CHAPTER 148

Management of Tuberculous Infections

ofthe Nervous System
RANA PATIR RAVI BHATIA

Infection of the central nervous system (CNS) by Mycobacterium tuberculosis is invariably secondary to a primary
focus elsewhere in the body. The avium, bovine, and atypical mycobacteria are rarely isolated from the nonimmunocompromised host.The primary sites are usually pulmonary,
bone, and gastrointestinal tract; genitourinary sites are less
common. The incidence of CNS tuberculosis (TB) is a
reflection of the overall incidence of TB in a population.
A third of the global population (i.e., 2 billion people)
harbors the M. tuberculosis bacillus and is at risk of developing active disease. It is still a leading cause of mortality from
a single infectious disease.1 The epidemiology of the disease has been greatly affected by the advent of the human
immunodeficiency virus (HIV);2-5 emergence of multidrugresistant TB (MDR TB) and extensively drug-resistant strains
of TB (XDR TB); widespread intravenous drug abuse; inadequate case detection, diagnosis, and therapy; collapse of
health infrastructures due to economic crisis and war; and
continuing poverty.
The health burden related to TB has prompted the
implementation of World Health Organizations (WHOs)
Stop TB Strategy, which includes the following goals: (1)
TB incidence should fall by 2015, (2) prevalence and death
rates should be halved by 2015 from the baseline of 1990,
(3) at least 70% of incident smear-positive cases should be
detected and treated in the Direct Observation of Treatment (DOTS) program, and (4) at least 85% of detected
incident smear-positive cases should be successfully
treated.6 The WHO has also been publishing an annual
report on global control of TB since 1997 to provide a comprehensive and up-to-date assessment of the TB epidemic
and progress in controlling the disease. The trends suggest
that neither the prevalence nor the death rate would be
halved in Africa and Europe by 2015. An estimated 37%
of incident TB cases are not being treated in the DOTS
program, 96% of incident case with MDR TB are not being
diagnosed and treated according to guidelines, the majority of HIV-positive TB cases do not know their HIV status,
and of those who do, the majority do not have access to
antiretroviral therapy.1
In the United States,7 the average decline of 5% per
year in the TB case rate plateaued, and from 1986 to 1992
there was an increase in the number of reported cases.4
Subsequent to aggressive management of TB, the average
annual percentage decline in TB was 7.3% per year during

the period from 1993 to 2000 and 3.8% during the period
from 2000 to 2008, along with a 75% reduction in drug
resistance.8

HIV and TB Coinfection

An estimated 9.27 million new cases of TB (15% of which
were among HIVpositive patients) were reported in 2007,
with Asia and Africa accounting for almost 90% of them.
There were 1.75 million deaths, 25% in HIV-positive individuals. There is a clear synergistic relation between HIV and
TB. Being HIV-positive increases the likelihood of developing TB 20 to 37 times.1,9 In Asia and the Pacific region, as
much as 40% to 70% of HIV patients have TB.10 The tubercle
bacillus has been demonstrated to enhance the replication
of HIV by transcriptional activation.11,12 The increased susceptibility and accelerated natural history of TB with HIV
infection leads to more rapid creation of drug resistance.
TB of the nervous system, which merits the attention
of a neurosurgeon, occurs in several forms, and more
than one form may be present in the same individual
(Table 148-1). This chapter deals only with tuberculomas,
tuberculous meningitis (TBM), and tuberculous spinal
arachnoiditis. Potts disease of the spine and tubercular
encephalopathy are extensively described in orthopedic
and neurologic texts. The significant threat to life and/or a
risk of subsequent severe handicap merits the classification
of all CNS-related TB as severe extrapulmonary TB.

Tuberculomas
INCIDENCE
The incidence of tuberculomas in India, which comprised
20% to 30% of all intracranial space-occupying lesions in
the 1950s and 1960s, has declined since 1980.13-16 Although
TB is widely prevalent in Nigeria17 and Taiwan,18 tuberculomas are rare. Tuberculomas are increasingly reported
in industrialized nations and account for 1% to 2% of all
intracranial lesions.19-22

LOCATION
Tuberculomas can occur at any site in the brain, most
commonly the various lobes and the cerebellum. Unusual
sites of tuberculomas include the dura mater,20-23 subdural

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Section Eight SURGICAL MANAGEMENT OF NERVOUS SYSTEM INFECTIONS

Table 148-1 Tuberculosis of the Nervous System

Anatomic Area
Intracranial Tuberculosis
Parenchymal

Meningeal
Calvarial
Spinal Tuberculosis
Vertebral
Meningeal
Parenchymal

Manifestation
Tuberculoma
Abscess
Tubercular encephalopathy
Chronic meningitis
Osteomyelitis
Potts disease of the spine
Arachnoiditis
Tuberculoma

stem,21,24-26

space, orbital fissure, intraventricular, brain

pituitary gland,27-31 and hypothalamus.32 Spinal intramedullary tuberculomas are rare.33-39

PATHOLOGIC FEATURES
The typical mature tuberculoma is a solid, creamy white,
well-defined, avascular mass with multiple nubbins
encased in a firm gliotic capsule and extending into and
compressing the surrounding brain. The cut section is pale
yellow with an often gritty caseating central core.40 The
immature form consists of multiple small tubercles, some
with caseating or liquefied centers dispersed within an
edematous brain. Severe edema, possibly caused by an
allergic response,40 may surround these tubercles. Tuberculomas vary in size from 1.5 to 8 cm. Giant tuberculomas can
occupy an entire cerebral hemisphere,41 and many adhere
to the dura. The dural attachment can be tenuous or so firm
that the tumor resembles a meningioma.
Microscopically, the central zone of caseous necrosis
is surrounded by tuberculous granulation tissue consisting of epithelioid cells, Langerhans giant cells, and some
lymphocytes, polymorphonuclear leukocytes, and plasma
cells (Fig. 148-1). Acid-fast bacilli, although sparse, are usually present in both layers. The brain surrounding a tuberculoma may show degenerated axons and nerve cells,
thrombosed vessels, and occasionally, swollen astrocytes
and oligodendroglial cells. The changes in the small vessels
can lead to microhemorrhages or microinfarcts, and these
areas may coalesce.42 Smaller satellite tuberculomas may
surround the main mass.
Tuberculomas can take several unusual forms,43,44 representing the spectrum of inflammatory reaction: (1) incipient
tuberculoma, which may appear as an irregular, fleshy, gray
cortical mass with associated meningeal tuberculomatosis
or even grape-like clusters of tuberculoma along cerebral
vessels; (2) subdural cyst overlying an intracerebral tuberculoma; (3) cystic tuberculoma; (4) tubercular abscess;
(5) extensive edematous encephalopathy without a tuberculoma; (6) severe cerebral edema with a small, inconsequential tuberculoma; and (7) rarely, tuberculoma that
has spread transdurally to the calvarium.
TB is a classic example of a disease the resistance to
which is mediated by cellular immunity. The nature of the
immunologic compromise in HIV, with its major effect on
cellular immunity, increases host susceptibility to TB and
abscess formation. Chronic inflammatory granulomas seen

