CNS Tuberculosis

Official reprint from UpToDate

www.uptodate.com ©2015 UpToDate

AuthorJohn M Leonard, MD

Section EditorsC Fordham von Reyn, MDMorven S Edwards, MD

Deputy EditorElinor L Baron, MD, DTMH

Central nervous system tuberculosis

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2015. | This topic last updated: Mar 16, 2015.

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 infection, 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 pulmonary

tuberculosis in HIV-uninfected patients".)

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 extrapulmonary and miliary

tuberculosis".)

Consequently, meningitis develops most commonly as a complication of postprimary 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 eight 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

●

Central nervous system tuberculosis http://www.uptodate.com.wdg.biblio.udg.mx:2048/contents/central-nerv...

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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 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 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]:

It is useful to categorize patients on presentation by the stage of illness, based upon the mental status and focal

neurologic signs [15]:

About one-third of patients on presentation have underlying generalized (miliary) tuberculosis, in which case careful

funduscopic examination often shows choroidal tubercles (image 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 will be positive in the majority [11,12], although a negative result does

tuberculoma.

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.

●

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.

●


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not exclude the diagnosis. (See "Diagnosis of latent tuberculosis infection (tuberculosis screening) in HIV-uninfected

adults".)

Cases with atypical features that mimic other neurologic conditions are important to recognize. As an example,

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 common is an encephalitic course manifested by stupor, coma, and

convulsions without overt signs of meningitis [16].

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 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. Typically, the CSF formula shows elevated protein and lowered glucose

concentrations with a mononuclear pleocytosis [17,18]. 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") [19].

Culture and sensitivity — The importance of repeated, careful examination and culture of CSF

specimens for Mycobacterium tuberculosis cannot be overemphasized. In general, a minimum of three serial lumbar

punctures should 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 [20]. The

sensitivity of the AFB smear of spinal fluid may be enhanced by attention to the following principles [12,17,20]:

Nucleic acid tests — CSF specimens should be submitted for nucleic acid testing whenever possible,

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 [21-28]. In a systemic 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 [27].

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 percent 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.

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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) [29]. 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

[30]. (See "Diagnosis, treatment, and prevention of drug-resistant tuberculosis", section on 'Nucleic acid tests'.)

Radiography — Computed tomography (CT) and magnetic resonance imaging (MRI) have greatly improved

characterization and management of CNS infections [31]. In patients with tuberculous meningitis, CT and MRI can

define the presence and extent of basilar arachnoiditis (image 2), cerebral edema, infarction, and hydrocephalus

(image 3). 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 [32,33]. 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 one of the

remaining 22 patients [34].

The following observations can be derived from a review of selected clinical series [32,33,35]:

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 2) [36,37]. (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 4) [38]. 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 [39,40]. 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 [41,42]. 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 [41-43]. 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

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 3).

●

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.

●


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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. 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 for evidence of tuberculosis elsewhere in the body [44].

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 [45].

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 — Specific antituberculous chemotherapy 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

General approach — Treatment begins with an "intensive phase" that consists of a four-drug regimen that

includes isoniazid, rifampin, pyrazinamide, and a fourth drug, either a fluoroquinolone (moxifloxacin or levofloxacin)

or an injectable aminoglycoside, administered daily for two months. Drug doses are shown in the Tables (table 2 and

table 3). This is followed by a "continuation phase" that consists of isoniazid and rifampin alone (if the isolate is fully

susceptible) administered daily or three times a week (table 2). Ethambutol penetrates poorly into even inflamed

meninges and can be replaced in standard treatment regimens with a fluoroquinolone (moxifloxacin or levofloxacin)

[46]. Aminoglycoside penetration is optimized during acute inflammation and its value beyond initial treatment is not

clear [46].

There are no randomized, controlled trials to establish the optimal drug combination, dose, or duration of

antituberculous therapy for central nervous system (CNS) tuberculosis. The principles of treatment are those that

govern the management of pulmonary TB. In general, treatment consists of an initial 2-month period of intensive

therapy (with four drugs) followed by a prolonged continuation phase (with isoniazid and rifampin) lasting 9 to 12

months, depending on the clinical response and drug sensitivity of the isolate [47,48]. The regimen for tuberculoma

generally warrants treatment duration of 18 months. The nature and duration of treatment may require adjustment


5 de 20 03/08/2015 07:06 p.m.

depending on individual patient circumstances. (See "Treatment of pulmonary tuberculosis in HIV-uninfected

patients".)

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 semidormant organisms.

Rifampin is active against both rapidly dividing organisms and semidormant subpopulations of organisms.

Pyrazinamide readily penetrates the CSF and is highly active against intracellular mycobacteria. Likewise,

moxifloxacin and levofloxacin exhibit good CNS penetration [46].

