Central Nervous
System Tuberculosis
ABSTRACT Central nervous system tuberculosis (CNS-TB) takes
three clinical forms: meningitis (TBM), intracranial tuberculoma,
and spinal arachnoiditis. TBM predominates in the western world
and presents as a subacute to chronic meningitis syndrome with
a prodrome of malaise, fever, and headache progressing to
altered mentation and focal neurologic signs, followed by
stupor, coma, and death within ve to eight weeks of onset.
The CSF formula typically shows a lymphocytic pleocytosis,
and low glucose and high protein concentrations. Diagnosis
rests on serial samples of CSF for smear and culture, combined
with CSF PCR. Brain CT and MRI aid in diagnosis, assessment for
complications, and monitoring of the clinical course. In a patient
with compatible clinical features, the combination of meningeal
enhancement and any degree of hydrocephalus is strongly
suggestive of TBM. Vasculitis leading to infarcts in the basal
ganglia occurs commonly and is a major determinant of
morbidity and mortality. Treatment is most eective when
started in the early stages of disease, and should be initiated
promptly on the basis of strong clinical suspicion without waiting
for laboratory conrmation. The initial 4 drug regimen (isoniazid,
rifampin, pyrazinamide, ethambutol) covers the possibility of
infection with a resistant strain, maximizes antimicrobial impact,
and reduces the likelihood of emerging resistance on therapy.
Adjunctive corticosteroid therapy has been shown to reduce
morbidity and mortality in all but late stage disease.
INTRODUCTION
Central nervous system (CNS) tuberculosis (TB) is
among the least common yet most devastating forms
of human mycobacterial infection. Conceptually, clini-
cal CNS infection is seen to comprise three categories
of illness: subacute or chronic meningitis, intracranial
tuberculoma, and spinal tuberculous arachnoiditis. All
three forms are seen with about equal frequencies in
high-prevalence regions of the world where postpri-
mary, extrapulmonary clinical infection is encountered
commonly among children and young adults (1). Men-
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JOHN M. LEONARD1
1
Department of MedicineInfectious Disease,
Vanderbilt University Medical Center, Nashville, TN 37232
ingitis syndrome predominates in low-prevalence coun-
tries such as the United States and in Europe, where
extrapulmonary TB is encountered primarily in older
adults with reactivation disease. The natural history of
tuberculous meningitis (TBM) is that of insidious onset
and subacute progression, prone to rapid acceleration
once neurologic decits supervene, leading to stupor,
coma, and, nally, death within 5 to 8 weeks of the onset
of illness. Consequently, in order to achieve a favorable
therapeutic outcome, it is important to begin treatment
promptly, empirically during the early stages of illness,
relying on clinical suspicion and a presumptive diagno-
sis rather than awaiting laboratory conrmation. Of
necessity, this requires some knowledge of the causes
and clinical features of granulomatous meningitis, the
pathology that subserves the neurologic manifestations
of disease, and the expected radiographic and laboratory
(chiey cerebrospinal uid [CSF]) ndings.
EPIDEMIOLOGY
With regard to TB in general, it is estimated that one-third
of the worlds population has been infected with Myco-
bacterium tuberculosis and that approximately 15 million
persons have active clinical disease. About 9 million new
cases and 1.5 million to 2 million deaths occur in the
Received: 30 September 2016, Accepted: 23 January 2017,
Published: 10 March 2017
Editor: David Schlossberg, Philadelphia Health Department,
Philadelphia, PA
Citation: Leonard JM. 2017. Central nervous system tuberculosis.
Microbiol Spectrum 5(2):TNMI7-0044-2017. doi:10.1128
/microbiolspec.TNMI7-0044-2017.
Correspondence: John M. Leonard, john.m.leonard@vanderbilt.edu
2017 American Society for Microbiology. All rights reserved.
1
Leonard
world each year (2). Incidence rates of TB vary widely
from country to country in relation to the prevalence of
cavitary pulmonary disease and poor socioeconomic con-
ditions. In the United States, where the incidence of TB
has declined gradually over the past two decades, 9,421
new cases were reported in 2014, an incidence rate of 2.9
cases per 100,000 persons (3). The proportion of new
cases is higher among foreign-born persons residing in the
United States (15.4 cases per 100,000) than among na-
tive-born individuals (1.2 cases per 100,000). Pulmonary
TB accounts for 70% of the total, isolated extrapul-
monary cases 20%, and combined extrapulmonary and
active pulmonary disease the remaining 10%.
