BAB I

PENDAHULUAN
Tuberculous meningitis Diagnostic and therapeutic challenges
Jerome H. Chin, MD, PhD, MPH

Summary

Neurologists are often the first medical providers to evaluate patients with possible
infectious meningitis. Knowledge of the clinical presentations and cerebro- spinal
fluid, microbiologic, and neuroimaging findings for different etiologies is essential
to make a prompt diagnosis and initiate appropriate treatment. Tuber- culosis is a
common cause of meningitis in develop- ing countries with a high prevalence of
pulmonary tuberculosis. However, tuberculosis affects popula- tions in every
country and all neurologists need to be vigilant for possible cases of tuberculous
meningi- tis presenting to their medical facilities. This article discusses the
challenges of diagnosing and treating tuberculous meningitis and highlights recent
advan- ces in diagnostic technology.

Tuberculosis (TB) is a highly prevalent global
 human infection caused by

Mycobacterium
 tuberculosis (MTB). One-third of the
 world’s population is
infected with latent
 TB. These individuals are not clinically affected but carry a
lifetime risk of 10% for developing active disease.1 There were an estimated 8.6
million incident cases of TB globally in 2012, with 1.3 million deaths.2 A total of
22 high-burden countries accounted for 81% of all estimated incident cases. TB is
the leading cause of death in people living with HIV, accounting for approximately
1 in 5 deaths.

The largest share of the global burden of TB is in the Southeast Asia, Western
Pacific, and African regions.2 However, TB is a global epidemic, with cases
reported annually in every country. In the United States in 2012, 9,951 new cases
of TB were reported, with 7.7% of cases coinfected with HIV.3 The majority of
cases (63%) were foreign-born persons. The top 5 countries of birth were Mexico,
the Philippines, India, Vietnam, and China. In the United Kingdom in 2012,4 8,751
new cases of TB were reported, with 73% among people born in high-burden
countries of South Asia and sub-Saharan Africa. In the United States and the United
Kingdom, populations at higher risk for TB include racial and ethnic minorities,
homeless persons, prisoners, and immunosuppressed individuals.3,4
Figure 1 Chest X-ray of pulmonary tuberculosis

Bilateral infiltrates and hilar adenipathy suggestive of active tuberculosis

Clinical presentation of tuberculous meningitis

Tuberculous meningitis (TBM) can occur as the sole manifestation of TB or

concurrent with pulmonary or other extrapulmonary sites of infection.5–7 TBM
carries a high mortality and morbidity, particularly among patients coinfected with
HIV.8–12 Delays in seeking medical care, diagnosis, and initiation of treatment are
contributing factors to the high mortality and morbidity, especially in resource-
limited regions. When diagnosed promptly, TBM can be cured with supervised
medication administration and supportive care.

Patients with TBM develop typical symptoms and signs of meningitis including
headache, fever, and stiff neck, although meningeal signs may be absent in the early
stages. The duration of symptoms before presentation ranges from several days to
several months.9,10 Especially in resource-limited settings, TBM cases may present
in advanced clinical stages, with Glasgow Coma Scale scores of 10 or less.9–12
Cranial nerve (CN) palsies, hemiparesis, paraparesis, and seizures are common and
should raise the possibility of MTB as the etiology of meningitis. Patients often
present with multiple CN palsies, most commonly involving CN III, VI, and VII.
Chest X-ray is suggestive of active or previous pulmonary TB in approximately
50% of cases (figure 1).5

CSF in TBM

If the clinical presentation is suggestive of TBM, cerebrospinal fluid (CSF) should

be sent for routine analyses (cell counts and differential, protein level, glucose
level) and microbiologic tests for bacteria, fungi, and MTB. Pleocytosis with
lymphocytic predominance, high protein levels, and low glucose levels are the
hallmark findings in the CSF of patients with TBM. In a consecutive series of 88
HIV-negative patients with definite TBM diagnosed by positive CSF culture,13 the
following median values were determined from CSF analyses: cell count (136/mL),
mononuclear cell percentage (63%), protein concentration (160 mg/dL), and CSF
glucose/blood glucose ratio (0.13). Atypical CSF findings may be obtained in HIV
coinfected individuals including normal cell counts (#5 cells/mL),
polymorphonuclear cell predominance, and normal glucose levels (.2.2 mmol/L).12

