INTRODUCTION Central nervous system (CNS) tuberculosis (TB) includes three

clinical categories: tuberculous meningitis, intracranial tuberculoma, and spinal

tuberculous arachnoiditis. All three categories are encountered frequently in regions of the
world where the incidence of TB is high and the prevalence of post-primary dissemination
is common among children and young adults [1,2]. In regions where the incidence rates
are low, such as North America and Western Europe, extrapulmonary manifestations of
diseases are seen primarily in adults with reactivation disease, and the dominant form of
CNS disease is meningitis.

The pathogenesis, clinical presentation, diagnosis, and treatment of central nervous

system tuberculosis will be reviewed here. The general principles of treatment of TB are
discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in HIV-
uninfected adults".)

PATHOGENESIS During the bacillemia that follows primary infection or late

reactivation tuberculosis (TB), scattered tuberculous foci (tubercles) are established in the
brain, meninges, or adjacent bone. (See "Natural history, microbiology, and pathogenesis
of tuberculosis".)

The chance occurrence of a subependymal tubercle, with progression and rupture into the
subarachnoid space, is the critical event in the development of tuberculous meningitis [3].
The widespread and dense distribution of infectious foci seen in association with
progressive miliary tuberculosis greatly increases the chance that juxta-ependymal
tubercles will be established. (See "Epidemiology and pathology of miliary and
extrapulmonary tuberculosis".)

Consequently, meningitis develops most commonly as a complication of progressive

primary infection in infants and young children and from chronic reactivation bacillemia in
older adults with immune deficiency caused by aging, alcoholism, malnutrition,
malignancy, human immunodeficiency virus (HIV) infection, or drugs (eg, tumor necrosis
factor [TNF]-alpha inhibitors). Advancing age or head trauma may also lead to
destabilization of an established quiescent focus resulting in meningitis in the absence of
generalized infection.

The spillage of tubercular protein into the subarachnoid space produces an intense
hypersensitivity reaction, giving rise to inflammatory changes that are most marked at the
base of the brain. Three features dominate the pathology and explain the clinical
manifestations [3,4]:

Proliferative arachnoiditis, most marked at the base of the brain, eventually

produces a fibrous mass that encases adjacent cranial nerves and penetrating
vessels.
 Vasculitis with resultant aneurysm, thrombosis, and infarction affects vessels that
traverse the basilar or spinal exudate or are located within the brain itself [5]. Multiple
lesions are common, and a variety of stroke syndromes may result, involving the
basal ganglia, cerebral cortex, pons, and cerebellum [6]. Intracranial vasculitis is a
common feature of autopsy studies and a major determinant of residual neurologic
deficits. In one autopsy study of 27 cases, for example, phlebitis and varying degrees
of arteritis were demonstrated in 22 cases, including 8 patients with associated
hemorrhagic cerebral infarction [7].
Communicating hydrocephalus results from extension of the inflammatory process
to the basilar cisterns and impedance of cerebrospinal fluid circulation and resorption.
Obstruction of the aqueduct develops less frequently, from contraction of exudate
surrounding the brainstem or from a strategically placed brainstem tuberculoma.

Host susceptibility The Toll-like receptor pathway appears to influence the

susceptibility of man to tuberculous meningitis; this was illustrated in a case-population
study design involving 175 HIV-uninfected patients with tuberculous meningitis, 183 HIV-
uninfected patients with pulmonary tuberculosis, and 392 control patients [8]. A
polymorphism in Tollinterleukin-1 receptor domain containing an adaptor protein that
mediates signaling from mycobacteria activated Toll-like receptors was associated with
susceptibility to meningeal tuberculosis (odds ratio [OR] 3.0) and to pulmonary
tuberculosis (OR 1.6). The polymorphism was also associated with decreased whole-blood
interleukin-6 production, suggesting immunomodulation as a mechanism for susceptibility.

FORMS OF CNS TUBERCULOSIS

Tuberculous meningitis Tuberculous meningitis accounts for about 1 percent of all

cases of tuberculosis (TB) and 5 percent of all extrapulmonary disease in
immunocompetent individuals [9]. Although pulmonary TB in the United States has
declined, the number of meningeal TB cases has changed little, and the case-fatality ratio
remains relatively high (15 to 40 percent) despite effective treatment regimens [9,10].