Clinical CNS TB occurs in 1 to 2% of all patients
with active TB and accounts for about 8% of all extra-
pulmonary cases of the infection reported to occur in
immunocompetent individuals. While the incidence of
pulmonary TB in the United States has declined steadily
in recent decades, the number of reported cases of CNS
infection has changed little, about 180 to 200 per year,
and the case fatality rate remains high, at 15 to 40%,
despite effective anti-TB chemotherapy (4, 5).
MENINGITIS
Pathogenesis
The sequence of events that leads to clinical neurologic
illness begins with the hematogenous dissemination of
Mycobacterium tuberculosis (bacillemia) that follows
primary pulmonary infection or late reactivation TB
elsewhere in the body. However, unlike the pathogene-
sis of pyogenic bacterial meningitis, this bacteremia
does not breach the blood-brain barrier to produce an
immediate invasion of the meninges and subarachnoid
space. Instead, during the bacillemic phase, sparse num-
bers of bacilli are scattered throughout the substance
of the brain, meninges, and adjacent tissues, leading to
the formation of multiple small granulomatous foci of
various sizes and degrees of encapsulation (tubercles).
The continued proliferation and coalescence of tubercles
result in larger caseous foci. Such lesions, if located ad-
jacent to the ependyma or pia, may subsequently rupture
into the subarachnoid space, producing meningitis. This
conceptual understanding of the pathogenesis of TBM is
derived from the observations of Rich and McCordock,
who performed meticulous autopsy examinations of
TBM patients dying at the Johns Hopkins Hospital
during the early part of the last century (6). In 77 of the
82 cases studied, an older, active caseous focus com-
municating with the subarachnoid space or ventricles
was found in the substance of the brain, meninges, or
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adjacent bone. While the number, character, and loca-
tion of granulomas within the CNS were variable, the
discharging caseous lesion (Rich focus) was most
commonly situated in the brain or meninges and only
rarely in bone or spinal cord. Thus, the chance distri-
bution and progression of a suitably located subepen-
dymal or subpial tubercle are the critical events in the
subsequent development of TBM.
It follows that the propensity of a lesion to produce
meningitis will be determined by its proximity to the
surface of the brain, the rapidity of progression, and the
rate at which encapsulation follows acquired immune
resistance. Moreover, the low-grade, incessant bacille-
mia associated with progressive disseminated TB greatly
increases the likelihood that a juxtaependymal tubercle
will be established and from this critical location break
through to infect the subarachnoid space (7). CNS TB
arises in this manner under conditions of sustained post-
primary bacillemia, as in the very young (children <3
years old) and the malnourished, and from the failure to
sustain immune control of dormant foci (tubercles) within
the brain or other tissues of the body, as in the elderly
and other adults on immunosuppressive medication or
infected with human immunodeciency virus (HIV).
Although tuberculous CNS infection may be seen as a
complication of clinically apparent progressive miliary
disease, most adults develop TBM from less apparent
or entirely hidden foci of chronic organ TB. Reactivation
of latent TB outside the CNS may result in intermittent or
chronic progressive bacillemia, producing subependymal
tubercles which remain quiescent for months or years,
yet harboring bacilli and having the potential to desta-
bilize as a result of local changes in the brain or a decline
in host cellular immunity. Aging, use of immunosuppres-
sive drugs, lymphoma, alcoholism, and HIV/AIDS are
among the factors known to facilitate progression to the
syndrome of late generalized tuberculosis. In an ex-
cellent clinical pathological analysis of 100 patients with
this syndrome, careful postmortem examination revealed
meningeal involvement in 54% of cases studied (8).
A signicant subset of adults with TBM has no clin-
ically evident extracranial infection or apparent defects
in host immunity. In the occasional patient, the history
of antecedent head and neck trauma suggests that Rich
foci within the brain may be destabilized by physical
factors as well.
Pathology
Regardless of where the Rich focus is located, the rup-
ture of tubercular protein into the subarachnoid space
initiates an intense, cytokine-mediated inammatory

reaction that becomes most marked at the base of the
brain. The resultant pathological changes take three prin-
cipal forms that, in turn, account for the dening clinical
features of the disease: a proliferative basal arachnoiditis,
vasculitis, and hydrocephalus (6, 9). Within days to weeks
a proliferative, basal arachnoiditis produces a thick, ge-
latinous exudate extending from the pons to the optic
chiasm. As it matures, the arachnoiditis becomes a brous
mass encasing nearby cranial nerves (CNs), most com-
monly CNs VI, III, and IV.
