Curr Infect Dis Rep (2017) 19:39

DOI 10.1007/s11908-017-0595-4

CENTRAL NERVOUS SYSTEM INFECTIONS (K BLOCH, SECTION EDITOR)

Tuberculosis Meningitis
Kassem Bourgi 1,2 & Christina Fiske 1,2 & Timothy R. Sterling 1,2

# Springer Science+Business Media, LLC 2017

Abstract TB meningitis continues to be a significant problem world-

Purpose of Review As the most severe form of tuberculosis wide. Despite recent advances, more studies are warranted to
(TB), TB meningitis disproportionately affects developing improve early disease detection and optimize therapy.
countries and results in significant morbidity and mortality.
In this report, we review recent updates in the epidemiology, Keywords Tuberculosis (TB) . Central nervous system
diagnosis, and management of TB meningitis. (CNS) . Cerebrospinal fluid (CSF)
Recent Findings Young children and people living with HIV
continue to be at highest risk for TB meningitis. Early diag-
nosis remains challenging, especially since conventional diag- Introduction
nostic tests have sub-optimal sensitivity and specificity.
Recently, nucleic acid amplification testing emerged as the Tuberculous meningitis is the most severe form of tuberculo-
preferred diagnostic modality due to its rapid turnaround time sis (TB), associated with significant morbidity—including se-
and high specificity. vere and irreversible neurologic sequelae—and mortality [1].
Summary Several recent studies have assessed the optimal Following inhalation of infectious droplet nuclei containing
treatment for TB meningitis. While the benefit of treatment Mycobacterium tuberculosis, hematogenous dissemination
intensification, by increasing rifampin dosing or adding a flu- occurs, seeding oxygen-rich areas of the body, including the
oroquinolone, is unclear, a growing body of evidence suggests brain and other parts of the central nervous system (CNS)
that steroids confer a survival advantage, particularly in pa- [2–4]. Meningitis occurs when infection spreads into the sub-
tients with mild disease. Additionally, TB meningitis manage- arachnoid space, resulting in an exudative inflammatory re-
ment is further complicated by high rates of HIV co-infection. sponse that can be complicated by obstruction of cerebrospi-
Recent data suggest that unlike other forms of TB, early initi- nal fluid (CSF) flow and vascular compression and occlusion,
ation of antiretroviral therapy in patients with TB meningitis is with occasional involvement of the cranial nerves in the brain
associated with higher rates of adverse reactions, without im- stem [2–4]. In this review, we highlight updates from the past
proved survival. 5 years in the epidemiology, diagnosis, and management of
TB meningitis.
This article is part of the Topical Collection on Central Nervous System
Infections
Epidemiology
* Kassem Bourgi
Kassem.Bourgi@Vanderbilt.edu Globally, the World Health Organization estimated that in
2015, there were 10.4 million new cases and 1.4 million
1
Division of Infectious Diseases, Department of Medicine, Vanderbilt deaths from tuberculosis [5]. Prior studies estimated that
University Medical Center, Nashville, TN, USA 10% of patients with active tuberculosis develop CNS disease,
2
Vanderbilt Tuberculosis Center, Vanderbilt University Medical resulting in an incidence as high as 20.6 per 100,000 in high-
Center, Nashville, TN, USA burden countries [6]. Young children [7] and persons living
39 Page 2 of 9 Curr Infect Dis Rep (2017) 19:39

with HIV (PLWH) [8–10] are at the highest risk for TB men- Staining and Microscopy
ingitis. The disease also disproportionately affects resource-
limited countries with a high prevalence of poverty, lack of The isolation of acid-fast bacilli in the CSF by culture is the
public health infrastructure, and limited access to healthcare gold standard for diagnosing TB meningitis. The Ziehl-
[11]. While mortality associated with TB meningitis has de- Neelsen stain, also known as the acid-fast stain, has poor sen-
creased with anti-tuberculosis treatment [2, 11], it continues to sitivity for the diagnosis of TB meningitis, reported to be as
be as high as 55–75%, especially in PLWH and those with low as 30% [27] and generally not exceeding 60% [28].
advanced disease on presentation [12]. Up to 50% of survivors Sensitivity can be improved through serial sampling and me-
suffer from long-term neurologic sequelae [12] such as devel- ticulous microscopic evaluation [28]. Performing cytospin
opmental delay [7], blindness [13], stroke, and seizures [11, 14]. with Triton X-100 prior to acid-fast staining, the modified
In 2016, 9287 new cases of tuberculosis were reported in Ziehl-Neelsen stain [29], as well as staining of early secretory
the USA, with an estimated incidence rate of 2.9 cases per antigen target (ESAT)-6 [30], has significantly better perfor-
100,000 [15]. Of the incident cases, 68% were in persons born mance than the conventional acid-fast stain.
outside of the USA [15]. US surveillance data for 2015 from CSF mycobacterial culture provides a definitive diagno-
the Centers for Disease Control and Prevention (CDC) report- sis of TB meningitis and allows for phenotypic drug sus-
ed 1933 incident cases of extrapulmonary tuberculosis, of ceptibility testing. However, cultures require an incubation
which 92 (4.5%) involved the meninges [16]. Prior CDC sur- period of up to 2 months and have imperfect sensitivity. The
veillance data from 1993 to 2006 had noted similar findings: microscopic observation drug susceptibility (MODS) assay
19% of tuberculosis patients had extrapulmonary disease, of provides faster results than standard culture and is based on
whom 5.4% had meningeal involvement [17]. microscopic evaluation of M. tuberculosis grown in liquid
culture [31]. However, MODS is not routinely available.