FIGURE 148-1 A photomicrograph of a typical tuberculoma with Langerhans giant cells, epithelioid cells, and lymphocytes. Hematoxylin and
eosin stain, magnification 100.

in immunocompetent patients are less common in patients

with HIV.45 Organisms belonging to the Mycobacterium
aviumintracellulare complex are the most common cause
of systemic bacterial infection in patients with HIV and
have been demonstrated in 50% of such patients coming to
autopsy.46 Tubercular abscess is a distinct entity from a tuberculoma with central liquefaction. The abscess has a wall of
chronic inflammatory cells without tubercular granulomas,
and the pus contains a large number of acid-fast bacilli.
The liquefaction produced by hydrolytic enzymes
released from brain tissue is thought to allow tubercle
bacilli to proliferate, leading to abscess formation. Enzyme
inhibitors from dead bacilli and necrotic tissue in caseous material have been reported to prevent liquefaction
in tuberculous lesions.47 The vessels in the reactive border
zone of tuberculomas show marked proliferation of the
basement membrane into several concentric layers associated with fragmentation. This basement membrane, consisting mainly of glycoproteins, may act as a newly formed
antigen, initiating a cellular antibody reaction that results in
vasculitis and brain damage.48

CLINICAL FEATURES
Tuberculoma is a disease of the young, with 70% of patients
younger than 30 years. However, it is uncommon in children
under 4 years of age. Both sexes are equally affected.40,49
The signs and symptoms of tuberculomas resemble
those of other intracranial space-occupying lesions. As
they enlarge gradually, the clinical picture is one of a slowly
progressive lesion, although in at least 50% of patients, the
symptoms are less than 6 months in duration. Features helpful in distinguishing tuberculomas from other brain tumors
are constitutional symptoms, such as weight loss, fever, or
malaise; a history of active or known TB elsewhere in the
body; close contact with a patient with an open case of
TB; a high frequency of seizures, even in association with a
cerebellar lesion; a positive result on the Mantoux test; and
an increased sedimentation rate. Infants and young children may have an enlarging head. The clinical diagnosis
is often presumptive. Pyrexia is variable and may not be
present in more than 20% to 25% of patients,49 and the Mantoux test result may be negative.40 The clinical course may
uncommonly show spontaneous remissions and relapses.24

148 Management of Tuberculous Infections of the Nervous System

Clinical evidence of an active focus of TB, such as the lungs

and lymph glands, may be present in only 33% of patients40
and in approximately 10% of close relatives. Rare signs
include scalp swelling, cerebrospinal fluid (CSF) rhinorrhea, features of a pituitary tumor,27-31 unilateral proptosis,
and trigeminal neuralgia.40 The clinical picture may be
confusing when multiple lesions are present. Intramedullary tuberculomas with no evidence of extracranial TB are
clinically indistinguishable from intramedullary tumors; the
diagnosis may be suspected on magnetic resonance imaging (MRI) and is usually established at surgery.
Extrapulmonary manifestations, particularly CNS
involvement, are frequently seen in patients with HIV.50
Seizures, headaches, and an altered mental state are common presentations, but fever is often absent. The infection
is usually a reactivation of latent TB.51
The clinical setting of a rare but well-described paradoxical response to antituberculous drugs52-56 has been
reviewed by Hejazi and Hassler.54 Most of these patients
were young adults in whom inoperable intracranial tuberculomas located in high-risk regions had developed while
they were receiving adequate antitubercular therapy. Frequently, intracranial tuberculomas develop or enlarge at
a stage when systemic TB is responding to therapy. This
paradoxical response is attributed to the load of antigenically active dead bacteria in a setting of a hypersensitive
cell-mediated response. In this group of patients, associated TBM was a common feature. In TBM, symptoms of
increased intracranial pressure (ICP) and development of
focal neurologic signs, such as motor weakness, cerebellar signs, field defects, visual compromise, and behavioral
problems in children, necessitate a search for expanding
tuberculomas.

RADIOGRAPHIC FEATURES
An abnormal chest radiograph is a pointer to the diagnosis of a tuberculoma.57-60 More sensitive is a computed
tomography (CT) scan of the chest in picking up a tubercular involvement. Calcification occurs in fewer than 6%
of tuberculomas and is rarely extensive or dense,41 with
the striking exceptions of the Inuit (Eskimos) and North
American Indians, in whom nearly 60% of tuberculomas
are known to have calcifications.46 Calcification does not
indicate an inactive lesion. Cerebral angiography invariably reveals an avascular mass, although surface tuberculomas adherent to the dura may show some peripheral
vascularity.41,60 An associated vascular spasm may be seen
that is ascribed to tuberculous vasculitis. These angiographic findings may also be seen on magnetic resonance
angiography.

