SNC

9/10/2017 Central nervous system tuberculosis - UpToDate
Official reprint from UpToDate

www.uptodate.com 2017 UpToDate
Central nervous system tuberculosis
Author: John M Leonard, MD

Section Editors: C Fordham von Reyn, MD, Morven S Edwards, MD
Deputy Editor: Elinor L Baron, MD, DTMH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Sep 28, 2017.
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 Toll
interleukin-1 receptor domain containing an adaptor protein that mediates signaling from mycobacteria activated Toll-like
https://www.uptodate.com/contents/central-nervous-system-tuberculosis/print?source=search_result&search=snc%20tuberculosis&selectedTitle 1/21
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 rifampin resistance; 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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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.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 8009 Version 35.0
GRAPHICS
Choroidal tuberculosis
Miliary choroids (tubercles) appear as ill-defined nodules varying in size from

pinpoint to several disc diameters on funduscopic examination.
Reprinted with permission. Copyright American Society of Contemporary

Ophthalmology. Annals of Ophthalmology 1989.21(6);226.
Graphic 61826 Version 6.0
Meningeal enhancement in TB meningitis on MRI
Image A is T1-weighted sequence following contrast and shows extensive basilar meningeal enhancement (arrows). Image B is also
a contrast-enhanced study showing meningeal enhancement (arrows).
MRI: magnetic resonance imaging; TB: tuberculous.
Courtesy of Asim Mian, MD and Glenn Barest, MD.
Hydrocephalus in TB meningitis on MRI
A T1-weighted MRI of the brain in the sagittal projection shows hydrocephalus of the lateral ventricle (asterisk) and fourth
ventricle (arrow). Image B is a FLAIR sequence in axial projection and shows moderate hydrocephalus of the lateral ventricles
(asterisks) with trans-ependymal edema (arrows), and diffuse cerebral edema and effacement of the sulci (arrowhead). Image
C is a FLAIR sequence showing hydrocephalus of the third ventricle (asterisk), transependymal edema (arrows), and
effacement of the sulci (arrowhead) indicating cerebral edema.
MRI: magnetic resonance imaging; TB: tuberculous.
Courtesy of Asim Mian, MD and Glenn Barest, MD.
Differential diagnosis of central nervous system tuberculosis
Fungal meningitis (cryptococcosis, histoplasmosis, blastomycosis, coccidioidomycosis)
Viral meningoencephalitis (herpes simplex, mumps)
Parameningeal infection (sphenoid sinusitis, brain abscess, spinal epidural abscess)
Partially treated bacterial meningitis
Neurosyphilis
Neoplastic meningitis (lymphoma, carcinoma)
Neurosarcoidosis
Neurobrucellosis
Tuberculoma of the brain on CT and MRI
A noncontrast CT scan (A) of a six-year-old male presenting with left-sided hemiplegia and
seizures shows a large soft tissue density mass (asterisk) containing central calcification
(arrowhead) involving almost the entire visualized frontoparietal region. Image B is a
contrast-enhanced CT scan reformatted in the coronal plane and shows the large mass
(asterisk) with central calcification (arrowhead) and an enhancing border (arrows). Image C
is a T1-weighted sagittal sequence showing an iso- to hypointense lesion (asterisk). Image
D is a contrast-enhanced T1-weighted MRI in the axial plane and shows the mass (asterisk)
with an enhancing rim (arrows). Image E is a T2-weighted MRI and shows the characteristic
low intensity mass (asterisk), surrounding edema (delta), midline shift (arrowhead), and a
dilated, partially obstructed left lateral ventricle (arrow).
CT: computed tomography; MRI: magnetic resonance imaging.
Courtesy of Fourie Bezuidenhout, MD.
Dosing of first-line antituberculosis drugs in adults*
Doses
Drug Preparations
Daily 1x/week 2x/week 3x/week
First-line drugs
Isoniazid Tablets (50 mg, 5 mg/kg (usual 15 mg/kg (usual 15 mg/kg (usual 15 mg/kg (usual
100 mg, 300 maximum dose 300 maximum dose 900 maximum dose 900 maximum dose 900
mg); elixir (50 mg) mg) mg) mg)
mg/5 mL);
aqueous solution
(100 mg/mL) for
intravenous or
intramuscular
injection
Rifampin Capsules (150 mg, 10 mg/kg (usual 10 mg/kg (usual 10 mg/kg (usual
(rifampicin) 300 mg); capsule maximum dose 600 maximum dose 600 maximum dose 600
contents may be mg) mg) mg)
suspended for oral
administration;
aqueous solution
for intravenous
injection
Rifabutin Capsule (150 mg) 5 mg/kg (usual Not recommended Not recommended
maximum dose 300
mg)
Rifapentine Tablet (150 mg, 10 to 20 mg/kg

