1.

Definisi
2. Epidemiologi

About 2000 million people in the world today are infected with tuberculosis, but only 10%
develop clinical disease. Before HIV the most important determinant for the development of
TBM was age. In populations with high TB prevalence TBM differs from pulmonary, and
other extrapulmonary tuberculosis, in that the peak age is from 0–4 years. In populations with
lower TB prevalence, most cases of TBM are in adults. Risk factors identified for these people
are alcoholism, diabetes mellitus, malignancy, and recent corticosteroid use. Coinfection with
HIV now dwarfs these risk factors. HIV increases the lifetime risk of developing clinical TB
postinfection to 1 in HIV also predisposes to the development of extrapulmonary TB, and in
particular TBM, a risk which increases as the CD4 count declines. The disease constitutes
either reactivation of latent infection, or new infection. Evidence from DNA fingerprinting of
strains using restriction fragment length polymorphism suggests that in the United States up to
40% of new disease in both HIV positive and non- HIV patients is due to recent infection. The
extent to which a person’s genetic constitution effects resistance or susceptibility to infection
is under debate. Certain ethnic groups seem to be more susceptible to M tuberculosis than
others. Studies using tuberculin conversion as a surrogate marker suggest that black skinned
people are more susceptible to infection than white people. Recently it has been proposed that
certain polymorphisms in the human NRAMP1 gene may affect susceptibility to pulmonary
tuberculosis in West Africans.13 Whether genetic factors influence prevalence of TBM within
a population is unknown.
The extent to which BCG vaccination affords protection against TBM is still debated. A meta-
analysis of the published trials on the efficacy of BCG vaccination suggested a protective effect
of 64% against TBM. This figure is higher than that suggested for pulmonary TB (50%), but
may only reflect more accurate case ascertainment of TBM given the universal requirement
for admission to hospital. Overall, these and other studies support the view that BCG
vaccination is protective against TBM.
Close correlation exists between the observed incidence of TBM in children aged 0–4 years,
and the population’s annual average risk of infection with M tuberculosis. The incidence of
TBM has been calculated to represent 1% of the annual risk of infection.15 Risk of infection
depends on the prevalence of infectious cases in a given community. Prevalence of infectious
cases is dependant not only on the risks pertinent to each person for developing disease, but to
the factors inherent in the community encouraging spread of infection. The main reason for the
spread of tuberculosis is poverty, with resulting homelessness, malnutrition, and
breakdown of public health infrastructure.
The total number of tuberculosis cases in the world is increasing.16 17 It is estimated that most
of these new cases will be in south east Asia16 fuelled by the rapid spread of HIV. It has been
predicted that without intervention 200 million people alive today will develop TB.1 The
physician needs to be aware of these changes, as less common forms of tuberculosis such as
TBM will be encountered more often.

3. Etiologi

Tuberculous meningitis (TBM) is caused by Mycobacterium tuberculosis (M. tuberculosis)

and is the most common form of central nervous system (CNS) tuberculosis (TB).
4. Faktor risiko

HIV co-infection, particularly in patients with severe immunosuppression, increases the risk
of disseminated forms of tuberculosis (TB), such as meningitis, and contributes significantly
to the TBM burden in high HIV/TB settings. The diagnosis of TBM is often complicated and
optimal management strategies are uncertain; such challenges are likely to contribute to poor
outcome nin affected patients.

5. Patofisiologi

A discussion on the pathogenesis of tuberculous meningitis can be directed on two levels. On