Adenosine Deaminase Testing

Diagnosis
Adenosine deaminase (ADA) testing can be used in the
Presenting Symptoms
diagnosis of pleural, pericardial, or peritoneal tuberculosis;
however, it has not been useful for the diagnosis of TB
The diagnosis of TB meningitis is often challenging, as clin-
meningitis. In a meta-analysis of 13 studies evaluating
ical symptoms are typically subacute and nonspecific [3].
ADA in the diagnosis of TB meningitis, test utility was
Compared to bacterial meningitis, patients with TB meningitis
highly dependent on the cut-off used, with a lower sensi-
typically report longer symptom duration—up to 1 month in a
tivity and higher specificity as the cut-off value increased
recent study [18]. Adults with TB meningitis commonly pres-
[32]. Similar findings were noted in PLWH [33]. An ADA
ent with stiff neck, headache, fever and vomiting—symptoms
cut-off value that optimizes both sensitivity and specificity
generally seen with other forms of bacterial meningitis. TB
has been difficult to establish.
meningitis, however, is characterized by a higher likelihood of
neurologic symptoms, with altered consciousness, personality
Nucleic Acid Amplification Testing
changes, and coma seen in 59, 28, and 21% of TB meningitis
patients, respectively [18]. Additionally, cranial nerve palsies,
Nucleic acid amplification tests (NAATs) are PCR-based
most frequently involving cranial nerve VI, are other common
assays that are highly specific but not sensitive for the di-
features, occurring in almost one-third of patients [19].
agnosis of TB meningitis, making them more useful as con-
Unfortunately, by the time more advanced neurological symp-
firmatory rather than diagnostic screening tests [34]. While
toms are apparent (cranial nerve palsies, elevated intracranial
higher sensitivities have been reported with novel real-time
pressure, altered level of consciousness), patients may have
PCR assays [35, 36], they are still insufficient to exclude a
already suffered irreversible long-term sequelae.
diagnosis of TB meningitis. The Xpert MTB/Rif assay
(Cepheid, Sunnyvale, CA, USA) is increasingly being used
Evaluation of Cerebrospinal Fluid for molecular diagnosis of pulmonary tuberculosis [37, 38].
With a 2-h turnaround time, this commercial NAAT pro-
Several algorithms have been proposed to distinguish TB vides a rapid, highly sensitive method for detection of tu-
meningitis from other more common causes of meningitis berculosis and rifampin resistance in pulmonary disease
[20–22]. Common features in the cerebrospinal fluid (CSF) [39]. While NAAT is highly specific for tuberculosis in
analysis are included in Table 1. Compared to bacterial men- patients with extrapulmonary disease, including TB menin-
ingitis, patients with TB meningitis have higher relative lym- gitis, the sensitivity of NAAT in these conditions is highly
phocytosis in the CSF [23]. variable [40–42]. In 2013, WHO recommended using it
Curr Infect Dis Rep (2017) 19:39 Page 3 of 9 39

Table 1 Characteristic CSF

findings in patients with different Bacterial Viral Cryptococcal Tuberculous
types of meningitis [24–26]
White blood cell ↑↑↑ ↑ Variable ↑
count
Cell differential Neutrophilic Lymphocytic Lymphocytic Lymphocytic
predominance predominance predominance predominance
Protein ↑↑ ↑ ↑↑↑ ↑↑↑
Glucose ↓ Usually normal ↓↓↓ ↓↓↓
Opening ↑ Usually normal ↑↑↑ ↑
pressure