Arteries and veins traversing the region are caught
up in the inammatory process, resulting in a vasculitis
that extends within the substance of the brain itself.
Initially, direct invasion of the vessel wall by mycobac-
teria, or secondary extension of adjacent inammation,
leads to an intense polymorphonuclear reaction within
the adventitia, followed by inltration of lymphocytes,
plasma cells, and macrophages. Progressive destruction
of the adventitia and disruption of elastic bers allow
the inammatory process to reach the intima; eventu-
ally, brinoid degeneration within small arteries and
veins leads to aneurysms, thrombi, and focal hemor-
rhages (10). Multiple lesions are common, and a variety
of stroke syndromes result from spasm, thrombosis, or
hemorrhage (11). Most commonly involved are branches
of the middle cerebral artery and perforating vessels to
the basal ganglia, pons, thalamus, and internal capsule.
Intracranial vasculitis is found commonly in those dying
from TBM and is the major cause of severe neurologic
decits in those who survive. In an autopsy series, phle-
bitis and various degrees of arteritis were found in 22 of
27 cases studied; of these, 8 involved patients who had an
obstructive tuberculous thrombophlebitis with hemor-
rhagic cerebral infarction (12).
Extension of the inammatory process to the basal
cisterns may impede CSF circulation and absorption,
leading to communicating hydrocephalus. This is seen
in the majority of cases in which symptoms have been
present for 3 weeks or more (13). Obstructive hydro-
cephalus, arising from edema of the midbrain or a local-
ized brain stem granuloma that occludes the aqueduct, is
encountered less often.
Clinical Presentation
Common symptoms and signs
The usual patient with TBM presents with a subacute,
progressive febrile illness that passes through three
discernible phases. Illness begins with a prodrome of
malaise, lassitude, low-grade fever, and intermittent
headache, sometimes a vague discomfort in the neck or
back, and subtle personality change. In 2 to 3 weeks,
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Central Nervous System Tuberculosis
a more well-dened meningitic phase emerges as the
patient experiences protracted headache, meningismus,
vomiting, mild confusion, and various degrees of CN
palsy and long-tract signs (1416). At this stage the pace
of illness may accelerate rapidly to the paralytic phase:
delirium followed by stupor and coma, seizures, multi-
ple CN decits, hemiparesis, and hemiplegia. In the un-
treated case, death commonly occurs within 5 to 8 weeks
of the onset of illness. In children, headache is less com-
mon, while irritability, restlessness, anorexia, and pro-
tracted vomiting are prominent symptoms, especially
in the very young (17). Seizures are more common in
children and apt to occur in the early stage of illness.
Table 1 lists common symptoms and signs at presenta-
tion, and the frequency reported, for 195 patients per
data compiled from four recent clinical series in separate
countries of the Western world (15, 16, 18, 19).
Atypical presentations
A small subset of patients present without the charac-
teristic prodrome and subacute progression described
above. In the occasional adult, TBM takes the form
of a slowly progressive dementia over many months,
marked by personality change, social withdrawal, and
memory decits. Others present with an acute, rapidly
progressive meningitis syndrome indistinguishable from
pyogenic bacterial infection. At times focal neurologic
decits (CN palsies, hemiparesis, and seizures) or symp-
toms of hydrocephalus (headache, papilledema, diplopia,
and visual disturbance) precede the signs of meningitis.
An encephalitic syndrome has been described to occur
in children, and occasionally adults, manifesting as stu-
por, coma, and convulsions with neither meningitis signs
nor signicant CSF abnormalities (20).
Clinical staging and prognosis
For purposes of prognosis and therapy, it is useful
to categorize patients into clinical stages according to
TABLE 1 Presenting symptoms and signs of TBMa
Symptom/sign(s) Frequency reported (%)
Fever 2070
Headache 2570
Meningeal irritation 3590
Lethargy/drowsiness 2530
Vomiting 3070
Confusion/delirium 3065
Focal neurologic signs 2540
CN palsy 2035
Hemiparesis 530
a See references 15, 16, 18, and 19.
3
Leonard
the degree of illness at presentation. Stage 1 comprises
patients who are conscious and rational, with or without
meningismus but having no focal neurologic signs or
evident hydrocephalus; stage 2 patients exhibit lethargy
and confusion and may have mild focal neurologic signs
such as CN palsy and hemiparesis; and stage 3 patients
exhibit signs of advanced disease such as stupor, coma,
seizures, multiple CN palsies, and dense hemiplegia (15).
The prognosis for treated TBM is greatly inuenced by
the clinical stage at which treatment is initiated.