Early recognition of tuberculous meningitis is of paramount importance because the

clinical outcome depends greatly upon the stage at which therapy is initiated. Empiric
antituberculous therapy should be started immediately in any patient with meningitis
syndrome and cerebrospinal fluid (CSF) findings of low glucose concentration, elevated
protein, and lymphocytic pleocytosis if there is evidence of TB elsewhere, either clinically
or historically, or if prompt evaluation fails to establish an alternative diagnosis. Serial
examination of the CSF by acid-fast stain and culture is the best diagnostic approach.
Smears and cultures will yield positive results even days after treatment has been initiated.
Nucleic acid amplification (NAA) testing also may be helpful. (See 'Diagnosis' below.)

Clinical manifestations Typically, patients with tuberculous meningitis present with a

subacute febrile illness that progresses through three discernible phases [11-14]:
 The prodromal phase, lasting two to three weeks, is characterized by the insidious
onset of malaise, lassitude, headache, low-grade fever, and personality change.
The meningitic phase follows with more pronounced neurologic features, such as
meningismus, protracted headache, vomiting, lethargy, confusion, and varying
degrees of cranial nerve and long-tract signs.
The paralytic phase supervenes as the pace of illness accelerates rapidly; confusion
gives way to stupor and coma, seizures, and often hemiparesis. For the majority of
untreated patients, death ensues within five to eight weeks of the onset of illness.

It is useful to categorize patients on presentation by the stage of illness, based upon the
mental status and focal neurologic signs [15]:

Stage I patients are lucid with no focal neurologic signs or evidence of

hydrocephalus.
Stage II patients exhibit lethargy, confusion; they may have mild focal signs, such as
cranial nerve palsy or hemiparesis.
Stage III represents advanced illness with delirium, stupor, coma, seizures, multiple
cranial nerve palsies, and/or dense hemiplegia.

About one-third of patients on presentation have underlying generalized (miliary)

tuberculosis, in which case careful funduscopic examination often shows choroidal
tubercles (picture 1). These are multiple ill-defined raised yellow-white nodules
(granulomas) of varying size near the optic disk. If present in a patient with meningitis,
choroidal tubercles are a valuable clue to the etiologic diagnosis. (See "Tuberculosis and
the eye".)

Signs of active TB outside the central nervous system (CNS) are of diagnostic import if
present but are often absent or nonspecific. Abnormalities on chest radiograph may be
seen in half of cases, ranging from focal lesions to a subtle miliary pattern. A tuberculin
skin test or an interferon-gamma release assay (IGRA) will be positive in the majority
[11,12], although a negative result does not exclude the diagnosis. (See "Diagnosis of
latent tuberculosis infection (tuberculosis screening) in HIV-uninfected adults".)

It is important to recognize cases with atypical features that mimic other neurologic
conditions. Patients may present with an acute, rapidly progressive meningitic syndrome
suggesting pyogenic meningitis or with a slowly progressive dementia over months or
even years characterized by personality change, social withdrawal, loss of libido, and
memory deficits. Less commonly, patients may present with an encephalitic course
manifested by stupor, coma, and convulsions without overt signs of meningitis [16].

Paradoxical reaction (PR), an exacerbation of clinical signs (eg, fever, change in

mentation) after beginning antituberculous chemotherapy, occurs in approximately one-
third of patients with tuberculous meningitis and is not limited to HIV-infected patients (in
whom PR is called immune reconstitution inflammatory syndrome); predictors include
female gender, concomitant HIV infection, and a shorter duration of illness [17].

Diagnosis The diagnosis of CNS TB can be difficult; maintaining a high degree of

suspicion is vital in order to initiate therapy promptly. Diagnostic tools consist of
cerebrospinal fluid (CSF) examination (including culture and nucleic acid testing) and
radiography.

Spinal fluid examination The examination of cerebrospinal fluid specimens is of

critical importance to early diagnosis of tuberculous meningitis [18]. Typically, the CSF
formula shows elevated protein and lowered glucose concentrations with a mononuclear
pleocytosis [19,20]. CSF protein ranges from 100 to 500 mg/dL in most patients; however,
patients with subarachnoid block may show extremely high levels in the range of 2 to
6 g/dL, associated with xanthochromia and a poor prognosis. The CSF glucose is less
than 45 mg/dL in 80 percent of cases. The usual CSF cell count is between 100 and
500 cells/microL.

Early in the course of illness, the cellular reaction is often atypical with only a few cells or
with polymorphonuclear leukocyte (PMN) predominance. Such cases usually rapidly
change to a lymphocytic cellular response on subsequent CSF examinations. Upon
initiation of antituberculous chemotherapy, the CSF of some patients briefly reverts to a
PMN cellular reaction, associated with transient clinical deterioration ("therapeutic
paradox") [21].