Computed Tomography and Magnetic

ResonanceImaging
Reviews from Africa,61 Asia,58-65 the West,65 and the Middle
East59 have pointed out that most tuberculomas are similar
in appearance on CT (Fig. 148-2). The CT scan image of a
tuberculoma is characterized by (1) a lesion that appears
isodense with the brain or slightly hyperdense and enhances
strongly with contrast, revealing a dense, unbroken ring of
enhancement; (2) in some cases, an enhancing disc or nodular mass with a regular or irregular margin; and (3) combinations of rings and discs, which may coalesce. Uncommonly,

1681

FIGURE 148-2 A contrast-enhanced CT scan shows multiple rings and

discs surrounded by areas of low attenuation, indicating edema characteristic of TB. The larger rings are abscesses. Courtesy of Rajiv Gupta
and Harsh Mahajan from Mahajan Imaging, New Delhi.

tuberculomas may present as a nonenhancing lesion or even

a strongly enhancing lesion that is indistinguishable from a
meningioma. Welchman61 described the rather rare target
sign, wherein a central focus of calcification and occasional
enhancement is surrounded by a peripheral ring of contrast
enhancement. The target sign is not specific for CNS TB and
may lead to an erroneous diagnosis of TB.66
Multiplicity is common in CT scans of patients with
tuberculomas. Bhargava and Tandon57,58 found that 50% to
60% of cases may demonstrate multiple lesions.

Microtuberculomas
The CT scan also picks up small lesions that are less than
1.5cm in size, disc-like or ring shaped, and single or multiple; have slightly increased attenuation that enhances with
contrast; and are surrounded by disproportionately extensive low-attenuating white matter edema. Bhargava and
Tandon58 labeled them microtuberculomas. Careful review
of these cases suggests that not all of those lesions are
tuberculous in etiology. Indian neurologists and neurosurgeons encounter these lesions frequently in children and
young adults, but reports have come from other countries
as well. The patients usually present with focal epilepsy and
no neurologic deficit. Although some of these cases are
definitely tuberculomas, as proved by biopsy, others result
from a variety of causes.67-75
Goulatia etal.70 suggested that edema and increased vascular permeability due to seizures may be responsible for the
CT appearance. Chandy etal.68,69 found cysticercosis as the
most common cause, and Ahuja etal.67 noted that 12 of their
38 patients were seropositive for cysticercosis and two were
seropositive for TB. On CT scan, tubercular lesions tend to
be larger than 20 mm, more frequently irregular in outline,
with a midline shift. Cysticercus cysts, in contrast, tend to be
smaller than 20 mm, with a regular outline and no midline

1682

Section Eight SURGICAL MANAGEMENT OF NERVOUS SYSTEM INFECTIONS

FIGURE 148-3 A contrast-enhanced

CT scan of a patient who had right
focal motor seizures shows (A) a
disc-like lesion with disproportionate surrounding low attenuation,
which (B) disappeared 2 months
later on anticonvulsant therapy
alone.

FIGURE 148-4 A, An MRI scan of a tuberculoma shows on T1-weighted images a slightly hyperintense rim (gliosis) surrounded by a complete or
partial rim of slight hypointensity (inflammatory cellular infiltrate) and central isointensity or of mixed isointensity and hypointensity (caseation necrosis and cellular infiltrate). B, On T2-weighted MRI images, the granuloma was hypointense (predominantly consisting of paramagnetic free radicals
in the macrophages and gliosis). This characteristic hypointensity of intraparenchymal tuberculomas is not found in most other space-occupying
lesions. Lesions may be hyperintense as well on T2-weighted images when the histology is of marked cellular infiltration with minimal gliosis.
Courtesy of D.C. Aggarwal, New Delhi, India.

shift.73 When first seen, they could represent tuberculomas,

abscesses, cysticercus granulomas, focal meningoencephalitis, astrocytomas, or metastases. A prospective study of the
predictive value of CT diagnosis of intracranial TB concluded
that although the sensitivity of CT in the diagnosis of intracranial tuberculomas is 100%, and its specificity is 85.7%, the
positive predictive value is only 33%. The low positive predictive value of making a diagnosis of intracranial TB based
on CT alone has been cited as a reason for obtaining histologic confirmation by open or stereotactic biopsy.74 Nearly
30% to 40% of these lesions may regress, either spontaneously or as a result of anticonvulsant drugs alone (Fig. 148-3).

Magnetic Resonance Imaging

In a review of 100 consecutive cases of tuberculoma, Wasay
et al. described the finding of a hypointense core surrounded by a hyperintense periphery as the most common
signal characteristic on T2-weighted images; in T1-weighted
images, the core was isointense with a hypointense rim (Fig.
148-4).65 This hyperintense signal on T2-weighted images
made lesions stand out even when there was only minimal
central liquefaction.76 On comparing MRI signal intensities
with histologic results, Kim etal.77 noted that the hyperintense
and hypointense rims on T1-weighted images corresponded
to layers of collagenous fibers and inflammatory cellular

148 Management of Tuberculous Infections of the Nervous System

Voxel location

1683

FIGURE 148-5 A, This axial T2-

weighted image shows a single
lesion with edema of surrounding white matter. B, In vivo proton
magnetic resonance spectroscopy
of the hypointense lesions shows a
characteristic lipid peak. Though the
choline peak is small in this case, it
is frequently as prominent as a lipid
peak in tuberculomas. Courtesy
of Rajiv Gupta and Harsh Mahajan
from Mahajan Imaging, New Delhi.

FIGURE 148-6 This clinical presentation was of a progressive paraparesis. The T2-weighted image shows
an intramedullary hyperintense lesion with a thin rim
of hypointensity around it. The surrounding cord is
swollen and edematous. The gadoliniumdiethylene
triamine penta-acetic acidenhanced image highlights the lesion. Courtesy of Rajiv Gupta and Harsh
Mahajan from Mahajan Imaging, New Delhi.

