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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".)
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]:
It is useful to categorize patients on presentation by the stage of illness, based upon the
mental status and focal neurologic signs [15]:
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].
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].
It is best to use the last fluid removed at lumbar puncture, and recovery of the
organism improves if a large volume (10 to 15 mL) is removed.
Organisms can be demonstrated most readily in a smear of the clot or sediment. If
no clot forms, the addition of 2 mL of 95% alcohol gives a heavy protein precipitate
that carries bacilli to the bottom of the tube upon centrifugation.
0.02 mL of the centrifuged deposit should be applied to a glass slide in an area not
exceeding one centimeter in diameter and stained by the standard Kinyoun or Ziehl-
Neelsen method.
Between 200 and 500 high-powered fields should be examined (approximately 30
minutes), preferably by more than one observer.
Nucleic acid tests CSF specimens should be submitted for nucleic acid amplification
(NAA) testing whenever possible, particularly in the setting of high clinical suspicion and
negative AFB staining [27-34]. General issues related to NAA tests are discussed further
separately.
We are in agreement with the World Health Organization, which has recommended use of
the Xpert MTB/RIF assay as an initial test for diagnosis of tuberculous meningitis [35]. In
one systematic review and meta-analysis including 18 studies, the sensitivity and
specificity for the Xpert MTB/RIF assay in cerebrospinal fluid (compared with culture) were
81 and 98 percent, respectively [33]. However, NAA tests of CSF have not been approved
by the US Food and Drug Administration.
NAA tests appear to have high specificity but moderate sensitivity in CSF [36-38]; in one
study, sensitivity and specificity of NAA testing in CSF were 59 and 100 percent,
respectively [36]. This suggests that NAA tests may be used to confirm the diagnosis of
tuberculous meningitis when used together with traditional CSF studies, but NAA tests
cannot be used to rule out TB meningitis.
The assay MTBDRplus is a molecular probe capable of detecting rifampin- and isoniazid-
resistance mutations (rpoB gene for rifampinresistance; katG and inhA genes
for isoniazid resistance) [39]. The assay has been shown to be useful for detection of drug
resistance for CSF samples that have a polymerase chain reaction (PCR)-positive result
[40]. (See "Diagnosis of pulmonary tuberculosis in HIV-uninfected adults", section on
'Molecular tests'.)
NAA tests of CSF have not been approved by the US Food and Drug Administration; many
United States laboratories have validated NAA tests that are reported as "research use
only."
The following observations can be derived from a review of selected clinical series
[42,43,45]:
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".)
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.
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 treatment for this form of disease is the same as for tuberculous meningitis.
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].
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 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".)
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)
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.
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.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
Beyond the Basics topic (see "Patient education: Tuberculosis (Beyond the
Basics)")
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
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