↑ mildly elevated, ↑↑ moderately elevated, ↑↑↑ significantly elevated, ↓ low, ↓↓↓ significantly low

preferentially over conventional microscopy and culture for Radiographic Imaging

initial TB meningitis testing in resource-limited settings
[43]. However, Xpert MTB/Rif test quality is highly depen- While there are no definitive radiographic findings that are
dent on the CSF volume [44] and sample processing [40]. pathognomonic for TB meningitis, brain imaging commonly
Additionally, Xpert MTB/Rif has a low positive predictive shows basilar meningeal enhancement, hydrocephalus, basal
value in countries with low tuberculosis prevalence, which ganglion enhancement, and infarcts. While several of these
could result in false positive results [45]. To overcome the findings can be detected on computerized tomography (CT),
imperfect sensitivity of Xpert MTB/Rif, a next-generation magnetic resonance imaging (MRI) is a superior imaging mo-
assay—Xpert MTB/Rif Ultra—has been developed by dality for TB meningitis [52]. MRI also allows for better de-
Cepheid [46]. A recent WHO report found Ultra to be tection of early infarcts [53], identification of basal ganglion
non-inferior to Xpert MTB/Rif in the diagnosis of TB, with enhancement [54], enhancing exudates in basal cisterns, as
improved sensitivity of the new assay in smear-negative well as carotid and cerebral vascular involvement [55].
culture-positive specimens, and in specimens obtained
from PLWH [47]. Accordingly, WHO plans to update their
policy in 2018, recommending the use of Ultra [47]. Treatment

Treatment Regimens
Interferon Gamma Release Assays
The treatment of TB meningitis is based on the standard anti-
Interferon gamma release assays (IGRAs) detect the im- tuberculosis regimen of a 2-month induction phase of isonia-
mune response to synthetic mycobacterial peptides present zid, rifampin, pyrazinamide, and ethambutol, followed by a
in M. tuberculosis, through measuring the amount of inter- continuation phase with isoniazid and rifampin [56–58].
feron gamma released, and providing results that are not Guidelines recommend a longer continuation phase for TB
influenced by prior bacilli Calmette-Guérin (BCG) vacci- meningitis than pulmonary TB, with a total treatment duration
nation [48]. IGRAs are not able to distinguish between la- of 9–12 months for TB meningitis [56–59]. Table 2 summa-
tent M. tuberculosis infection and active TB disease. Their rizes recommended doses and expected CSF penetration for
role in the diagnosis of TB meningitis has been evaluated in common anti-tuberculosis medications.
several studies [49, 50]. A recent systematic review evalu- Recent studies have focused on the role of higher rifampin
ated the use of IGRA on blood (8 studies) and CSF samples doses as well as the addition of fluoroquinolones in the treat-
(6 studies) for the diagnosis of TB meningitis [51]. The ment of TB meningitis [61•, 62, 63]. A phase 2 trial conducted
sensitivities for blood and CSF IGRA tests were 77 and in Indonesia evaluating the role of intensified TB meningitis
78%, respectively, while the specificity was lower for blood regimens (increased rifampin dose and/or adding
than that for CSF (61 vs. 88%) [51]. The performance of the moxifloxacin) for the first 2 weeks of treatment (together with
test is significantly improved when combined with other isoniazid, pyrazinamide, and corticosteroids) showed that the
diagnostic tools. Combined with a low CSF ADA higher rifampin dose (13 mg/kg intravenous vs. 10 mg/kg
(< 5.8 U/L), CSF IGRA has a sensitivity of 94% [50] and oral) was associated with an almost 50% decrease in 6-
a high negative predictive value. When combined with a month mortality, more rapid resolution of coma, and higher
negative CSF bacterial Gram stain and a negative crypto- likelihood of complete neurologic recovery after 6 months of
coccal antigen latex test, the specificity is almost 100% treatment [62]. Moxifloxacin did not appear to have any sur-
[49], resulting in a high positive predictive value. vival benefit at either the 400 or 800-mg dose [62].
39 Page 4 of 9 Curr Infect Dis Rep (2017) 19:39

Table 2 Recommended use,

doses, and CSF penetration of Drug Recommended adult dose (/day) CSF penetration
anti-tuberculosis medications in
treatment of TB meningitis First-line drugs
[56–58, 60] Isoniazid 300 mg (5 mg/kg) Good (90%)
Rifampin 600 mg Variable (7–56%)
Pyrazinamide 1500–2000 mg Good (100%)
Ethambutol 15–25 mg/kg (up to 1600 mg) Variable (25–50%)
Second-line drugs
Amikacin 15 mg/kg (up to 1 g) Poor (0–30%)
Fluoroquinolones Levofloxacin 750–1000 mg Variable (30–50%)
Moxifloxacin 400 mg Fair (50%)
Ethionamide 15–20 mg/kg (up to 1 g) Good (50–100%)