infiltrate, respectively, whereas the central zone consisted

of caseation necrosis and cellular infiltrate. T2-weighted
images did not discriminate among the various layers.
Gupta et al.78 found that granulomas that consisted predominantly of macrophages and gliosis were hypointense
on T2-weighted images. This characteristic hypointensity
of intraparenchymal tuberculomas is not found in most
other space-occupying lesions.22 When the histologic pattern was one of marked cellular infiltration, with minimal
gliosis, the appearance was hyperintense on T2-weighted
images. Invivo proton magnetic resonance spectroscopy in
hypointense lesions shows a marked increase in lipids compared with normal brain parenchyma79,80 (Fig. 148-5). In
comparison to neurocysticercosis, the magnetic resonance
spectroscopy of tuberculomas shows more choline and less

creatinine.81-83 Although the course of TB is more fulminant

in the patient with HIV, the imaging findings are similar to
those in nonimmunosuppressed patients.84
Spinal intramedullary tuberculomas appear isointense
or hypointense on T1-weighted images, and on T2-weighted
images, the lesion is isointense, hypointense, or hyperintense, surrounded by a ring of hyperintensity because of
the edema that commonly accompanies these lesions. On
contrast enhancement, there is rim or nodular enhancement
(Fig. 148-6).
TB of the pituitary gland is rare, and clues to a tubercular
etiology include intense contrast enhancement, meningeal
enhancement, and a thick pituitary stalk.28,29 Pachymeningeal TB typically is isointense on T1-weighted images and
isointense to hypointense on T2-weighted images.20,23

1684

Section Eight SURGICAL MANAGEMENT OF NERVOUS SYSTEM INFECTIONS

Table 148-2 Antituberculous Drugs

Drug
Isoniazid

Dosage

Contraindications
Drug-induced liver disease

Rifampicin

Oral/intramuscular 300 mg/day

(3-10 mg/kg)
Oral 450-600 mg/day (10 mg/kg)

Pyrazinamide
Ethambutol
Streptomycin

Oral (20-30 mg/kg)

Oral (15 mg/kg)
Intramuscular 1 g/day (20-25 mg/kg)

Liver damage
Optic neuritis
Pregnancy

MEDICAL TREATMENT
Antituberculous Drugs

Jaundice, pregnancy

The drugs usually prescribed nearly always belong to a

group of five antibiotics known to be effective in the treatment of extracranial TB (Table 148-2). The first-line agents
most commonly used are isoniazid, rifampicin (rifampin),
and pyrazinamide, all of which are bactericidal. Ethambutol, a bacteriostatic drug, or streptomycin, in children too
young to be monitored for visual acuity, is included in the
initial treatment regimen if there is a possibility of drug
resistance.85
The optimal duration of treatment is not definite
because, apart from early trials with streptomycin,86 there
is only one controlled trial in the treatment of intracranial
tuberculomas or TBM. Rajeswari etal.87 tested the efficacy
of a short-course chemotherapy in the treatment of brain
tuberculoma in 108 patients and concluded that a 9-month
course was effective. This is in marked contrast to the treatment of pulmonary TB, which is based on data obtained
from well-controlled trials. Guidelines for treating severe
extrapulmonary TB suggest an initial 2 months of four drugs
followed by 4 to 6 months with isoniazid and rifampicin.88
In practice, such guidelines are not commonly followed for
CNS TB. At present, four drugs are administered for the initial 3 or 4 months, and two drugs are given for an additional
14 to 16 months.49,85 Occasionally, drug treatment may have
to be prescribed in larger doses for 18 months to 3 years for
symptomatic intracranial tuberculomas developing during
treatment of TBM.89,90
Transient disturbance in liver function is often observed
in patients taking a combination of isoniazid and rifampicin. This needs to be monitored at regular intervals. The
incidence of serious liver disturbance appears to be higher
in Asians.91 Pyridoxine (10 mg/day) is invariably added to
prevent peripheral neuropathy due to isoniazid intake.
Most intracranial tuberculomas resolve with medical
therapy.49,61-64,91 The clinical and radiographic improvements are a result of the reduction in the size of the tuberculoma and the perilesional edema. Regardless of their size,
lesions usually start to regress after 4 to 6 weeks, and most
tuberculomas resolve within 12 to 14 months of treatment.
In approximately one third of cases, telltale evidence of the
lesion consists of an area of calcification or sometimes just
a speck of low attenuation.49 Some ring lesions change their
character and become disc-like or nodular on treatment. In
general, patients with increased ICP are slower to respond
than those with seizures alone.
Medical treatment may occasionally result in liquefaction of the center of the lesion without any reduction in
size.26 In some patients, the tuberculoma may either show

Side Effects
Peripheral neuritis, psychosis, optic neuritis,
occasionally lupus syndrome, convulsions
Liver toxicity, gastrointestinal symptoms, rarely
shock, respiratory collapse
Hepatitis
Optic neuritis, color blindness, peripheral neuritis
Ototoxicity, renal damage

no change or increase in size on use of antituberculous

drugs (described earlier).54,56,92 Tuberculomas seem to
enlarge and compress the surrounding brain without causing the destruction usually associated with a malignant
tumor; as a result, they can resolve with minimal residual
deficits. The treatment of TB in HIV-positive patients is the
same as for those who are HIV negative with the exception
that thioacetazone is contraindicated in the HIV-positive
patients.

Drug Resistance
Drug resistance of M. tuberculosis has been recognized
since the early days of streptomycin therapy. More recently,
there has been an emergence of MDR TB, defined as TB
that is resistant to the two most effective first-line therapeutic drugs, isoniazid and rifampicin. There are also virtually
untreatable strains of MDR TB labeled as XDR TB that are
also resistant to the most effective second-line therapeutic
drugs: fluoroquinolones and at least one of three injectable
second-line drugs used to treat TB (amikacin, kanamycin,
or capreomycin). Because of the limited responsiveness of
XDR TB to available antibiotics, mortality rates are similar
to the preantibiotic era. The mechanism is by chromosomal
mutation with emergence of resistant clones on the backdrop of inadequate drug therapy. The incidence of acquired
multidrug resistance (i.e., resistance to both isoniazid and
rifampicin) ranges from 0% to 48%.93,94 The WHO estimates that there are nearly 0.5 million new cases of MDR
TB, which accounts for 5% of the total of 9 million new TB
cases. The highest rate is in Baku, the capital of Azerbaijan,
where 22.3% of new cases were MDR TB.95 High rates were
reported from New York City,96 Estonia, and Latvia. A subsequent report of a decline in the prevalence of drug resistance in New York97 and in the United States as a whole,98
as well as the two Baltic countries,95 highlights the effectiveness of a strong TB program and the need for continuous
surveillance of drug resistance.99
Second-line drugs include the bactericidal drugs, fluoroquinolones, amikacin, kanamycin, ethionamide, capreomycin, prothionamide, and the bacteriostatic cycloserine.
Guidelines for treating MDR TB involve the use of at least
four new drugs never used by the patient, including a fluoroquinolones and at least one of the three injectable drugs
(amikacin, kanamycin, or capreomycin). Resistance to pyrazinamide and ethambutol is less likely, and they can be
included in the initial treatment. The initial treatment is for
at least 6 months, followed by a continuation phase of 12
to 18 months with the three most active and best tolerated
drugs.88 Patients with organisms resistant to rifampicin and
isoniazid have a high rate of treatment failure. Patients with