In the past, streptomycin (15 mg/kg per day intramuscularly [IM] in adults to a maximum dose of 1 g; 20 to 40 mg/kg

per day in children) 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.

Drug resistance — There are no definitive guidelines for the duration of therapy in patients with multidrug-

resistant infection. 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 "Diagnosis,

treatment, and prevention of drug-resistant tuberculosis".)

The prevalence of CNS infection caused by strains resistant to one or more first-line drugs is increasing [49]. Those

at greatest risk for drug-resistant disease include individuals from areas of the world where tuberculosis (TB) is

endemic, those with a history of previous antituberculous treatment, homeless individuals, and those with exposure

to source patients harboring drug-resistant organisms.

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 [50]. 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 [51].

Glucocorticoids — In general, glucocorticoid therapy is warranted for HIV-uninfected patients with convincing

epidemiologic or clinical evidence for tuberculous meningitis [52-55]. Urgent warning signs that warrant prompt

initiation of glucocorticoids include:

The regimen consists of dexamethasone or prednisone, as follows [52]:

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 mmH O or if

there is clinical or computed tomographic (CT) evidence of cerebral edema

● 2

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)

●

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 three, then 0.1

mg/kg/day week four, then 4 mg per day and taper 1 mg off the daily dose each week; total duration

●


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A review including seven trials involving 1140 participants established that adjunctive corticosteroids reduce death

and disability from tuberculous meningitis by about 30 percent [55].

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) [52]. 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) [53]. 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 [56].

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.

HIV COINFECTION — There are few reports to indicate that central nervous system (CNS) tuberculosis (TB) is a

widespread problem in AIDS patients [57,58]. In one study comparing the clinical features, laboratory findings, and

mortality rates in patients having tuberculous meningitis with or without HIV infection, cerebral tuberculomas were

more common in the HIV-infected group (60 versus 14 percent); otherwise, coinfection with HIV did not alter the

clinical manifestations, cerebrospinal fluid (CSF) findings, or response to therapy [59].

In other parts of the world where TB is endemic, there have been reports of an increase in tuberculous meningitis in

HIV-infected patients [60-62]. As an example, in a study of 200 patients with confirmed meningitis from Zimbabwe,

12 percent had tuberculous meningitis compared with 45 percent with cryptococcal meningitis [61]. Eighty percent of

all patients with suspected meningitis were HIV infected in this series; HIV seropositivity was 88 and 100 percent,

respectively for those with TB and cryptococcal meningitis.

Patients with HIV and CNS tuberculosis who are not already on antiretroviral therapy should delay initiation of

antiretroviral therapy until after completion of TB therapy. Timing of initiation of antiretroviral therapy is discussed

separately. (See "Treatment of pulmonary tuberculosis in the HIV-infected patient", section on 'Timing of ART in the

treatment-naive patient'.)

Among patients with tuberculosis and immune reconstitution inflammatory syndrome (IRIS), CNS tuberculosis

occurs in approximately 12 percent of cases, and mortality of up to 30 percent has been reported [63].

Manifestations include meningitis, intracranial tuberculoma, brain abscess, radiculomyelitis, and spinal epidural

abscess [63-66]. Tuberculous meningitis in the setting of IRIS is characterized by high CSF neutrophil counts and

CSF culture positivity at presentation [67].

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.

●


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INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and

“Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5 to 6 grade

reading level, and they answer the four or five key questions a patient might have about a given condition. These

articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the

Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the

10 to 12 grade reading level and are best for 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.)

SUMMARY AND RECOMMENDATIONS

Clinical manifestations

Diagnosis

th th

th th

Beyond the Basics topics (see "Patient information: Tuberculosis (Beyond the Basics)")●

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.)

●

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.)

●


8 de 20 03/08/2015 07:06 p.m.

Treatment

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Dastur DK, Manghani DK, Udani PM. Pathology and pathogenetic mechanisms in neurotuberculosis. RadiolClin North Am 1995; 33:733.

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Wasay M, Farooq S, Khowaja ZA, et al. Cerebral infarction and tuberculoma in central nervous systemtuberculosis: frequency and prognostic implications. J Neurol Neurosurg Psychiatry 2014; 85:1260.

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Chan KH, Cheung RT, Lee R, et al. Cerebral infarcts complicating tuberculous meningitis. Cerebrovasc Dis6.

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. (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.)

●

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

tuberculosis and 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 Centers for Disease Control and Prevention, which recommend an initial two month period of

intensive therapy, with four drugs (Grade 1B). The usual four drug regimen includes daily isoniazid, rifampin,

pyrazinamide, and either moxifloxacin or levofloxacin or streptomycin for fully sensitive isolates. (See

'Antituberculous therapy' above.)