film coated) once weekly during
continuation phase
of treatment
Pyrazinamide Tablet (500 mg, Dosing summarized Dosing summarized Dosing summarized
scored) in separate table in separate table in separate table
Ethambutol Tablets (100 mg, Dosing summarized Dosing summarized Dosing summarized
400 mg) in separate table in separate table in separate table
Adult dosing listed in this table is used in patients 15 years old or weighing >40 kg.
Antituberculous agents are used in multidrug combination regimens of varying duration, which are described in detail in a
separate table (refer to the UpToDate table on regimens for treatment of drug-susceptible tuberculosis) and in the
accompanying text.
* Dosing based on actual weight is acceptable in patients who are not obese. For obese patients (>20% above ideal body weight [IBW]),
dosing based on IBW may be preferred for initial doses. Some clinicians prefer a modified IBW (IBW + [0.40 (actual weight IBW)])
as is done for initial aminoglycoside doses. Because tuberculosis drug dosing for obese patients has not been established, therapeutic
drug monitoring may be considered for such patients.
Pyridoxine (vitamin B6; 25 to 50 mg/day) is given with isoniazid to individuals at risk for neuropathy (eg, pregnant women,
breastfeeding infants, and individuals with HIV infection, diabetes, alcoholism, malnutrition, chronic renal failure, or advanced age). For
patients with peripheral neuropathy, experts recommend increasing pyridoxine dose to 100 mg/day.
Rifabutin dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase
inhibitors. Refer to the UpToDate topic on treatment of pulmonary tuberculosis in HIV-infected adults for specific dose adjustments.
Rarely used in practice; it may be an alternative in the continuation phase of treatment in a once-weekly regimen to facilitate directly
observed therapy. For further details, refer to the UpToDate topic on rifamycins.
Data adapted from:
1. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious
Diseases Society of American clinical practice guidelines: Treatment of drug-susceptible tuberculosis. Clin Infect Dis 2016. Epub
ahead of print
2. Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A Survival
Guide for Clinicians, Third Edition.
Suggested pyrazinamide doses, using whole tablets, for adults weighing 40 to 90

kilograms
Weight (kg)*
40 to 55 56 to 75 76 to 90
Daily, mg (mg/kg) 1000 (18.2 to 25) 1500 (20 to 26.8) 2000 (22.2 to 26.3)
Thrice weekly, mg (mg/kg) 1500 (27.3 to 37.5) 2500 (33.3 to 44.6) 3000 (33.3 to 39.5)
Twice weekly, mg (mg/kg) 2000 (36.4 to 50) 3000 (40 to 53.6) 4000 (44.4 to 52.6)
* Based on estimated lean body weight.

Maximum dose regardless of weight.
Reproduced from: Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and
Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect
Dis 2016; 63(7):e147-e195, by permission of Oxford University Press on behalf of the Infectious Diseases Society of America. Copyright
2016 Oxford University Press. Available at: www.idsociety.org.
Suggested ethambutol doses, using whole tablets, for adults weighing 40 to 90 kilograms
Weight, kg*
40 to 55 56 to 75 76 to 90
Daily, mg (mg/kg) 800 (14.5 to 20) 1200 (16 to 21.4) 1600 (17.8 to 21.1)
Thrice weekly, mg (mg/kg) 1200 (21.8 to 30) 2000 (26.7 to 35.7) 2400 (26.7 to 31.6)
Twice weekly, mg (mg/kg) 2000 (36.4 to 50) 2800 (37.3 to 50) 4000 (44.4 to 52.6)
* Based on estimated lean body weight.

Maximum dose regardless of weight.
Reproduced from: Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and
Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect
Dis 2016; 63(7):e147-e195, by permission of Oxford University Press on behalf of the Infectious Diseases Society of America. Copyright
2016 Oxford University Press. Available at: www.idsociety.org.
Contributor Disclosures
John M Leonard, MD Nothing to disclose C Fordham von Reyn, MD Grant/Research/Clinical Trial Support: Oxford
Immunotec [Tuberculosis (vaccine)]. Morven S Edwards, MD Grant/Research/Clinical Trial Support: Pfizer Inc. [Group B
Streptococcus]. Elinor L Baron, MD, DTMH Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by
vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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9/10/2017 Central nervous system tuberculosis - UpToDate

Official reprint from UpToDate

Central nervous system tuberculosis

Author: John M Leonard, MD

FORMS OF CNS TUBERCULOSIS

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

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

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 8009 Version 35.0

Miliary choroids (tubercles) appear as ill-defined nodules varying in size from

Reprinted with permission. Copyright American Society of Contemporary

Graphic 61826 Version 6.0

Meningeal enhancement in TB meningitis on MRI

MRI: magnetic resonance imaging; TB: tuberculous.

Courtesy of Asim Mian, MD and Glenn Barest, MD.

Graphic 98270 Version 2.0

Hydrocephalus in TB meningitis on MRI

MRI: magnetic resonance imaging; TB: tuberculous.

Courtesy of Asim Mian, MD and Glenn Barest, MD.

Graphic 98269 Version 1.0

Differential diagnosis of central nervous system tuberculosis

Fungal meningitis (cryptococcosis, histoplasmosis, blastomycosis, coccidioidomycosis)

Viral meningoencephalitis (herpes simplex, mumps)

Parameningeal infection (sphenoid sinusitis, brain abscess, spinal epidural abscess)

Partially treated bacterial meningitis

Neoplastic meningitis (lymphoma, carcinoma)

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Tuberculoma of the brain on CT and MRI

CT: computed tomography; MRI: magnetic resonance imaging.

Courtesy of Fourie Bezuidenhout, MD.

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Dosing of first-line antituberculosis drugs in adults*

Rifapentine Tablet (150 mg, 10 to 20 mg/kg

Data adapted from:

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Suggested pyrazinamide doses, using whole tablets, for adults weighing 40 to 90

* Based on estimated lean body weight.

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* Based on estimated lean body weight.

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