148 Management of Tuberculous Infections of the Nervous System

HIV infections not only are more prone to TB but also are
more susceptible to drug-resistant TB.100-102 Such patients
require a longer duration of therapy and may still die of TB
despite optimal treatment.102
Corticosteroids are used in the presence of elevated ICP
or severe cerebral edema as noted on imaging. Treatment is
seldom prolonged beyond 2 to 3 weeks, during which time
the corticosteroid therapy can produce dramatic improvement in the patients clinical state. Occasionally, patients
require steroids for a much longer period.

Anticonvulsant Medications
The high incidence of seizures with tuberculomas mandates the routine use of anticonvulsants. The commonly
used drugs are phenytoin, carbamazepine, oxcarbamazepine, and sodium valproate. Patients taking phenytoin and
isoniazid may acquire phenytoin toxicity because high levels of isoniazid in the serum can block metabolism of the
anticonvulsant.

SURGERY
A tuberculoma that severely elevates ICP and threatens life
or vision merits emergent surgical excision. In addition, surgical intervention comes into consideration in (1) patients
who do not respond clinically or radiographically to antituberculous drugs; (2) patients whose diagnosis is in doubt,
such as those with an atypical CT or MRI scan of the lesion;
and (3) patients with obstructive hydrocephalus.
Complete excision of tuberculomas is usually reserved
for smaller lesions in noneloquent areas of the brain. Larger
lesions require subtotal excision when they cause pressurerelated symptoms. An insistence on total excision at the
cost of an undesirable neurologic deficit is to be discouraged. In cases of multiple tuberculomas, only the largest
mass need be decompressed.
An appropriate craniotomy or craniectomy is performed
over the site of the lesion. Perioperative ultrasonography and
image guidance are useful for accurate localization of small,
deep-seated lesions. A clear plane of cleavage40,41 exists
between the firm, avascular tuberculoma and the edematous brain. The edema is usually not as pronounced as that
associated with metastatic deposits. Tuberculous lesions are
often on the cortical surface and adherent to the overlying
dura. Although dural adhesions are usually separable with
ease, the dural attachment at times can be extremely vascular, resembling that of meningiomas.41 After the tumor surface is identified, it is removed piecemeal from within the
confines of the granuloma. The ultrasonic aspirator is a useful aid in decompression. Where the center is liquefied or
necrotic, aspiration of the contents is sufficient; no attempt
should be made to excise the capsule. Subcortical lesions
are approached through a small corticectomy with preservation of as many vessels as possible. Parts of the tuberculoma
adherent to major vessels, venous sinus, or brain stem are
left in situ. The practice of frontal and temporal lobectomy or
excision of edematous brain is seldom necessary to achieve
decompression. Antitubercular chemotherapy is mandatory
even after a complete excision of a tuberculoma. After several months of administration of antituberculous drugs, the
lesion may be tough in consistency and resistant to curetting.
CT- or MRI-guided stereotactic biopsy and aspiration
constitute the preferred mode of diagnosis and treatment

1685

for (1) deep-seated lesions, such as those in the thalamus or

basal ganglia, and (2) tubercular abscesses or tuberculomas
with a liquefied center that can be readily decompressed
by this method.62 Atypical lesions also merit a stereotactic
instead of an open biopsy. Although stereotactic biopsy can
be quite safe,25,103 because of cost considerations, a trial
with antituberculous therapy is a worthwhile alternative in
patients with strong circumstantial evidence of tubercular
etiology, reserving surgery only for those lesions that continue to grow despite antituberculous drugs. Stereotactic
biopsy may also be a procedure of choice for patients with
so-called single, small lesions, described earlier, if they fail
to resolve on antiepileptic therapy.
Chiasmal decompression may be indicated for a suprasellar tuberculoma developing during treatment for TBM.
Brain stem tuberculomas are a rarity and seldom require
surgical decompression; they may be sampled for biopsy
specimen if the diagnosis is in doubt.25 We have some reservations regarding the safety of biopsy of brain stem lesions,
which can be extremely firm. A ventriculoperitoneal shunt
may be required for a tuberculoma that causes hydrocephalus, resulting either from obstruction of the CSF pathway or
from associated TBM. Tuberculomas of the pituitary gland
are rare lesions,27-31 and a diagnosis is frequently made only
after surgery. The postoperative course can be stormy with
features of panhypopituitarism, such as diabetes insipidus,
hypothermia, and hypotension.

RESULTS
Initial reports of mortality ranged from 10% to 27% for intracranial tuberculomas, but the results have improved dramatically in recent years. Harder etal.59 reported no deaths
in 20 cases. In our experience of 50 consecutive cases,49
1 patient died in the hospital and 1 died 2 years after treatment, probably as a result of infection with a drug-resistant
organism. Both of these patients had multiple tuberculomas and markedly elevated ICP. Numerous reports have
been published of patients with deep-seated, inaccessible
lesions and lesions in the brain stem who have had excellent
recoveries.