Measurement of the CSF adenosine deaminase (ADA) level may be a useful adjunctive
test for diagnosis of tuberculous meningitis [18,22]. However, elevated CSF ADA level
may also be observed in the setting of bacterial infections [22,23], and there is no clear
threshold to distinguish TB meningitis from meningitis caused by other infectious agents.
One meta-analysis included 10 studies (most of which defined an elevated ADA as 9 or
10 U/L) estimated the sensitivity and specificity of ADA for diagnosis of TB meningitis to be
79 and 91 percent, respectively [24]. Another meta-analysis including 13 studies noted the
sensitivity and specificity of ADA for diagnosis of TB meningitis depended on the definition
of an elevated ADA level [25]. For ADA threshold of 4 U/L, the sensitivity and specificity
were >93 and <80 percent, respectively; for ADA threshold of 8 U/L, the sensitivity and
specificity were <59 and >96 percent, respectively.

Culture and sensitivity The importance of repeated, careful examination and culture of
CSF specimens for Mycobacterium tuberculosis cannot be overemphasized. A large
volume of CSF improves diagnostic yield. Some authorities recommend a minimum of
three serial lumbar punctures be performed at daily intervals, although empiric therapy
need not be delayed during this time. In one series, 37 percent of cases were diagnosed
on the basis of an initial positive acid-fast bacilli (AFB) smear; the diagnostic yield
increased to 87 percent when up to four serial specimens were examined, even though
antituberculous therapy had been administered before a positive smear was obtained in
some cases [12].

In a study including 132 adults with clinical tuberculous meningitis, a bacteriologic

diagnosis was achieved in 82 percent of cases; AFB smear and culture were positive in 58
and 71 percent of cases, respectively [26]. The sensitivity of the AFB smear of spinal fluid
may be enhanced by attention to the following principles [12,19,26]:

It is best to use the last fluid removed at lumbar puncture, and recovery of the
organism improves if a large volume (10 to 15 mL) is removed.
Organisms can be demonstrated most readily in a smear of the clot or sediment. If
no clot forms, the addition of 2 mL of 95% alcohol gives a heavy protein precipitate
that carries bacilli to the bottom of the tube upon centrifugation.
0.02 mL of the centrifuged deposit should be applied to a glass slide in an area not
exceeding one centimeter in diameter and stained by the standard Kinyoun or Ziehl-
Neelsen method.
Between 200 and 500 high-powered fields should be examined (approximately 30
minutes), preferably by more than one observer.

Nucleic acid tests CSF specimens should be submitted for nucleic acid amplification
(NAA) testing whenever possible, particularly in the setting of high clinical suspicion and
negative AFB staining [27-34]. General issues related to NAA tests are discussed further
separately.

We are in agreement with the World Health Organization, which has recommended use of
the Xpert MTB/RIF assay as an initial test for diagnosis of tuberculous meningitis [35]. In
one systematic review and meta-analysis including 18 studies, the sensitivity and
specificity for the Xpert MTB/RIF assay in cerebrospinal fluid (compared with culture) were
81 and 98 percent, respectively [33]. However, NAA tests of CSF have not been approved
by the US Food and Drug Administration.

NAA tests appear to have high specificity but moderate sensitivity in CSF [36-38]; in one
study, sensitivity and specificity of NAA testing in CSF were 59 and 100 percent,
respectively [36]. This suggests that NAA tests may be used to confirm the diagnosis of
tuberculous meningitis when used together with traditional CSF studies, but NAA tests
cannot be used to rule out TB meningitis.

The assay MTBDRplus is a molecular probe capable of detecting rifampin- and isoniazid-
resistance mutations (rpoB gene for rifampinresistance; katG and inhA genes
for isoniazid resistance) [39]. The assay has been shown to be useful for detection of drug
resistance for CSF samples that have a polymerase chain reaction (PCR)-positive result
[40]. (See "Diagnosis of pulmonary tuberculosis in HIV-uninfected adults", section on
'Molecular tests'.)
NAA tests of CSF have not been approved by the US Food and Drug Administration; many
United States laboratories have validated NAA tests that are reported as "research use
only."

Radiography Computed tomography (CT) and magnetic resonance imaging (MRI)

have greatly improved characterization and management of CNS TB disease [41]. In
patients with tuberculous meningitis, CT and MRI can define the presence and extent of
basilar arachnoiditis (image 1), cerebral edema, infarction, and hydrocephalus (image 2).
In two large community-based series, hydrocephalus was seen in approximately 75
percent of patients, basilar meningeal enhancement in 38 percent, cerebral infarcts in 15
to 30 percent, and tuberculomas in 5 to 10 percent [42,43]. A case series from Hong Kong
documented hydrocephalus on presentation in 9 of 31 patients with tuberculous
meningitis; hydrocephalus occurred after the start of antituberculous therapy in only 1 of
the remaining 22 patients [44].