TBM and HIV infection
All forms of extrapulmonary disease occur with greater-
than-expected frequency in HIV patients with active TB
(21). Among 52 AIDS patients diagnosed with TB over a
3-year period, 10 had CNS disease manifested by men-
ingitis, tuberculoma, or cerebral abscess (22). In another
study of 455 HIV patients with TB, 10% developed
meningitis, compared to only 2% of a matched HIV-
negative cohort with TB (23). Moreover, HIV-positive
patients accounted for 59% of TBM cases seen during
the study period. Apart from intracerebral tuberculo-
mas, which are seen more frequently in HIV patients
with CNS TB, coinfection with HIV does not appear
to alter the clinical manifestations, CSF ndings, or re-
sponse to therapy (24, 25).
In areas of endemicity where rates of coinfection with
HIV and TB are high, rapid-onset extrapulmonary TB,
including meningitis, often follows initiation of anti-
retroviral therapy (ART) in HIV patients with latent
or subclinical TB. This is a form of the immune recon-
stitution inammatory syndrome that often follows ini-
tiation of ART in treatment-naive patients and likely
represents a cytokine-mediated exacerbation of latent
active TB.
Diagnosis
Once the diagnosis is considered for a patient with
compatible clinical features and suspicious laboratory
abnormalities, a rapid, thorough assessment for sup-
porting evidence should be conducted, followed by
the decision of whether to begin empirical treatment.
Careful attention to the past medical record, epidemio-
logical setting, and general physical examination may
reveal important information. A strong family history
of TB and history of head trauma in recent months
are helpful clues. Recent exposure to persons with active
TB is apt to be present in cases involving children and in
adults with impaired cellular immunity. In urban areas,
the association of extrapulmonary TB with under-
lying conditions such as alcoholism, injection drug use,
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poverty, and other conditions or therapies that impair
cellular immune function add urgency to the consid-
eration. Signs of active infection elsewhere in the body
are not infrequent and when present provide the most
reliable basis for the presumptive diagnosis in patients
presenting with meningeal TB. A careful, thorough ex-
amination may reveal choroidal tubercles on the retina
(26) or splenomegaly in patients with active dissemi-
nated infection or lymphadenopathy, bone and joint
lesions, or scrotal mass and draining stula in patients
with focal extrapulmonary disease.
Routine studies
The chest X ray should be examined carefully for hilar
adenopathy, interstitial miliary pattern, and parenchy-
mal inltrate or apical scarring. Such abnormalities are
present in the majority of childhood cases and about
50% of adults. Routine blood counts and chemistries are
of little value except as they reveal evidence of chronic
disease and disseminated infection. Mild anemia and
leukocytosis are common. The hyponatremia of inap-
propriate secretion of antidiuretic hormone has been
described in a minority of cases with miliary TB com-
plicated by meningitis (27). Skin testing for tuberculin
hypersensitivity is useful, especially in children; how-
ever, a negative skin test occurs with such frequency in
all forms of active extrapulmonary TB as to be of no use
in excluding the diagnosis.
CSF examination and culture
The key to the diagnosis in most instances rests with the
proper interpretation of the spinal uid cellular char-
acteristics and chemistries (the CSF formula) combined
with the demonstration of mycobacteria in the CSF by
stained smear or culture. At lumbar puncture the open-
ing pressure is usually elevated. The uid is clear or has a
ground-glass appearance, and a delicate web-like clot
often forms at the top. Typically, the CSF formula shows
a mononuclear pleocytosis accompanied by high protein
and low glucose concentrations (28). The total cell count
is between 100 and 500/mm3 in the majority, less than
100 cells/mm3 in 15%, and between 500 and 1,500 cells/
mm3 in 20% of cases. Early in the course of illness the
cellular reaction may be atypical, with few cells, a mixed
pleocytosis, or a transient polymorphonuclear predom-
inance, which, on subsequent examinations, evolves in
the direction of the expected lymphocytic response (29).
The CSF protein concentration is in the range of 100 to
500 mg/dl in most patients, under 100 mg/dl in 25%,
and greater than 500 mg/dl in about 10% of reported
cases. An extremely high protein concentration, in the
 Central Nervous System Tuberculosis

range of 2 to 6 g/dl, is indicative of subarachnoid block
and carries a poor prognosis. The CSF glucose concen-
tration is abnormally low, less than 45 mg/dl, in 80% of
cases; given that the patient will usually have a subacute
or chronic meningitis presentation, this feature consti-
tutes strong evidence of a granulomatous infection of the
CNS.