Tuberculous Meningitis
TBM is a major cause of morbidity and mortality in countries where pulmonary TB is still common. TBM is a disease of childhood whose highest incidence is in the first
3years of life.104 An increasing incidence in adults has been
reported, and in our experience, adults account for 50% of
all patients. The incidence of TBM is five times higher in
patients with HIV.105
The major neurosurgical interest in TBM is the occurrence of hydrocephalus, tuberculomas, and rarely, chiasmal
and spinal arachnoiditis. In the acute stage, increased ICP is
related to the general inflammatory process, increased CSF
proteins, and impaired CSF absorption. When the disease
becomes subacute or chronic, the inflammatory basal exudates extend along small proliferating blood vessels into the
brain substance, leading to a border zone encephalitis associated with diffuse or focal ischemic changes due to vasculitis. Larger vessels, commonly the internal carotid artery
siphon, its bifurcation, proximal segments of the middle
cerebral artery, and sometimes the anterior cerebral artery,

1686

Section Eight SURGICAL MANAGEMENT OF NERVOUS SYSTEM INFECTIONS

FIGURE 148-7 This MRI scan of a 25-year-old woman who had headache and seizures for 5 months shows a thickened leptomeninges over
the parietal convexity. Courtesy of Rajiv Gupta and Harsh Mahajan
from Mahajan Imaging, New Delhi.

may get involved, leading to occlusion and infarction.

Theaffected artery shows changes of periarteritis, massive
subintimal fibrosis with narrowing or obstruction.106,107
Hydrocephalus is almost invariable in children who survive for more than 4 to 6 weeks and is most often caused by
blockage of the basal cisterns and the sylvian fissures by
tubercular exudates.108-110 In more chronic phases, hydrocephalus is caused by vascular adhesive arachnoiditis. In
some cases, hydrocephalus may be caused by obstruction
at the outlet of the fourth ventricle and less commonly by
obstruction at the level of the aqueduct, either as a result of
circumferential narrowing of the brain stem by exudates or
of an intraluminal tuberculoma. Obstruction of CSF circulation in TBM often occurs at multiple sites.104 TBM may rarely
be followed by the development of syringomyelia despite
appropriate chemotherapy.111
As the disease becomes more chronic, the exudates
become firm and organized. The clinical evidence of meningitis disappears, leaving behind thickened, localized,
hard, fibrotic leptomeninges that may form a plaque-like
cover over the cerebral hemispheres, posterior fossa, foramen magnum, or spinal cord. The disease, although localized, is still active and can cause progressive symptoms.112
This condition is increasingly being recognized as a manifestation of CNS TB20,23 (Fig. 148-7) and must be differentiated from idiopathic hypertrophic pachymeningitis.

PROBLEMS OF DIAGNOSIS
In many patients, the diagnosis of TBM still poses considerable difficulties. Examination of CSF is often inconclusive,

tubercle bacilli being found on direct smears in no more

than 10% to 15% of initial samples. A notable exception was
the report of Kennedy and Fallon,113 who isolated M. tuberculosis in 83% of 52 patients. The gold standard in the diagnosis of TB remains culturing in a Lowenstein-Jensen medium,
the BACTEC radiometric system, a mycobacterial growth
indicator tube, or luciferase reporter mycobacteriophage
assays. The main limitation is the time taken for culture (2-6
weeks). The BACTEC 460 radiometric system can detect
mycobacteria as early as 5 to 10 days.114 As an alternative to
bacteriologic methods, several newer techniques have been
used to diagnose TB that are faster. These include nucleic
acid amplification methods and serologic tests.
Serologic tests include enzyme-linked immunosorbent
assay to detect M. tuberculosis antigen 5,115-117 38-kD antigen,115 antigen 60 immunoglobulin G,118 and lipoarabinomannan antigen.116,119,120 In general, serologic tests for
HIV-related TB are disappointing.115,119 Although specificity is very high, no single test gives 100% sensitivity. Future
research is being directed toward identifying the best possible combination of antigens for the serodiagnosis of TB
or a combination of serodiagnosis and polymerase chain
reaction (PCR) to improve sensitivity.121 In the liposomal
agglutination card test, a cocktail of cell wallassociated
antigens incorporated onto the surface of liposomal particles react with antibodies in clinical samples to produce
a blue agglutination. This test, with a sensitivity of 94%,
specificity of 98.3%, low cost, and speed, makes it useful for
screening large populations for active disease.122 Similarly,
the Assure TB rapid test123 based on a solid phase immunochromatographic assay, relies on a cocktail of antigens.
Infinitesimal quantities of tuberculostearic acid, a component of M. tuberculosis detected by gasliquid chromatography in CSF, are considered diagnostic of TBM.124-126
Diagnosis of TB in HIV-infected patients poses special problems. The preponderance of extrapulmonary forms with
the very low number of tubercle bacilli in the available test
samples makes detection difficult. The resemblance of TB
to some opportunistic infections in HIV-infected patients
has popularized molecular diagnosis in these patients.
On the whole, the clinical validity of nucleic acid amplification methods to detect M. tuberculosis remains controversial because, although the tests are rapid and sensitive,
they remain inferior to culture with regard to sensitivity
and specificity.127-130 In specific clinical situations such as
nonpurulent meningitis diagnosed based on cytology and
biochemistry of CSF, in which the immediate diagnosis of
TB is essential, such methods are used, overriding considerations of cost and sensitivity. While the sensitivity and
specificity is acceptable in smear-positive specimens, it
is not so for smear-negative specimens.131 When nucleic
amplification results are negative, the test has to be
repeated with a fresh specimen or with material obtained
from fluid culture systems after 1 to 2 weeks of incubation
to maximize the sensitivity. In tropical countries, CSF cultures tend to be less sensitive than nucleic acid amplification methods. Nguyen et al.132 from Vietnam reported on
99 cases of confirmed or probable TBM based on clinical
features of TBM and response to antitubercular treatment.
They found that PCR had a sensitivity of 32%, culture of 17%,
and microscopy of 1%. The Indian story has been similar,
with positive culture rates of approximately 15% in the best

148 Management of Tuberculous Infections of the Nervous System

of circumstances.133-134 To arrive at an early diagnosis of a

disease in which any delay involves higher mortality and
morbidity, Ahuja etal.134 defined a set of criteria based on
clinical features, CSF examination, CT findings, and the
presence of extraneural TB. Seventy-six patients suspected
of having TBM were divided into definite, highly probable,
probable, and possible TBM categories based on the criteria. The validity of the criteria was tested using information from bacterial isolation, PCR test for TB, response to
therapy, and autopsy. On antituberculous therapy, 91% of
the patients with highly probable and 66% with probable
TB improved.
Advances in molecular diagnostic tests for evaluating
drug resistance need to be mentioned.128,135 Molecular
data are available for rifampicin, streptomycin, and isoniazid, but genetic data for other first-line drugs are partially
understood136 and for second-line drugs are not available.
Mutations identified in the gene encoding the ribonucleic
acid polymerase B subunit directly confer rifampicin resistance to M. tuberculosis. The genetic resistance mechanism
to isoniazid is more complicated and appears to be based
on more than one molecular variant.137,138 Although identifying strains resistant to rifampicin is possible with firstgeneration methods including PCR, the more widely used
procedure involves nucleic acid hybridization with oligonucleotide probes.139-141 While genotypic assays are rapid,
their limitations are that they detect only known mutations,
thus reducing their sensitivity. In addition, tests may not be
sensitive enough to detect small drug-resistant populations.
Until details of genes conferring resistance are known for
all first-line drugs, growth-dependent methods will remain
the gold standard for determining drug susceptibility.