The following observations can be derived from a review of selected clinical series
[42,43,45]:

In a patient with compatible clinical features, CT or MRI evidence of basilar

meningeal enhancement combined with any degree of hydrocephalus is strongly
suggestive of tuberculous meningitis (image 2).
The CT scan is normal in approximately 30 percent of cases with stage I meningitis,
and patients with a normal scan nearly always recover completely on therapy.
Hydrocephalus combined with marked basilar enhancement is indicative of
advanced meningitic disease and carries a poor prognosis. Marked basilar
enhancement correlates well with vasculitis and, therefore, with a risk for basal
ganglia infarction.

MRI is superior to CT in defining lesions of the basal ganglia, midbrain, and brainstem and
for evaluating all forms of suspected spinal TB (image 1) [46,47]. (See "Skeletal
tuberculosis".)

Differential diagnosis The differential diagnosis of tuberculous meningitis is that of a

subacute or chronic meningitis syndrome with a CSF formula characterized by a
lymphocytic pleocytosis, lowered glucose concentration, and a high protein content. This is
seen most commonly with cryptococcosis and occasionally with other deep-seated
granulomatous fungal infections, brucellosis, and neurosyphilis. A similar syndrome may
be encountered in patients with a parameningeal suppurative infection (eg, sphenoid
sinusitis, brain abscess, or spinal epidural space infection). Patients with herpes
encephalitis may exhibit similar CSF findings, including mild lowering of CSF glucose
concentration. Careful evaluation for CNS tuberculosis is warranted in the patient
suspected of any of the diagnoses listed in the table (table 1).
Tuberculoma Tuberculomas are conglomerate granulomatous foci within the brain
parenchyma; they may be observed on histopathology or radiographic imaging (image 3)
[48]. They develop from coalescing tubercles acquired during an earlier period of
hematogenous bacillemia. Centrally located lesions may reach considerable size without
producing meningeal inflammation. Clinically silent single or multiple nodular enhancing
lesions are commonly seen in the setting of meningitis; occasionally, they are seen in
patients with miliary tuberculosis and no meningitis [49,50]. These lesions generally
disappear on therapy but may heal with calcification.

Symptomatic intracranial mass lesions ("clinical tuberculomas") are observed most

frequently in individuals from areas where the prevalence of tuberculosis is high. Typically,
a child or young adult presents with seizure or headache; occasionally, hemiplegia or
signs of raised intracranial pressure are observed [51,52]. On contrast CT imaging, early-
stage lesions are low density or isodense, often with edema out of proportion to the mass
effect and little encapsulation [51-53]. Later-stage tuberculomas are well encapsulated,
isodense or hyperdense, and have peripheral ring enhancement.

Symptoms of systemic illness and signs of meningeal inflammation are rarely observed.
Lumbar puncture is usually avoided because of concern for raised intracranial pressure
and risk of brainstem herniation; in the occasional reported case where cerebrospinal fluid
has been examined, the findings are normal or nonspecific. The diagnosis is made in
relation to clinical, epidemiologic, and radiographic features or by needle biopsy. Unless
the location of the lesion threatens obstructive hydrocephalus or brainstem herniation,
surgical intervention should be avoided as it may precipitate severe meningitis.

Differential diagnosis The diagnostic distinction between clinical tuberculoma and

intraparenchymal neurocysticercosis (NCC) can be challenging, particularly in children.
Both CNS infections share similar clinical, epidemiologic, and radiographic features.
(See "Clinical manifestations and diagnosis of cysticercosis".)

In adults, NCC is a pleomorphic disease that tends to occur months to years after primary
infection, and brain imaging usually demonstrates multiple lesions of varying age and
morphology. The range of radiographic features includes cystic lesions showing the
scolex, multiple cysts, giant cyst, ring- or disc-enhancing lesions, and multiple punctuate
parenchymal calcifications. Cases with solitary CNS granulomas may be misdiagnosed as
tumor and identified only after surgical resection.