The CSF findings noted above are not specific for TBM and can be seen in other
conditions including non-MTB bacterial meningitis, fungal meningitis,
carcinomatous meningitis, and subarachnoid hemorrhage. For all patients with
suspected TBM, CSF samples should be exam- ined by Ziehl-Neelsen (ZN) staining
for acid-fast bacilli, Gram staining for bacteria, India ink preparations for fungi, and
antigen testing for Cryptococcus neoformans. In non-MTB bacterial meningitis,
60%–90% of CSF Gram stains are positive, allowing rapid identification of the
causative organism for most cases.14 In contrast, ZN staining has a very low
sensitivity in cases of TBM.9,13 For example, in a prospective observational study
from Indonesia, only 11% of CSF samples taken from 207 suspected cases of TBM
were positive by ZN staining.13 In the same study, a low percentage of CSF samples
yielded growth of MTB by solid culture (36%) and by liquid culture (44%). Since
MTB cultures can take several weeks or longer to detect growth, a presumptive
diagnosis of TBM in cases with a negative CSF ZN stain needs to be made without
waiting for the results of CSF MTB culture.

A recent diagnostic advance is Xpert MTB/RIF, an automated rapid nucleic acid

amplifica- tion test for MTB endorsed by the WHO in December 2010.15 Xpert
technology employs single-use sealed disposable cartridges that avoid
contamination of testing equipment and requires minimal technical training to
operate. The Xpert MTB/RIF assay employs 3 specific primers and 5 unique
molecular probes to detect MTB and rifampicin resistance simulta- neously in less
than 2 hours. Molecular probes are included to detect DNA of sample processing
control bacteria (figure 2). Rifampicin resistance is strongly indicative of multi-
drug-resistant TB (MDR-TB), defined as TB caused by organisms resistant to
isoniazid and rifampicin.15

A 2013 Cochrane Review of Xpert MTB/RIF in pulmonary TB that included 18

unique studies reported a pooled sensitivity of the assay of 98% for smear-positive,
culture-positive TB and 68% for smear-negative, culture-positive TB, and an assay
specificity of 98%.15 A prospective study from South Africa reported a sensitivity
of 67% and a specificity of 94% for Xpert MTB/RIF comparing 54 HIV-infected
patients with definite TBM and 65 patients with “non-TBM” meningitis.16 A recent
study of suspected TBM cases (20.8% HIV- infected) from Vietnam reported a
sensitivity of 72% and a specificity of 99.5% for Xpert MTB/RIF comparing 151
definite cases of TBM with 197 cases of not TBM meningitis.17

Figure 2 Xpert MTB/RIF nucleic acid amplification test

Xpert MTB/RIF result on the csf of a 53-year-old patiend with tuberculosis

meningitis and hiv coinfection Ziehl- Neelsen stain of CSF for acid-fast bacilli was
negative.

Neuroimaging in TBM

Contrast-enhanced brain CT or MRI can help support a diagnosis of TBM because

of the high frequency of abnormalities on initial presentation (figure 3). The most
common findings in descending order are meningeal enhancement, hydrocephalus,
basal exudates, infarcts, and tuberculomas.18 Infarcts occur as a result of vasculitis
affecting the vessels of the Circle of Willis, the perforating branches of the middle
cerebral artery, and the vertebrobasilar circulation.

Figure 3 Neuroimaging in tuberculosis meningitis

(A) Brain CT of a 19-year-old patient with tuberculous meningitis (TBM) shows

hydrocephalus and basal meningeal enhancement. (B) Brain MRI of a 56-year-old
patient with TBM shows basal ganglia infarcts.