IMAGING
Computed Tomography

Although normal scan results may be seen in the early

stages of TBM, the following features may be demonstrable
in the course of the illness: exudates in the basal cisterns
or sylvian fissures, hydrocephalus, infarcts, tuberculomas,
gyral and meningeal enhancement, and edema in the white
matter109,142-144 (Fig. 148-8). The exudate enhancement is
irregular and is unlike the sharply defined enhancement
of circulating blood in normal vessels in the fissures and
cisterns. Hydrocephalus is seen in more than one third of
cases in the first scan and becomes more frequent as the
disease progresses.145
In most cases, associated periventricular lucency indicates transependymal CSF flow caused by elevated ICP
and is therefore an important sign of impending deterioration. Bullock and Van Dellen142 pointed out that in TBM,
periventricular lucency is likely to be a result of spread of
the inflammatory process, making it an unreliable sign of
elevated intraventricular pressure.

Magnetic Resonance Imaging

No consistent or characteristic signal abnormality attributed to meningeal inflammation or basal cistern exudate
has been described (Fig. 148-9). When hydrocephalus is
present, CSF is forced transependymally. This interstitial
accumulation of CSF is seen as bilateral, rather uniform periventricular areas of increased intensity. MRI is more sensitive in demonstrating early infarcts than is CT.146

1687

FIGURE 148-8 Contrast-enhanced CT extensively shows exudates in

the cisterns, along with prominent ventricles. Courtesy of Rajiv Gupta
and Harsh Mahajan from Mahajan Imaging, New Delhi.

MEDICAL TREATMENT
There is evidence that bacille CalmetteGurin vaccination
offers some protection against TBM.147,148 Once meningitis
is established, drug therapy similar to that for tuberculomas
is initiated (Table 148-2). Short-course chemotherapy is well
established for treatment of pulmonary TB but not for extrapulmonary disease. Goel etal.149 reviewed 35 cases of TBM
in which chemotherapy was given for periods of less than
2 years. Short-term therapy was associated with recrudescence of TBM and, in some cases, with the development
of deep cerebral infarcts and permanent neurologic deficit.
In a critical reappraisal of the literature on adjunctive
corticosteroid therapy in TB, Dooley etal.150 concluded steroids did not reduce the efficacy of adequate antimycobacterial therapy and appeared to offer significant short- and
long-term benefits in TBM. Several randomized trials of steroids in TBM have appeared in the literature. In the first prospective, randomized, controlled trial of dexamethasone in
TBM, Kumarvelu et al.151 concluded that dexamethasone
appeared to be a useful adjunct, especially in patients with
severe disease. A similar prospective, randomized, controlled trial of steroids in TBM in 141 consecutive children
concluded that the survival rate and intellectual outcome
were significantly better with steroids. There was enhanced
resolution of basal exudates and tuberculomas on serial CT
scanning. However, ICP and the incidence of basal ganglia
infarction remained unchanged.152 In a randomized, doubleblind trial involving 59 adults with TBM, prednisolone
was not found to be beneficial in patients with poor neurologic status, increased ICP, and cranial nerve palsies.153
A controlled trial on 545 adults with TBM demonstrated

1688

Section Eight SURGICAL MANAGEMENT OF NERVOUS SYSTEM INFECTIONS

FIGURE 148-9 Gadoliniumdiethylene

triamine penta-acetic acidenhanced
T1-weighted axial, sagittal, and coronal images demonstrate enhancement of the leptomeninges over the
surface of the brain. There are also
multiple tubercles studding the brain
parenchyma. Courtesy of Rajiv Gupta
and Harsh Mahajan from Mahajan
Imaging, New Delhi.

that dexamethasone improved survival but did not improve

disability.154 It is not clear how steroids work. Steroids do
not appear to act by attenuating immunologic mediators of
inflammation.155
In the absence of anticonvulsants, seizures occurred in
less than 10% of children in the first 3 months. Patwari etal.156
advocated that all children with focal seizures and those
with generalized tonicclonic seizures and tonic spasms
manifesting more than once during hospitalization or associated with abnormal CT or electroencephalographic findings be given long-term anticonvulsants. Children without
seizures and those with generalized tonicclonic seizures
before hospitalization or not more than one seizure during
the first week of hospitalization and without abnormal CT
or electroencephalographic findings were not given longterm anticonvulsants. Close follow-up is essential, especially
when anticonvulsant therapy has been withheld.

SURGERY
Cairns157 first advocated ventricular decompression during the acute stage of TBM. Since then, numerous procedures have been tried, and reports have conclusively
documented the efficacy of ventriculoatrial or ventriculoperitoneal shunts for this condition.146,157-160 The fear of
spreading tubercle bacilli through the shunt is unfounded.