The demonstration of M. tuberculosis by stained
smear and culture establishes the specic diagnosis. Cul-
tures are positive in about 75% of cases but require 3 to
6 weeks for detectable growth. Consequently, the dem-
onstration of acid-fast bacilli (AFB) by stained smear
of CSF sediment remains the most rapid means of
reaching an early diagnosis. The sensitivity of the AFB
smear and culture is variable, inuenced in part by the
selection and volume of the specimen submitted by the
clinician and the diligence applied to the process by
laboratory personnel. There is value in submitting mul-
tiple CSF specimens from repeated lumbar punctures. In
the clinical series reported by Kennedy and Fallon, the
yields on smear and culture were 37% (smear) and 56%
(culture) based upon the rst CSF specimen submitted
but increased to 87 and 83%, respectively, when two
additional specimens were examined (15). Importantly,
in 30% of cases the diagnosis was made from CSF ob-
tained 1 to 3 days after therapy had been initiated. In
another study involving 132 adult patients, designed
specically to evaluate the effectiveness of careful mi-
crobiological technique, a positive smear was estab-
lished for 58% and the yield on culture was 71%. The
combined sensitivity of smear and culture was 82% (30).
Based on these observations, it is recommended that a
minimum of three serial CSF samples be obtained for
smear and culture, submitting a 10-ml aliquot of the last
uid removed at lumbar puncture. It is not necessary to
defer anti-TB therapy, as the yield remains good for a
few days after treatment is started.
warrants empirical therapy for CNS TB, and initial
stains for AFB are negative, CSF specimens should be
submitted for PCR, bearing in mind that a negative re-
sult neither excludes the diagnosis nor provides a basis
for discontinuing therapy.
At the present time the World Health Organization
recommends the Xpert MTB/RIF assay as the initial
molecular diagnostic test for CSF specimens from pa-
tients suspected of having TBM. This is an automated,
cartridge-based NAAT that simultaneously detects M.
tuberculosis and rifampin (RIF) resistance in less than
2 h. In a meta-analysis of 13 studies (839 CSF samples)
in which Xpert MTB/RIF was evaluated against culture,
the pooled sensitivity was 80.5% and the specicity
97.8% (35).
Neuroradiological evaluation
The application of computed tomography (CT) and
magnetic resonance imaging (MRI) has greatly facili-
tated the assessment and management of patients with
CNS TB (3639). These imaging studies are useful for
dening the presence and extent of basal arachnoiditis,
cerebral edema and infarction, and the presence and
course of hydrocephalus (Fig. 1 and 2). In two early,
sizable community-based series, CT scanning demon-
FIGURE 1 Computerized axial tomogram for a patient with
TBM. Note the enlarged ventricles and eacement of sulci,
indicating raised intracranial pressure.

Molecular diagnostic techniques

The nucleic acid-based amplication technique (NAAT),
based on PCR, is an effective method for the rapid de-
tection of specic bacterial DNA in clinical specimens
(31, 32). However, the reliability of PCR testing for
M. tuberculosis DNA in CSF is not well established,
primarily because of variability in sensitivity and speci-
city across multiple laboratories. In a comparison study
of seven participating laboratories, the sensitivity varied
widely and the rate of false-positive test results ranged
from 3 to 20% (33). A meta-analysis of NAATs for TB
meningitis showed a pooled sensitivity of 56% and a
pooled specicity of 98% (34). When clinical suspicion

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Leonard
FIGURE 2 MRI of the same patient as for Fig. 1. (A) After
contrast enhancement, showing two dense, bilateral inam-
matory masses (tuberculomas) in the region of the thalamus;
(B) T-2 weighted image showing inammatory edema and
possible ischemic changes of vasculitis in the basal region of
the temporal lobe (arrowhead).
strated hydrocephalus in 75% of patients, basal men-
ingeal enhancement in 38%, cerebral infarcts in 15 to
30%, and tuberculomas in 5 to 10% (13, 40). A number
of useful clinical observations can be derived from a
review of selected neuroimaging studies reported over
the past two decades (13, 40, 41). In a patient with
compatible clinical features, CT evidence of basal en-
hancement combined with any degree of hydrocephalus
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is strongly suggestive of TBM. If the CT scan is normal
at the time therapy is initiated, the prognosis for com-
plete recovery on therapy is excellent. Hydrocephalus
combined with marked basal enhancement is indica-
tive of advanced disease and carries a poor prognosis.
