Central Nervous System TuberculosisUPTODATE NOV 2015 (1)

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4/12/2015 Central nervous system tuberculosis

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Offi cial reprint from UpToDatewww.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: Nov 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 adults".)

PATHOGENESIS During the bacillemia that follows primary infection or late reactivation tuberculosis (TB),

scattered tuberculous foci (tubercles) are established inthe 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 postprimary infection in infants andyoung 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
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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 Tollinterleukin-1 receptor domain containing an adaptor protein that mediates signaling from

mycobacteria activated Toll-like receptors was associated with susceptibility to meningeal tuberculosis (odds ratio

[OR] 3.0) and to pulmonary tuberculosis (OR 1.6). The polymorphism was also associated with decreased whole-

blood interleukin-6 production, suggesting immunomodulation as a mechanism for susceptibility.

FORMS OF CNS TUBERCULOSIS

Tuberculous meningitis Tuberculous meningitis accounts for about 1 percent of all cases of tuberculosis (TB)

and 5 percent of all extrapulmonary disease in immunocompetent individuals [9]. Although pulmonary TB in the

United States has declined, the number of meningeal TB cases has changed little and the case fatality ratio

remains relatively high (15 to 40 percent) despite effective treatment regimens [9,10].

Early recognition of tuberculous meningitis is of paramount importance because the clinical outcome depends

greatly upon the stage at which therapy is initiated. Empiric antituberculous therapy should be started immediately

in any patient with meningitis syndrome and cerebrospinal fluid (CSF) findings of low glucose concentration,

elevated protein, and lymphocytic pleocytosis if there is evidence of TB elsewhere 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

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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does 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 orderto 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 82percent 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

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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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 brainimaging 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). Ethambutolpenetrates 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
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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

depending on individual patient circumstances. (See "Treatment of 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 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 levofloxacinexhibit 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 isoniazidin 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 inmentation) 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)
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A review including seven trials involving 1140 participants established that adjunctive corticosteroids reduce deathand 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 prednisonefor 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 lesionproduces 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 HIV-infected adults", 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].

Dexamethasone Children 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

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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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].

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
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Treatment

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REFERENCES

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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.)

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57. Braun MM, Byers RH, Heyward WL, et al. Acquired immunodeficiency syndrome and extrapulmonarytuberculosis in the United States. Arch Intern Med 1990 150:1913.

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infection. Arch Neurol 1996 53:671.61. Hakim JG, Gangaidzo IT, Heyderman RS, et al. Impact of HIV infection on meningitis in Harare, Zimbabwe:

a prospective study of 406 predominantly adult patients. AIDS 2000 14:1401.

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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 enha

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 ventr

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 diff

edema and effacement of the sulci (arrowhead). Image C is a FLAIR sequence showing hydroceph

third ventricle (asterisk), transependymal edema (arrows), and effacement of the sulci (arrowhea

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, 100mg, 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 mg/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 t o 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 t o 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, MD

Grant/Research/Clinical Trial Support: Pfizer Inc. [Group B Streptococcus]. Consultant/Advisory Boards: Novartis Vaccines [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

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