Clinical tuberculoma arises as an early postprimary infection event and typically presents
as a single large, dense mass (image 3). Children with early NCC may present with focal
seizures and a single ring-enhancing lesion, often with surrounding edema. In such cases,
the distinction between tuberculoma and NCC requires careful attention to subtle
radiographic features combined with thorough evaluation of risk for tuberculosis and for
evidence of tuberculosis elsewhere in the body [54].
Spinal tuberculous arachnoiditis Spinal tuberculous arachnoiditis is observed most
commonly in endemic areas [1,2]. The pathogenesis is similar to that of meningitis, with
focal inflammatory disease at single or multiple levels leading to gradual encasement of
the spinal cord by a gelatinous or fibrous exudate.

Symptoms develop and progress slowly over weeks to months and may culminate with a
meningitis syndrome. Patients present with the subacute onset of nerve root and cord
compression signs: spinal or radicular pain, hyperesthesia or paresthesias; lower motor
neuron paralysis; and bladder or rectal sphincter dysfunction [55]. Vasculitis may lead to
thrombosis of the anterior spinal artery and infarction of the spinal cord. Other forms
include extradural or intradural tuberculoma and epidural abscess.

The diagnosis of spinal tuberculous arachnoiditis is based on findings of elevated

cerebrospinal fluid protein levels and MRI findings of nodular arachnoiditis combined with
tissue biopsy.

The treatment for this form of disease is the same as for tuberculous meningitis.

TREATMENT Antituberculous therapy should be initiated on the basis of strong clinical

suspicion and should not be delayed until bacteriologic proof has been obtained. The
clinical outcome depends greatly on the stage at which therapy is initiated; much more
harm results from delay, even for only a few days, than from inappropriate therapy as long
as efforts are continued to confirm the diagnosis.

Antituberculous therapy There are no randomized controlled trials to establish the

optimal drug combination, dose, or duration of antituberculous therapy for central nervous
system (CNS) tuberculosis (TB). The principles of treatment are those that govern the
management of pulmonary TB. The treatment regimens outlined below conform to
published United States Centers for Disease Control and Prevention (CDC) and American
and British Society guidelines for treatment of all forms of CNS tuberculosis [56,57].

General approach In general, treatment of CNS tuberculosis consists of an initial

intensive phase (four drugs administered for 2 months) followed by a prolonged
continuation phase (usually two drugs administered for an additional 7 to 10 months). The
treatment regimen should be tailored to the drug sensitivity of the isolate and the patient's
clinical response.

For empiric treatment of CNS tuberculosis not known or suspected to be drug resistant,
the preferred intensive-phase four-drug regimen consists
of isoniazid, rifampin, pyrazinamide, and ethambutol administered daily for two months
[56]. Drug doses are shown in the tables (table 2 and table 3 and table 4) [56,58].

The inclusion of ethambutol in the intensive-phase regimen is a hedge against drug

resistance. Once the infecting isolate is known to be sensitive to isoniazid and rifampin,
ethambutol may be discontinued and a three-drug regimen may be continued for the
remainder of the two-month intensive phase. However, ethambutol penetrates into the
CNS poorly even with inflamed meninges, and some experts suggest using an alternative
fourth drug, such as ethionamide or a fluoroquinolone.

In the setting of infection known or presumed to be caused by susceptible strains, the

continuation phase consists of isoniazid and rifampin and should be continued for 7 to 10
months; pyrazinamide and ethambutol may be discontinued after completion of the
intensive phase. In the setting of tuberculoma, an extension of the treatment duration to 18
months is warranted. The regimen and duration of treatment may require further
adjustment depending on individual patient circumstances. (See "Treatment of drug-
susceptible pulmonary tuberculosis in HIV-uninfected adults".)

Isoniazid, rifampin, and pyrazinamide are bactericidal, can be administered orally,

penetrate inflamed meninges, and achieve cerebrospinal fluid (CSF) levels that exceed the
inhibitory concentration needed for sensitive strains. Isoniazid has excellent CNS
penetration and is more active against rapidly dividing than against semi-dormant
organisms. Rifampin is active against both rapidly dividing organisms and semi-dormant
subpopulations of mycobacteria. Pyrazinamide readily penetrates the CNS and is highly
active against intracellular mycobacteria.

Other antimicrobials may warrant consideration in the management of CNS tuberculosis:

In children, for whom potential ethambutol-associated optic neuritis can be difficult to

monitor, we are in agreement with the American Academy of Pediatrics, which
recommends the substitution of ethionamide, or an aminoglycoside such
as streptomycin, for ethambutol in the initial therapeutic regimen [59].
Fluoroquinolones (levofloxacin and moxifloxacin) exhibit good CNS penetration and
are bactericidal [60]. The use of an intensified regimen (rifampin 15 mg/kg per day
and levofloxacin 20 mg/kg per day for the first eight weeks of treatment) may be
beneficial for patients with isoniazid-resistant CNS infection [61]. (See 'Drug
resistance' below.)
In the past, streptomycin was added to isoniazid in order to enhance sterilization
and to reduce the risk of clinical relapse from resistant organisms. With the availability
of rifampin and pyrazinamide, reliance upon streptomycin or other drugs of its class is
generally limited to regions of the world with high prevalence of isoniazid resistance.
(See "Treatment of drug-resistant pulmonary tuberculosis in adults".)