Hydrocephalus may resolve with medical treatment alone;

however, surgical diversion of CSF is indicated when hydrocephalus is associated with symptomatic elevated ICP.
After a shunt is inserted, a progressive reduction in size
of the ventricles occurs, but the ventricles may not return
to normal size.109 A low-pressure shunt appears to be best
suited to these patients. Infrequently, separate shunts are
required for each lateral ventricle if a CSF block is present at the level of the foramen of Monro. Alternatively, an
endoscopic fenestration of septum pellucidum eliminates
the need for two ventricular ends. Loculations within ventricles could similarly be fenestrated to reduce the number of shunts required. Where the obstruction is at the
aqueduct or the fourth ventricular outlet on imaging, it is
tempting to perform a third ventriculostomy, but the surgeon must keep in mind that CSF frequently is obstructed
at multiple sites, and bypassing one obstruction may simply uncover another. In acute TBM, the combination of an
inflamed, opaque, tubercle-studded third ventricular floor
and exudates in the underlying subarachnoid space makes
the procedure risky and prone to failure. The success rate
is quite variable, ranging from 41% to 77%. Whether it is
a third ventriculostomy or an endoscopic fenestration of
septate, the results would be better when performed following 4 weeks or more of anti-TB treatment or when the

148 Management of Tuberculous Infections of the Nervous System

Table 148-3 Modified Vellore Grading of TBM

andHydrocephalus
Grade
I
II
III
IV

Description
GCS 15
Headache, vomiting, fever with or without neck
stiffness, no neurologic deficit
GCS 15
Neurologic deficit present
GCS 9-14
Neurologic deficit may or may not be present
GCS 3-8
Neurologic deficit may or may not be present

GCS, Glasgow Coma Scale score.

disease has been quiescent.161-164 Rarely, optochiasmal

arachnoiditis may be responsible for the development of
visual deterioration and may indicate a need for decompression of the optic nerves and chiasm.92 Cerebral tuberculomas can develop insidiously during treatment of
TBM,52-56 and the patient may die as a result of elevated
ICP. These tuberculomas tend to occur in deep structures,
making surgical access difficult and hazardous. Steroids
may be of help during the crisis.54

RESULTS
The prognosis of TBM depends on the delay in treatment,
the patients level of consciousness, the presence and
degree of exudates, and the presence of hydrocephalus
and cerebral infarcts.109,160-168 After TBM, there is frequent
marked, generalized impairment of cognitive and motor
development.169 Palur etal.160 reviewed 114 patients with
TBM and hydrocephalus who underwent shunt surgery
and followed them for a period ranging from 6 months to
13 years (mean 45.6 months). They described a grading
score at admission based on sensorium and neurologic
deficit, which was found to correlate statistically significantly with the outcome (p < 0.001) The grading system
has since been modified to include the Glasgow Coma
Scale to improve reproducibility170 (Table 148-3). The
utility of this grading system has been ratified by other
researchers.171,172
Early shunt surgery is advocated for patients in grades I
and II. For patients in grade III, surgery may be performed
either without a trial of external ventricular drainage or
when an improvement in sensorium occurs after such a
trial. All patients in grade IV should undergo external ventricular drainage, and only those who show a significant
change in their neurologic status within 24 to 48 hours
of drainage should undergo shunt surgery. There would
be a few patients in this group who show no improvement on drainage yet may show improvement after shunt
surgery.173
Nadvi etal. compared two groups of 15 patients each,
one with TBM and the other whose patients were also
HIV positive, and concluded that the mortality and outcome following shunt surgery was significantly worse
in patients who were HIV positive even though at initial
presentation they had a better sensorium and fewer neurologic deficits. None of the HIV-positive patients had a
good recovery, and there were no survivors in grades

1689

III and IV. They concluded that all patients of TBM who
were HIV positive should be given a trial of CSF drainage, and only those who show an improvement should
undergo shunt surgery.174

Tuberculous Spinal Arachnoiditis

Tuberculous spinal arachnoiditis usually occurs as a result
of a spread of meningitis from within the cranium during the
course of treatment, while the disease is still active, or after
a variable period of months to years after the disease has
burnt out.175,176 Sometimes the disease may start primarily in the spinal meninges because of rupture into the subarachnoid space of a superficial spinal tuberculoma.177,178
Rarely, the disease occurs as a result of a direct transdural
spread in spinal caries.179
The maximal involvement is in the thoracic and thoracolumbar region, with longitudinal extensions ranging
from a few segments to the entire cord. The disease is
more marked posterior to the cord, and it may be difficult
to distinguish the meninges from the cord. The meninges may become thickened and hard, whereas the cord
is atrophied, soft, and edematous, with one or more visible tuberculomas on the surface. As the exudates organize, the spinal cord or roots get entrapped, producing a
myeloradiculopathy.180

CLINICAL FEATURES
The appearance of root pain, weakness of the lower limbs,
and sphincter disturbances in a patient with TBM suggests
the diagnosis of an evolving spinal arachnoiditis. Examination reveals a mixture of upper and lower motor neuron
signs with patchy sensory deficits.

IMAGING
Tuberculous arachnoiditis on myelography shows an
irregular thecal sac; nodularity; thickening of the nerve
roots, with clumping of the roots to one another and the
thecal sac; and CSF block. These findings are reflected on
MRI scans. In addition, there are CSF loculations and an
increase in CSF intensity on T1-weighted images, leading
to loss of cordCSF interface or a shaggy outline. Cord
involvement is seen in more than 80% of cases in the form
of increased intensity on T2-weighted images and cord
cavitation. With contrast, there is meningeal enhancement in 80% of cases (Fig. 148-10), although enhancement
of the roots and cord is less frequently seen. Associated findings of tuberculous spondylitis, basal exudate,
and intracranial granulomas are additional clues to the
diagnosis.181-183

TREATMENT
It is generally accepted that steroids are a useful adjunct
in treating patients threatened with paraplegia. Intrathecal
steroids may help in further resolution of the exudate. Gourie-Devi and Satish Chandra184 have advocated intrathecal
hyaluronidase to lyse the adhesions. Recurrence is common, and available treatments are not very effective. The
outcome of surgical intervention is quite unpredictable, and
it may be offered as a treatment option if the diagnosis is in
doubt, in localized lesions, or if imaging suggests a cyst at
the expected clinical level.

1690

Section Eight SURGICAL MANAGEMENT OF NERVOUS SYSTEM INFECTIONS

FIGURE 148-10 A case of tubercular MDR TB with spinal arachnoiditis,

seen as an enhancement of the leptomeninges. There is in association
an intensely enhancing plaque over the clivus, along with a conglomerate of rings within the brain parenchyma in the posterior fossa.

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