Marked basal enhancement correlates well with the
presence of vasculitis and, therefore, the risk for basal
ganglion infarction. MRI is superior to CT for evaluat-
ing children and is the preferred modality for dening
lesions of the brain stem, midbrain, and basal ganglia in
patients of all ages (36, 42).
Dierential diagnosis
In most cases the differential diagnosis is that of the pa-
tient with classic features of the granulomatous menin-
gitis syndromea subacute inammatory condition of
the CNS marked by fever, headache, meningeal signs,
altered mentation, and a CSF formula showing a lym-
phocytic pleocytosis, lowered glucose concentration,
and high protein content. Table 2 lists the other principal
infections that may manifest in this fashion, along with
noninfectious conditions that may mimic certain of these
features. Cryptococcal meningitis is the major consid-
eration because it is the most common, along with the
other deep-seated fungal infections listed. The syndrome
may also be encountered in patients with parameningeal
suppurative foci complicating endocarditis, sphenoid
sinusitis, and brain abscess. At times TBM can be con-
fused with herpes simplex and mumps encephalitis when
the presentation is that of fever, rapid neurologic dete-
rioration, and mild lowering of the CSF glucose. Careful
attention to such details as the overall length of illness,
meningeal signs, degree of protein elevation, and specic
CT/MRI abnormalities will be most helpful in differen-
tiating herpes encephalitis from tuberculous CNS infec-
tion. The other diagnoses listed are of importance, as
they should cause the clinician to consider the possibility
of TBM in any patient suspected of having one of these
conditions.
TABLE 2 Differential diagnosis of TBM
Fungal meningitis (cryptococcosis, histoplasmosis, blastomycosis,
coccidioidomycosis)
Neurobrucellosis
Neurosyphilis
Neuroborreliosis
Focal parameningeal infection (sphenoid sinusitis, endocarditis,
brain abscess)
CNS toxoplasmosis
Partially treated bacterial meningitis
Neoplastic meningitis (lymphoma, carcinoma)

TUBERCULOMA
Tuberculomas are conglomerate caseous foci in the
brain that develop from deep-seated tubercles acquired
during a recent or remote disseminated bacillemia. Cen-
trally located, active lesions may reach considerable
size without producing meningitis (6, 43). When the host
response to infection is poor, this process may result
in focal cerebritis and frank abscess formation. More
commonly, the lesions coalesce to form caseous granu-
lomas with brous encapsulation (tuberculomas). The
advent of CT and MRI brain imaging has disclosed
that clinically silent single or multiple CNS granulomata
occur commonly in patients with TBM and in those with
miliary TB without meningitis. On CT, the characteristic
appearance is a nodular enhancing lesion with a central
hypodense region; on MRI, the early focal cerebritis
stage is marked by edema and ill-dened enhancement,
the later mature stage by central hypointensity and pe-
ripheral enhancement on T-2 weighted images (4446).
These lesions usually disappear on therapy, without in-
cident. There are occasional reports of clinically signi-
cant, transient tuberculomas appearing during the early
course of anti-TB therapy (47).
Clinical Tuberculoma
Tuberculoma manifesting as a clinically evident mass
lesion of the brain is distinctly uncommon in the West,
but in India, the near East, and parts of Asia, it is re-
ported to account for 20 to 30% of all intracranial
tumors (48). The usual patient is a child or young adult
who presents with headache, seizure, progressive hemi-
plegia, and/or signs of raised intracranial pressure. Most
have neither symptoms of systemic infection nor signs of
meningitis (1, 4850). While the presumptive diagnosis
can be made on the basis of clinical and epidemiological
considerations, or by needle biopsy, CT scanning with
contrast enhancement has proven to be a major advance
in the diagnosis and management of these cases. CT is
especially useful for assessing the presence of cerebral
edema and the risk of brain stem herniation, and for
monitoring the response to medical therapy (50). Early
surgical intervention, except perhaps for diagnostic
needle biopsy, is to be avoided, as it may precipitate
severe meningitis (50, 51). Conservative medical man-
agement is effective for most cases; surgery is reserved
for cases in which critically located lesions have pro-
duced obstructive hydrocephalus or compression of the
brain stem (48, 50). Corticosteroids are helpful where
cerebral edema out of proportion to the mass effect is
producing altered mental status or focal neurologic
decits.