HIV coinfection The incidence of tuberculous meningitis is increased among HIV-

infected patients [62-64]. In one study including 200 patients in Zimbabwe with meningitis
(80 percent of whom were HIV infected), 12 percent had tuberculous meningitis [63].

Management of treatment-nave HIV-infected patients with TB is especially challenging in

areas with high rates of coinfection. Initiation of antiretroviral therapy (ART) may be
complicated by the immune reconstitution inflammatory syndrome (IRIS), which can
manifest as reactivation of latent TB, progression of active TB disease, or clinical
deterioration in patients previously improving on antituberculous therapy.

For ART-nave HIV-infected patients with CNS tuberculosis, initiation of ART should be
delayed for the first eight weeks of antituberculous therapy, regardless of CD4 count [56].
Issues related to management of TB in HIV-infected patients are discussed further
separately. (See "Treatment of pulmonary tuberculosis in HIV-infected adults".)

In one study including 253 patients with tuberculosis meningitis and HIV infection, initiation
of ART within two weeks of antituberculous therapy was associated with increased rates of
adverse events and increased mortality [65]. In a case series including 279 patients with
TB-associated IRIS, progression to CNS tuberculosis developed in 12 percent of cases,
and excess mortality (attributable to IRIS) was observed in 30 percent of patients [66].
CNS manifestations of disease progression include meningitis, intracranial tuberculoma,
brain abscess, radiculomyelitis, and spinal epidural abscess [66-69]. Tuberculous
meningitis in the setting of IRIS is characterized by high CSF neutrophil counts and CSF
culture positivity at presentation [70].

Drug resistance The prevalence of M. tuberculosis strains resistant to one or more

first-line drugs is increasing [71]. Those at greatest risk for drug-resistant CNS infection
include individuals from areas of the world where tuberculosis is endemic, those with a
history of previous antituberculous treatment, homeless individuals, and those with
exposure to source patients harboring drug-resistant organisms.

Drug resistance has been associated with diminished prognosis among patients with CNS
tuberculosis. One study in Vietnam including 180 adults with tuberculous meningitis noted
resistance to at least one antituberculosis drug in 40 percent of isolates; resistance
to isoniazid and rifampin was observed in 5 percent of cases [72]. Combined isoniazid and
rifampin resistance was strongly predictive of death (relative risk of death 11.6; 95% CI
5.2-26.3) and independently associated with HIV infection. Similarly, among 350 cases of
tuberculous meningitis in South Africa, resistance to isoniazid and rifampin was observed
in 8 percent of cases; 57 percent of patients died [73]. In another study of 324 patients
reported to the New York City registry between 1992 and 2001, excess late mortality (after
60 days of therapy) was observed among patients with isoniazid-resistant isolates [74].
Rifampin resistance was tightly associated with HIV coinfection and an early mortality that
exceeded 90 percent.

Isoniazid resistance is the most prevalent resistance pattern observed among clinical
isolates of M. tuberculosis. In regions where the incidence of isoniazid-resistant infection is
relatively high, or for any case where drug resistance is suspected, it is reasonable to
increase the dose of rifampin (to 15 mg/kg per day) and add a fluoroquinolone
(moxifloxacin or levofloxacin 20 mg/kg per day) and/or an injectable aminoglycoside to the
initial standard treatment regimen. Levofloxacin achieves therapeutic CSF levels and
exhibits early bactericidal activity that mirrors that of isoniazid [60].
This approach is supported by a randomized trial including 817 Vietnamese patients (the
proportion of baseline isoniazid resistance was 26.7 percent) in which intensification of the
standard initial regimen via augmenting the rifampin dose (to 15 mg/kg per day) and the
addition of levofloxacin (20 mg/kg per day) improved survival in HIV-uninfected patients
with isoniazid-resistant tuberculous meningitis [75]. Of the HIV-uninfected patients, 6 of 17
(35.3 percent) died in the standard treatment arm, compared with 1 of 22 (4.65 percent) in
the intensified treatment arm.

