfection does not
typically alter the radiographic or neurologic presentation of CNS TB, ART can
influence the natural history of CNS TB (eg, IRIS), so HIV status should be
determined in all patients presenting with TB infection.

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TUBERCULOSIS OF THE CNS

CASE 8-3 A 44-year-old man presented with a 2-week history of back pain,
headache, confusion, and intermittent loss of consciousness. He had
moved to the United States from China 7 years previously. His family
history was notable for a brother who had died of central nervous system
(CNS) tuberculosis (TB). Neurologic examination was notable for mild
reflex asymmetry at the biceps.
MRI of the spine revealed osteomyelitis of the L4 vertebra with right-
sided paravertebral abscess and osteomyelitis at T9-T10. MRI of the brain
demonstrated numerous ring-enhancing lesions, all less than 1 cm in
diameter, involving the brain, brainstem, and cerebellum (FIGURE 8-3A). In
addition, large lesions were seen in the left pons and medial thalamus
extending into the third ventricle. He underwent biopsy of the spinal
osteomyelitis, which revealed acid-fast bacilli positivity; CSF acid-fast
bacilli culture was positive for fully sensitive Mycobacterium
tuberculosis complex. X-ray of the chest and abdomen was
unremarkable.
The patient was started on isoniazid, rifampin, pyrazinamide, and
ethambutol, with adjunctive dexamethasone, and phenytoin for potential
seizures, and, initially, he had marked improvement. A follow-up MRI
with gadolinium showed reduction in the size of the ring-enhancing
granulomas (FIGURE 8-3B). He then developed elevation of his
transaminases and his treatment was changed to capreomycin,
moxifloxacin, ethambutol, cycloserine, and dexamethasone. He later
developed tinnitus, and capreomycin was held. The following week, he
developed oral candidiasis and granulocytopenia, and his dexamethasone
was tapered and phenytoin was held. One week later, he developed
increasing somnolence, headache, and vomiting; dexamethasone was
restarted, and his symptoms improved. After 12 months of therapy, MRI
with gadolinium showed resolution of the ring-enhancing granulomas
(FIGURE 8-3C). He had resolution of symptoms and had returned to daily
work. His speech was fluent in Chinese, he had no motor impairment or
reflex asymmetry, and tandem walking was notable for occasional
step-outs.

COMMENT This case illustrates the potential long delay between moving from a
country where TB is endemic (China) to presentation with CNS TB in the
United States. In addition, although this patient’s treatment was
challenging because of various complications associated with medication
toxicity, his clinical course was remarkable for nearly complete recovery,
demonstrating that despite innumerable TB granulomas, the long-term
outcome of CNS TB can be quite good. Close follow-up in a clinic that
specializes in treatment of TB is essential for recognizing the common side
effects of treatment for TB.

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FIGURE 8-3
Axial postcontrast T1-weighted MRIs of the patient in CASE 8-3. A, Numerous ring-enhancing
granulomas throughout the cerebrum, brainstem, and cerebellum are shown. B, After 1 month of
antituberculous treatment, reduction in the size of the ring-enhancing granulomas is seen. C, After
8 months of antituberculous treatment, resolution of the ring-enhancing granulomas is seen.

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TUBERCULOSIS OF THE CNS

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