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Central Nervous System Tuberculosis
SPINAL TUBERCULOUS ARACHNOIDITIS
Arachnoiditis or tuberculoma can arise at any level of
the spinal cord in association with the breakdown of a
Rich focus within the cord or meninges, or by extension
from an adjacent area of spondylitis (29). The resulting
inammatory reaction is usually conned locally and
progresses gradually over weeks to months, producing a
partial or complete encasement of the cord by a gelati-
nous or brous mass (43). Patients usually present with
some combination of nerve root and cord compression
signs secondary to impingement by the advancing arach-
noiditis. Clinical manifestations are predominately neu-
rologic rather than infectious, are protean in nature, and
take the form of an ascending or transverse radiculo-
myelopathy of variable pace at single or multiple levels
(52). Symptoms include pain, hyperesthesia, or pares-
thesia in the distribution of the nerve root, lower motor
neuron paralysis, and bladder or rectal sphincter in-
continence. Localized vasculitis may result in thrombosis
of the anterior spinal artery and infarction of the cord.
All forms of tuberculous arachnoiditis commonly pro-
duce subarachnoid block characterized by unusually
high CSF protein levels, regardless of whether there is a
cellular pleocytosis. The diagnosis of spinal TB arach-
noiditis should be considered for a patient with any
combination of the following clinical and laboratory
features: subacute onset of spinal or nerve root pain,
rapidly ascending transverse myelopathy or multilevel
myelopathy, increased CSF protein concentration and
cell count, signs of arachnoiditis or epidural space in-
fection by MRI, and evidence of TB elsewhere in the
body (29, 53). Tissue biopsy for histopathology stains
and culture is required for diagnosis. Progression from
an initial spinal syndrome to frank TBM occurs in some
patients late in the course.
TREATMENT
Anti-TB Therapy
As has been emphasized, the rst principle of anti-TB
therapy is that it should be initiated on the basis of
strong clinical suspicion rather than delayed until proof
of the diagnosis has been obtained. The prognosis is
good when treatment is begun before the development of
focal neurologic signs and altered state of consciousness.
Accordingly, the risks of delay, even for only a few days,
are greater than those of unnecessary drug treatment so
long as one persists in the effort to conrm the diagnosis.
There are no randomized trials to establish the optimal
drug combination, dose, and duration of treatment for
TBM. The principles governing the therapy for TBM are
7
Leonard
those derived in relation to the management of pulmo-
nary TB (54). The purpose of using combination drug
regimens is to enhance the bactericidal effect, cover the
possibility of some degree of primary drug resistance,
and reduce the likelihood of emerging resistance on
therapy. A brief description of the major rst-line drugs
is given below.
Isoniazid (INH) diffuses readily into the CSF, achiev-
ing concentrations severalfold higher than that required
for bactericidal activity (55). The daily dose for children
is 10 g/kg, and that for adults is 300 mg. Pyridoxine,
at 25 or 50 mg daily, should be given concurrently so as
to avoid the neurologic complications associated with
INH-induced pyridoxine deciency. A parenteral form
of INH is available if needed.
RIF is active early against rapidly dividing organisms
and achieves reliable CSF concentrations in the presence
of meningeal inammation. This drug is active against
semidormant bacilli, which may be an advantage in
achieving late resolution of infectious foci in the CNS
and elsewhere in the body. The daily dose in children
and adults is 10 mg/kg to a maximum dose of 600 mg.
An intravenous formulation is available from the man-
ufacturer on a compassionate-use basis.
Pyrazinamide (PZA) penetrates readily into the CSF
and is highly active against intracellular organisms.
Therapeutic efcacy is enhanced when this agent is used
in combination with INH and RIF, but the dose and
duration are limited by the propensity to cause hepato-
toxicity. At a dose of 25 to 35 mg/kg, and limited to no
more than 2 months, the combination is safe and effec-
tive (56). For children, the daily dose is 15 to 20 mg/kg.
For adults, the dose is determined by weight: 40 to
60 kg, 1,000 mg; 56 to 75 kg, 1,500 mg; and 76 to
90 kg, 2,000 mg.
Ethambutol (EMB) is a weak drug that achieves
moderately effective CSF concentrations. Its major tox-
icity is optic neuritis, which developed at a rate of 3%
or more when patients were treated with 25 mg/kg.
This complication is rare at the currently recommended
dose of 15 mg/kg; however, it is advisable to monitor
patients monthly by following visual acuity, red-green
color vision, and visual elds (57).
Recommended Regimen
Chemotherapy for TBM is initiated with a 4-drug,
intensive-phase regimen consisting of INH, RIF, PZA,
and EMB (for children, ethionamide or an aminogly-
coside is substituted for EMB). Following 2 months of
the 4-drug regimen, for infections known or presumed
to be caused by susceptible strains, PZA and EMB may
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be discontinued. INH and RIF are continued for an
additional 7 to 10 months (58, 59). If PZA is omitted or
not tolerated, the duration of treatment should be ex-
tended to 18 months.