●

Typically, intensive therapy is followed by a prolonged continuation phase lasting 9 to 12 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 three times a week. (See 'Antituberculous therapy' above.)

●

Treatment of drug-resistant CNS TB must be individualized and should be guided by the drug susceptibility

pattern of the particular isolate. We suggest extending the duration of therapy to 18 to 24 months. (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.)

●

Patients with HIV and CNS tuberculosis who are not already on antiretroviral therapy should delay initiation of

antiretroviral therapy until after completion of TB therapy. (See 'HIV coinfection' above.)

●


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2005; 19:391.

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Kent SJ, Crowe SM, Yung A, et al. Tuberculous meningitis: a 30-year review. Clin Infect Dis 1993; 17:987.14.

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Merritt HH, Fremont-Smith F. The cerebrospinal fluid, WB Saunders, Philadelphia 1938.17.

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Patel VB, Theron G, Lenders L, et al. Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) fortuberculous meningitis in a high burden setting: a prospective study. PLoS Med 2013; 10:e1001536.

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Vadwai V, Boehme C, Nabeta P, et al. Xpert MTB/RIF: a new pillar in diagnosis of extrapulmonarytuberculosis? J Clin Microbiol 2011; 49:2540.

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Ozateş M, Kemaloglu S, Gürkan F, et al. CT of the brain in tuberculous meningitis. A review of 289 patients.Acta Radiol 2000; 41:13.

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Kingsley DP, Hendrickse WA, Kendall BE, et al. Tuberculous meningitis: role of CT in management andprognosis. J Neurol Neurosurg Psychiatry 1987; 50:30.

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Schoeman J, Hewlett R, Donald P. MR of childhood tuberculous meningitis. Neuroradiology 1988; 30:473.36.

Offenbacher H, Fazekas F, Schmidt R, et al. MRI in tuberculous meningoencephalitis: report of four cases andreview of the neuroimaging literature. J Neurol 1991; 238:340.

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Weisberg LA. Granulomatous diseases of the CNS as demonstrated by computerized tomography. Comput

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Harder E, Al-Kawi MZ, Carney P. Intracranial tuberculoma: conservative management. Am J Med 1983;74:570.

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Traub M, Colchester AC, Kingsley DP, Swash M. Tuberculosis of the central nervous system. Q J Med 1984;53:81.

42.

Whelan MA, Stern J. Intracranial tuberculoma. Radiology 1981; 138:75.43.

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67.

Topic 8009 Version 24.0


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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 5.0


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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.



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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.



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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



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Tuberculoma of the brain on CT and MRI

A non-contrast 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.



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Doses of first-line antituberculosis drugs for adults*

Drug PreparationDoses

Daily 1x/week 2x/week 3x/week

First-line drugs

Isoniazid Tablets (50 mg, 100

mg, 300 mg); elixir

(50 mg/5 mL);

aqueous solution (100

mg/mL) for

intravenous or

intramuscular

injection

5 mg/kg (300

mg)

15 mg/kg

(900 mg)

15 mk/kg

(900 mg)

15 mg/kg

(900 mg)

Rifampin Capsule (150 mg, 300

mg); powder may be

suspended for oral

administration;

aqueous solution for

intravenous injection

10 mg/kg (600

mg)

- 10 mg/kg

(600 mg)

10 mg/kg

(600 mg)

Rifabutin Capsule (150 mg) 5 mg/kg (300

mg)

- 5 mg/kg

(300 mg)

5 mg/kg

(300 mg)

Rifapentine Tablet (150 mg, film

coated)

- 10 mg/kg

(continuation

phase) (600

mg)

- -

Pyrazinamide Tablet (500 mg,

scored)

Weight-based

dosing

summarized in

separate table

Ethambutol Tablet (100 mg, 400

mg)

Weight-based

dosing

summarized in

separate table

* Doses per weight is based on ideal body weight. For purposes of this document, adult dosing begins at

age 15 years.

Data from: Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease

Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit

Care Med 2003; 167:603.



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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 with permission from: Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic

Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of

tuberculosis. Am J Respir Crit Care Med 2003; 167:603. Official Journal of the American Thoracic Society.

Copyright ©2003 American Thoracic Society.


¶

¶

¶


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Disclosures: John M Leonard, MD Nothing to disclose. C Fordham von Reyn, MD Nothing to disclose. Morven S Edwards, MDGrant/Research/Clinical Trial Support: Pfizer Inc. [Group B Streptococcus]. Consultant/Advisory Boards: Novartis Vaccines [Group BStreptococcus]. 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 amulti-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content isrequired of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

Disclosures


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CNS Tuberculosis

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