There are no definitive guidelines for the duration of therapy in patients with drug-resistant
CNS disease. In such cases, it may be advisable to extend the duration of therapy to 18 to
24 months, taking into account the severity of illness, rate of clinical response, and the
patient's immune status. (See "Treatment of drug-resistant pulmonary tuberculosis in
adults".)

Glucocorticoids In general, glucocorticoid therapy is warranted for HIV-uninfected

patients with convincing epidemiologic or clinical evidence for tuberculous meningitis [76-
80]. Urgent warning signs that warrant prompt initiation of glucocorticoids include:

Patients who are progressing from one stage to the next at or before the introduction
of chemotherapy
Patients with an acute encephalitis presentation, especially if the CSF opening
pressure is 400 mmH2O or if there is clinical or computed tomographic (CT)
evidence of cerebral edema
Patients who demonstrate "therapeutic paradox," an exacerbation of clinical signs
(eg, fever, change in mentation) after beginning antituberculous chemotherapy
Spinal block or incipient block (CSF protein >500 mg/dL and rising)
Head CT evidence of marked basilar enhancement (portends an increased risk for
infarction of the basal ganglia) or moderate or advancing hydrocephalus
Patients with intracerebral tuberculoma, where edema is out of proportion to the
mass effect and there are any clinical neurologic signs (altered mentation or focal
deficits)

The regimen consists of dexamethasone or prednisone, as follows [76]:

Dexamethasone Children <25 kg: 8 mg/day for two weeks, then taper gradually
over four to six weeks. Adolescents and adults >25 kg: 0.3 to 0.4 mg/kg/day for two
weeks, then 0.2 mg/kg/day week 3, then 0.1 mg/kg/day week 4, then 4 mg per day
and taper 1 mg off the daily dose each week; total duration approximately eight
weeks.
Prednisone Children: 2 to 4 mg/kg per day. Adolescents and adults: 60 mg/day.
Administer initial dose for two weeks, then taper gradually over the next six weeks (ie,
reduce daily dose by 10 mg each week); total duration approximately eight weeks.
A review including nine trials involving 1337 participants established that adjunctive
corticosteroids reduce death and disability from tuberculous meningitis by about 25
percent [79].

A randomized trial including 545 adolescents and adults with CNS tuberculosis in Vietnam
noted reduced mortality among those who received dexamethasone (32 versus 41
percent) [76]. The mortality benefit was most evident for patients with stage I disease (17
versus 30 percent), approached significance for stage II (31 versus 40 percent), and was
not significant in patients with stage III disease (55 versus 60 percent). There was no
demonstrable reduction in residual neurologic deficits and disability among surviving
patients at nine months follow-up. The survival benefit associated with steroid therapy may
have been in part due to a reduction in severe adverse events (9.5 versus 16.6 percent),
particularly hepatitis (which necessitated changes in antituberculosis drug regimens). No
mortality benefit from dexamethasone was evident in 98 HIV-infected patients included in
the study.

Another randomized trial including 141 children with tuberculous meningitis noted reduced
mortality among children with stage III disease who received prednisone for the first month
of treatment (4 versus 17 percent) [77]. In addition, those who received prednisone were
more likely to have subsequent IQ >75 (52 versus 33 percent), and enhanced resolution of
basal exudate and tuberculomas was observed radiographically.

Surgery Patients with hydrocephalus may require surgical decompression of the

ventricular system in order to effectively manage the complications of raised intracranial
pressure. In such patients with clinical stage II disease, the combination of serial lumbar
puncture and steroid therapy may suffice while judging the early response to
chemotherapy. However, surgical intervention should not be delayed in patients with
stupor and coma or when the clinical course of therapy is marked by progressive
neurologic impairment [81].

Unlike other CNS mass lesions, medical management is preferred for clinical
tuberculomas unless the lesion produces obstructive hydrocephalus or compression of the
brainstem. In the past, surgical resection was often complicated by severe, fatal
meningitis.

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines

from selected countries and regions around the world are provided separately.
(See "Society guideline links: Diagnosis and treatment of tuberculosis".)