Risk factors for drug-resistant infection include
prior treatment with anti-TB drugs, exposure to persons
with known resistant TB, homelessness, and acquisition
of primary infection in high-prevalence regions of the
world. The impact of drug resistance on outcome is
variable, depending on whether the isolate is resistant
to INH, to RIF, or to both (60). The second-line drugs
ethionamide and cycloserine penetrate well into the CSF
and are useful. Novel approaches to the management of
drug-resistant TBM, using newer aminoglycosides and
uoroquinolones, have been reported (61).
In managing ART-naive HIV patients with TBM,
it is recommended that initiation of ART be delayed
until after 8 to 10 weeks of anti-TB therapy. This is
to avoid early TB-associated immune reconstitution in-
ammatory syndrome, which, in the context of menin-
gitis, increases the risk of serious and fatal neurologic
complications (59).
Adjunctive Corticosteroids
Despite uncertainty regarding the efcacy, and whether
the benet outweighs the risk, patients with TBM have
routinely been treated with corticosteroids in an effort
to reduce inammation, limit damage to the CNS, and
thus improve outcome. Early clinical studies bearing
on this issue are awed because of the study design, the
limited number of cases, and the failure to carefully
stratify patients by severity of illness and specic neu-
rologic manifestations. There is at present, however, a
growing number of carefully designed, controlled stud-
ies from clinical centers around the world showing that
adjunctive steroid therapy is benecial for children and
adults with TBM (6265).
In a prospective trial, 141 children with TBM were
randomized to receive either prednisone or a placebo
for 4 weeks (64). Prednisone therapy increased the rate
of resolution of basal exudate and tuberculomas and
improved survival and subsequent measures of intel-
lectual development. A randomized, double-blind trial
in Vietnam compared dexamethasone with a placebo
(tapered dose over 6 to 8 weeks) in 545 patients older
than 14 years of age (65). The mortality rate was re-
duced signicantly in the treated group (32%, versus
41%). The benet was greatest for patients in clinical
stage 1 (17%, versus 30%). No mortality benet was
seen in patients in stage 3 or in the 98 patients coinfected
with HIV. A follow-up survey conducted by question-

naire at 9 months failed to demonstrate a reduction in
residual neurologic decits and disability.
Adjunctive corticosteroid therapy is recommended
for all patients with convincing clinical evidence of CNS
TB, the possible exception being adults with mild stage
1 disease. Complications for which corticosteroids are
considered to be most benecial are increased intracra-
nial pressure, cerebral edema, and spinal block. Specic
indications based on urgent warning signs are as fol-
lows: progression from one clinical stage to the next
at or before the start of anti-TB therapy, CT evidence
of marked basal enhancement (high risk for vascular
complications), moderate or advancing hydrocephalus,
spinal block or incipient block (CSF protein above
500 mg/dl), and intracerebral tuberculoma when edema
is out of proportion to the mass effect and there are neu-
rologic signs (altered mentation or focal decits). Either
dexamethasone or prednisone may be used. When using
dexamethasone the dosage is 8 mg daily for children
weighing less than 25 kg and 12 mg/day for adults and
children weighing more than 25 kg. When using pred-
nisone the dosage is 2 to 4 mg/kg daily for children and
60 mg/day for adults. The duration is 3 weeks at the
initial dose, followed by a gradual tapering over the next
3 to 4 weeks.
Response and Outcome
The clinical outcome for treated TBM is inuenced by
age, duration of illness, and extent of arachnoiditis and
vasculitis. The clinical stage at the time therapy is initi-
ated also greatly affects both mortality and incidence
of subsequent neurologic sequelae (15, 16). This was
illustrated in the series of 52 cases reported by Kennedy
and Fallon (15). When therapy was begun before pa-
tients had progressed beyond clinical stage 1 or early
stage 2 disease, the mortality rate was less than 10% and
residual neurologic decits minimal. Of the 11 patients in
stage 3 at the time of treatment, 6 died or suffered severe
neurologic sequelae. The incidence of residual neurologic
decits after treatment of TBM varied from 10 to 30% in
recent series (14, 15, 19, 20). Late sequelae include CN
palsies, gait disturbance, hemiplegia, blindness, deafness,
learning disabilities, dementia, and various syndromes of
hypothalamic and pituitary dysfunction.
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