Treatment of TBM

If the clinical presentation, CSF findings, and neuroimaging studies of a patient

with menin- gitis are compatible with TBM and other etiologies (e.g., bacterial and
fungal) have been ex- cluded by initial CSF analysis, a presumptive diagnosis of
TBM should be made and treatment should be initiated promptly. Parenteral
empirical antibiotics should be administered to cover non-MTB bacterial etiologies
until CSF and blood cultures for bacteria are negative for .48 hours. Guidelines for
the treatment of TBM in adults and children have been published by the WHO in
201019,20 and the British Infection Society in 20095 and are based on standard
regimens for pulmonary TB (table). Controlled trials to determine the optimal drug
regimen and treatment duration for TBM have not been conducted.

The British Infection Society guidelines recommend a first-line regimen of 2

months of iso- niazid, rifampicin, pyrazinamide, and ethambutol followed by 10
months of isoniazid and ri- fampicin.5 The WHO guidelines recommend a first-line
regimen of 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol
(children) or streptomycin (adults) followed by 10 months of isoniazid and
rifampicin.19,20 Both guidelines recommend adjunctive corticoste- roids based on a
Cochrane review that concluded that adjunctive corticosteroids reduce the risk of
death or disabling residual neurologic deficit from TBM.8 Newer regimens
combining fluoroquinolones with high-dose rifampicin show promise for
improving outcomes in TBM.21–23 For patients with suspected or confirmed MDR-
TB, recently published WHO guidelines should be followed24 and an expert in
treating MDR-TB should be consulted. The Food and Drug Administration recently
approved the use of bedaquiline fumarate as part of

combination therapy for adults with a diagnosis of pulmonary MDR-TB. Although

clinical trials of bedaquiline for the treatment of extrapulmonary MDR-TB are not
available, pub- lished guidelines indicate that use on a case-by-case basis is
reasonable given the high mor- tality rate and limited treatment options.25

HIV-infected patients receiving treatment for TBM are at risk for clinical
deterioration after initiation of antiretroviral therapy (ART) due to immune
reconstitution inflammatory syn- drome (TBM-IRIS).26,27 The rapid restoration of
immune function in the presence of my- cobacterial antigens provokes an
intensified inflammatory reaction resulting in worsening, recurrent, or new clinical
signs and symptoms. Diagnosis of TBM-IRIS requires exclusion of other causes of
clinical deterioration including drug resistance, poor adherence to treatment,
misdiagnosis, and other opportunistic infections. The optimal time to initiate ART
is uncer- tain. Some guidelines recommend deferring ART to 4–6 weeks after
beginning anti-TB medication.26 Although corticosteroids do not appear to prevent
TBM-IRIS,27 restarting or increasing the dose and duration of corticosteroid
treatment is recommended for the man- agement of TBM-IRIS.26,27
DISCUSSION

TB is one of the most challenging causes of meningitis to diagnose because of the

difficulties in rapidly identifying MTB in CSF samples. TBM should be strongly
considered in any patient presenting with symptoms and signs of meningitis in
regions with a high burden of TB and in high-risk individuals in regions with lower
burdens of TB. Clinical, microbiologic, and radio- logic findings should be used
conjunctively to support a diagnosis of TBM. Empirical treat- ment with anti-TB
drugs is the standard of care in presumptive cases with negative ZN staining of CSF
for acid-fast bacilli. The Xpert MTB/RIF assay provides the ability to rapidly
diagnose infection with MTB, although additional studies are needed to define the
sensitivity and specificity for the diagnosis of TBM.

Drug Daily dosage (children), mg/kg Daily dosage (adults), mg/kg Duration

Isoniazid 10–15 (max 300 mg) 4–6 (max 300 mg) 12 mo

Rifampicin 10–20 (max 600 mg) 8–12 (max 600 mg) 12 mo

Pyrazinamide 30–40 20–30 2 mo

Ethambutol 15–25 15–20 2 mo

Streptomycina 12–18 2 mo

Dexamethasoneb 0.6 0.4 6–8 wk

a WHO guidelines recommend replacing ethambutol with IM streptomycin for adults.19

b Dexamethasone should be given intravenously at first and then orally as tolerated. Dosage
should be tapered weekly.5
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