One study evaluating the efficacy and pharmacokinetics of same question noted that mortality risk was higher among
adding fluoroquinolones to the standard TB meningitis regi- patients in cohorts treated for more than 6 months [66].
men suggested that fluoroquinolones improve TB meningitis However, most deaths occurred in the first 6 months, indicat-
outcomes if they are started early in the disease course [63]. ing that the difference is likely a reflection of other confound-
However, these results [62, 63] were not replicated in a larger ing factors and not the duration of therapy [66].
randomized trial involving both PLWH- and HIV-uninfected
patients that evaluated the effect of intensified anti-
Drug-Resistant Tuberculous Meningitis
tuberculosis therapy on mortality in patients with TB menin-
gitis [61•]. Compared to standard anti-tuberculosis regimens,
Isoniazid (INH) is a key component of anti-tuberculosis regi-
researchers concluded that neither the addition of levofloxacin
mens and has high CSF penetration [67]. Unfortunately, INH
(20 mg/kg/day) nor the increase in the dose of rifampin
resistance has been reported in 6% [68]—18% [69] of TB
(15 mg/kg compared to the traditional 10 mg/kg) reduced
meningitis cases. Prior studies showed similar treatment out-
mortality by 9 months from initiating therapy. However, this
come in patients with isoniazid-resistant pulmonary tubercu-
intensified regimen was associated with an increased risk of
losis compared to those with drug-susceptible infection.
seizures and visual impairment [61•].
However, CDC surveillance data from 1993 to 2005 demon-
A recent study involving PLWH diagnosed with TB men-
strated that isoniazid resistance on initial susceptibility testing
ingitis found that the standard dosing regimen for rifampin
is associated with a significant increase in mortality risk
results in sub-optimal CSF and systemic rifampin exposure.
among patients with CSF culture-positive TB meningitis
In addition, standard pyrazinamide dosing resulted in elevated
[68]. The most effective treatment for isoniazid-resistant TB
CSF concentrations that were independently associated with
meningitis remains unclear [67], although several guidelines
neurological toxicity and increased mortality [64].
recommend treatment with daily rifampin, ethambutol, and
pyrazinamide with or without adding a fluoroquinolone to
the regimen [58, 70].
Duration of Treatment

The optimal duration of treatment for TB meningitis is not Adjunctive Interventions in Management of TB
clearly established. Current guidelines from the World Meningitis
Health Organization [57, 59], American Thoracic Society,
Centers for Disease Control and Prevention, Infectious Steroids
Diseases Society of America [56], and British Infection
Society [58] recommend 12 months of treatment. To date, A 2016 Cochrane review of nine randomized trials, including
no randomized trials have directly compared 6-month vs. lon- 1337 patients with TB meningitis, evaluated the effects of
ger (9–12 months) treatment durations for TB meningitis. adding corticosteroids to anti-tuberculosis medications [71].
While an earlier systematic review suggested that shorter The mortality of TB meningitis in patients who were treated
treatment duration for TB meningitis (6 months compared to with an anti-tuberculosis regimen alone was 40%; the addition
9–12 months) is not associated with increased mortality, re- of corticosteroids reduced the risk of death by one-fourth. The
sidual neurological deficits, or relapse [65], the findings were survival benefit of corticosteroids was mostly seen in patients
based on observational studies that had highly variable results. with mild disease; there was no significant advantage in pa-
In contrast, a more recent Cochrane review evaluating the tients with advanced neurologic symptoms [12]. Additionally,
Curr Infect Dis Rep (2017) 19:39 Page 5 of 9 39