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Beyond the Basics patient education pieces are longer, more sophisticated, and more
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patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topic (see "Patient education: Tuberculosis (Beyond the
Basics)")

SUMMARY AND RECOMMENDATIONS

Clinical manifestations

Central nervous system (CNS) tuberculosis (TB) includes three clinical categories:
meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis.
(See 'Introduction' above.)
Clinical manifestations in patients with tuberculous meningitis progress through
three phases (see 'Clinical manifestations' above):
The prodromal phase, lasting two to three weeks, characterized by the insidious
onset of malaise, lassitude, headache, low-grade fever, and personality change.
The meningitic phase with more pronounced neurologic features (eg,
meningismus, protracted headache, vomiting, lethargy, confusion, and varying
degrees of cranial nerve and long-tract signs).
The paralytic phase, in which the pace of illness accelerates rapidly; confusion
gives way to stupor and coma, seizures, and often hemiparesis.
Patients with tuberculous meningitis are categorized by stage on presentation,
based upon mental status and focal neurologic signs as follows:
Stage I patients are lucid with no focal neurologic signs or evidence of
hydrocephalus.
Stage II patients exhibit lethargy, confusion; they may have mild focal signs,
such as cranial nerve palsy or hemiparesis.
Stage III represents advanced illness with delirium, stupor, coma, seizures,
multiple cranial nerve palsies, and/or dense hemiplegia.
Tuberculomas are conglomerate caseous foci within the substance of the brain that
develop from deep-seated tubercles acquired during a recent or remote
hematogenous bacillemia. (See 'Tuberculoma' above.)
Spinal tuberculous arachnoiditis is a focal inflammatory disease at single or multiple
levels producing gradual encasement of the spinal cord by a gelatinous or fibrous
exudate. (See 'Spinal tuberculous arachnoiditis' above.)

Diagnosis
 The diagnosis of CNS TB can be difficult. However, early recognition is of
paramount importance because the clinical outcome depends greatly upon the stage
at which therapy is initiated. (See 'Diagnosis' above.)
The examination of cerebrospinal fluid (CSF) specimens is of critical importance to
early diagnosis of tuberculous meningitis. Typically, the CSF formula shows elevated
protein and lowered glucose concentrations with a mononuclear pleocytosis.
(See 'Spinal fluid examination'above.)
The demonstration of acid-fast bacilli (AFB) in the CSF remains the most rapid and
effective means of reaching an early diagnosis. We recommend that a minimum of
three lumbar punctures be performed at daily intervals, bearing in mind that empiric
therapy need not be delayed during this time. (See 'Culture and sensitivity' above.)
CSF specimens should be submitted for nucleic acid testing whenever feasible,
particularly in the setting of high clinical suspicion and negative AFB staining. We are
in agreement with the World Health Organization, which has recommended use of the
Xpert MTB/RIF assay as an initial test for diagnosis of tuberculous meningitis,
although NAA testing of CSF is not approved by the US Food and Drug
Administration. (See 'Nucleic acid tests' above.)
Magnetic resonance imaging (MRI) is superior to computed tomography (CT) in
defining lesions of the basal ganglia, midbrain, and brainstem and for evaluating all
forms of suspected spinal TB. (See 'Radiography' above.)

Treatment

We recommend initiation of antituberculous therapy on the basis of strong clinical

suspicion of CNS tuberculosis should not be delayed until proof of infection has been
obtained (Grade 1B). (See 'Treatment' above.)
We agree with recommendations of the American and British Thoracic Societies,
Infectious Disease Society of America, and the United States Centers for Disease
Control and Prevention, which recommend an initial two-month period of intensive
therapy, with four drugs (Grade 1B). For patients not known or suspected of being
infected with a resistant strain, the preferred four-drug regimen includes
daily isoniazid, rifampin, pyrazinamide, and ethambutol. (See 'Antituberculous
therapy' above.)
Typically, intensive therapy is followed by a prolonged continuation phase lasting 7
to 10 months, depending on clinical response and established drug sensitivity of the
isolate. The usual regimen in drug-sensitive disease is isoniazid and rifampin, given
daily or five times a week. (See 'Antituberculous therapy' above.)
In the setting of known or suspected infection with an isoniazid-resistant strain, it is
reasonable to increase the dose of rifampin and add a fluoroquinolone and/or an
injectable aminoglycoside to the initial standard treatment regimen. In addition, it may
be advisable to extend the duration of therapy to 18 to 24 months, taking into account
 the severity of illness, rate of clinical response, and the patient's immune status.
(See 'Drug resistance' above.)
We recommend adjunctive glucocorticoid therapy for all children and adults with
convincing epidemiologic or clinical evidence for tuberculous meningitis (Grade 1A).
Dosing is summarized above. (See 'Glucocorticoids' above.)
For human immunodeficiency virus (HIV)-infected patients with TB involvement of
the CNS who are not already on antiretroviral therapy (ART), we recommend deferral
of ART until eight weeks after starting TB treatment, regardless of CD4 count (Grade
1B). Development of immune reconstitution inflammatory syndrome in patients with
CNS TB may cause severe or fatal neurological complications. (See 'HIV
coinfection' above.)
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