improvement in survival was not associated with a decrease in (ART) with suspected meningitis, M. tuberculosis was the
disabling neurological deficits [71]. However, there was no third most commonly identified CSF pathogen after
increased risk of adverse events in patients receiving steroids. Cryptococcus and Epstein Barr virus [77].
Similar results were found in a 2013 systematic review eval-
uating the role of steroids in all patients with tuberculosis [72], Disease Presentation in PLWH
with pooled results from trials evaluating the role of steroids in
TB meningitis showing a lower mortality and no increased The symptoms of TB meningitis are similar regardless of HIV
risk of adverse events. serostatus [60]. However, it has been noted that PLWH com-
monly present with extra meningeal involvement [78] and are
Surgery more likely to suffer from altered mental status [60]. Previous
studies have reported lower lumbar puncture opening pres-
Surgical management is infrequently warranted in the treat- sure, lower pleocytosis in cerebrospinal fluid [79, 80], and
ment of TB meningitis. Indications for surgery include persis- higher AFB culture yield among PLWH patients with TB
tent hydrocephalus, in which a ventriculoperitoneal shunt is meningitis compared to those of HIV-uninfected persons [81].
placed to alleviate the increased intracranial pressure; this in-
tervention has been associated with improved clinical out- Immune Reconstitution Inflammatory Syndrome
comes [73]. Cerebral abscesses and extradural lesions with
resultant cerebral or vertebral compression and neurologic The management of TB meningitis in PLWH is usually com-
deficits are other indications for surgical intervention. plicated by multiple drug-drug interactions as well as the risk
of immune reconstitution [82]. Immune reconstitution inflam-
Aspirin matory syndrome (IRIS) is a phenomenon that results from an
excessive immune response against Mycobacterium
Patients with TB meningitis are at risk for ischemic strokes tuberculosis after initiation of antiretroviral therapy.
secondary to vascular occlusion, and hemorrhagic strokes as- Extrapulmonary tuberculosis, low CD4+ counts, and high
sociated with venous sinus thrombosis. Two randomized con- HIV viral load prior to initiating ART are factors associated
trolled trials evaluated the role of aspirin in decreasing the risk with significant increase in risk of tuberculosis-associated
of stroke in adults [74] and children [75] with TB meningitis. IRIS [83]. TB IRIS is seen in nearly half of PLWH with TB
Both trials failed to show a significant association between meningitis [84] and is associated with high morbidity and
aspirin and stroke prevention. mortality rates [85]. Manifestations of TB meningitis IRIS
include worsening headaches, decreased level of conscious-
ness, new onset seizures, and paresis [84]. Studies suggest a
Tuberculous Meningitis in People Living with HIV higher risk of IRIS in patients with positive CSF cultures,
indicating that high baseline tuberculosis antigen load drives
Prevalence of TB Meningitis in PLWH an inflammatory response manifesting as TB IRIS [84, 86].
Additionally, it was noted that higher neutrophil counts and
HIV infection is associated with a significant increase in TB percentage as well as higher levels of inflammatory cytokines
risk [8, 9] and particularly an increase in the risk of such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α
extrapulmonary TB. Globally, PLWH are 20–30 times more at the time of TB meningitis presentation were associated with
likely to develop TB disease compared to HIV-uninfected higher likelihood of developing TB IRIS [84, 86–88].
persons, with 12% of patients with TB worldwide being co- A similar phenomenon referred to as a “paradoxical wors-
infected with HIV [5]. In the USA, HIV co-infection in pa- ening” is also seen among HIV-uninfected patients with TB
tients with TB was as high as 48% in 1993, dropping to 5.5% meningitis, who can experience worsening of symptoms after
in 2015 [16]. The prevalence of HIV co-infection in patients TB treatment initiation [89–93•].
with TB is the highest in the 25–44-year age group [16].
Among patients with TB, 40% of all cases in PLWH are Initiating Antiretroviral Therapy
extrapulmonary, compared to 10% in HIV-uninfected coun-
terparts [9, 10, 17, 76]. Similarly, for patients with TB, PLWH Since ART initiation and secondary IRIS can unmask previ-
have a five-fold increase in the likelihood of having CNS ously undiagnosed tuberculosis, or cause paradoxical worsen-
involvement [11, 58] and disseminated TB [10] compared to ing of known tuberculosis disease [94], it is critical to gauge
HIV-uninfected persons [8, 60]. This risk significantly in- the timing of ART initiation in relation to anti-tuberculosis
creases among patients with CD4+ lymphocyte cell count treatment.
< 100 cells/mL [10]. In a prospective cohort study conducted The concomitant treatment of tuberculosis and HIV is as-
in Uganda involving PLWH not on antiretroviral therapy sociated with improved survival compared to starting ART
39 Page 6 of 9 Curr Infect Dis Rep (2017) 19:39

after completion of anti-tuberculosis treatment [95]. However, authors have been previously published and complied with all applicable
ethical standards.
it has been noted that the initiation of ART within 2–3 weeks
of starting anti-tuberculosis therapy is associated with an in-
creased risk of IRIS [96–99], particularly in persons with < 50
CD4+ lymphocytes/mm3. Despite the IRIS risk, initiating References
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