a macroscopic level there are the mechanisms by which the tuberculous bacilli disseminate to
the CNS. This is discussed alongside the role of granulomatous inflammation, the currency of
tuberculous pathology, in causing gross pathological changes within the CNS. On a
microscopic level there are the cellular and immune mechanisms that can result in both the
disease and its control. The development of TBM is a two step process Mtuberculosis bacilli
enter the host by droplet inhalation, the initial point of infection being the alveolar macrophage.
Escalating localised infection within the lung with dissemination to the regional lymph nodes
produces the primary complex. During this stage there is a short but significant bacteraemia
that can seed tubercle bacilli to other organs in the body. In those who develop TBM, bacilli
seed to the meninges or brain parenchyma, forming small subpial or subependymal foci. These
are called Rich foci, after the original pathological studies of Rich and McCordick.28 In about
10% of cases, particularly in children, the primary complex does not heal but progresses.
Tuberculous pneumonia develops with heavier and more prolonged tuberculous bacteraemia.
Dissemination to the CNS is more likely, particularly if miliary TB develops.
The second step in the development of TBM is rupture of a Rich focus into the subarachnoid
space. This heralds the onset of meningitis, which if left untreated, will result in severe and
rreversible neurological pathology. In 75% of children the onset of TBM is less than 12 months
after the primary infection. Three general processes produce the subsequent neurological
pathology: adhesion formation, an obliterative vasculitis, and an encephalitis or myelitis.
Adhesions result from a dense basal meningeal exudate that develops after inoculation of
bacilli into the subarachnoid space. The exudate contains lymphocytes, plasma cells, and
macrophages, with increasing quantities of fibrin. Blockage, through adhesion formation, of
the basal subarachnoid cisterns can result in obstruction of the CSF and hydrocephalus.
Adhesions around the interpendicular fossa and related structures can compromise cranial
nerves, particularly II,IV, and VI, and the internal carotid artery. An obliterative vasculitis of
both large and small vessels develops that can result in infarction and stroke syndromes. These
commonly occur in the territories of the internal carotid, proximal middle cerebral, and the
perforating vessels to the basal ganglia.31 Infarction through vasculitis is the mechanism by
which many of the diverse clinical neurological abnormalities in TBM occur, and accounts for
an appreciable part of the irreversible neurological sequelae. The intensity of the basal
inflammatory process extends into the parenchyma resulting in encephalitis. Oedema
occurring as a consequence can be marked throughout both hemispheres. This will contribute
to rising intracranial pressure and the global clinical neurological deficit. A rare complication
of TBM is tuberculous encephalopathy. Usually occurring in a young child with progressive
primary TB, the presentation is of reducing conscious level with few focal signs and minimal
meningism. Diffuse oedema and white matter pallor with demyelination are found
pathologically. The pathogenesis is uncertain, but is presumed to be immune mediated.
Diagnosis is important as anecdotal
reports suggest a good response to corticosteroids.
The pathogenesis of TBM at a cellular level is poorly understood. Knowledge regarding the
pathogenesis of pulmonary infection is limited, but certain key principles may serve to
illuminate some of the processes evident in the CNS. The formation of caseating
granulomatous inflammation is fundamental. Current theories of immunopathogenesis seek to
explain the roles and interactions between the macrophage, the helper T cell, and the organism.
Cell mediated immunity is central to both the control of infection and the production of tissue
damage.34 Lurie’s experiments on tuberculosis in rabbits describe the fundamental stages of
the disease. Theories of immunopathogenesis aim to explain these stages.
The initial stage of infection is the ingestion of the inhaled tubercle bacilli by the alveolar
macrophage. Depending on the ability of the macrophage to resist infection the bacilli multiply
and destroy the macrophage. The innate and possibly genetically determined resistance to
infection at this stage has been discussed earlier. During the second stage bacilli grow
logarithmically within newly recruited macrophages. After about 2 weeks CD4 T cells specific
for mycobacterial peptides appear. Production of ã-interferon activates macrophages enabling
more efficient intracellular killing of tubercle bacilli. Activated macrophages produce
interleukin 1-â, and tumour necrosis factor (TNF) which promotes granuloma formation.
The basal inflammatory exudate is central to the pathogenesis of TBM. The primary complex
results in the development of cell
mediated immunity; therefore, the rupture of the Rich focus with release of bacilli into the
subarachnoid space will result in a local T-cell dependent response. The necrotizing
granulomatous response is fundamental to the subsequent pathology. Dannenberg
hypothesizes that necrosis is the result of a delayed type hypersensitivity reaction to exposed
tuberculoproteins. Others propose that the granuloma architecture dictates the extent of the
central necrosis: a reduced capacity for focusing T lymphocytes within a point of infection
may result in failure to deliver adequate cytokine concentrations to the centres of large
granulomas, resulting in degeneration and necrosis.
Studies in bacterial meningitis have shown that CSF concentrations of TNF-á correlate with
disease severity.38 TNF-á concentrations in TBM are lower than they are in bacterial
meningitis. In TB sensitised animals small concentrations of TNF result in substantial tissue
necrosis.39 Rabbit models of TBM show that CSF concentrations of TNF-á correlate with
clinical progression.40 Intervention with antibiotics and thalidomide, an anti-TNF agent,
resulted in an improvement in survival
and neurological outcome.40 The protective role of TNF should not be forgotten, with the
promotion of granuloma formation36 and enhanced killing of infected cells in vitro.41 These
models provide evidence for the important role of cytokines, in particular TNF, in the
pathogenesis of TBM. They suggest alternative immunomodulatory therapeutic approaches
that may supercede the blind use of corticosteroids.

6. Manifestasi klinis

TBM typically presents sub-acutely after an average of 5 - 30 days of neurological symptoms

(e.g. headache, vomiting, neck pain/stiffness, seizures, focal neurological signs and
confusion)[3] – unlike bacterial meningitis, which usually presents more acutely, but similar
to cryptococcal meningitis (CM). However, shorter (a few days) or longer (>1 monthduration
of neurological symptoms is well described and does not exclude the diagnosis of TBM.
Systemic symptoms of Mycobacterium tuberculosis infection, such as cough, night sweat and
loss of weight, may be indicative of TB, but may also be present with other causes of
meningitis. Untreated HIV infection frequently results in loss of weight.

7. Diagnosis

The diagnosis of TBM can be difficult and may be based only on clinical and preliminary
cerebrospinal fluid (CSF) findings without definitive microbiologic confirmation. Certain
clinical characteristics such as longer duration of symptoms (>six days), moderate CSF
pleiocytosis, and the presence of focal deficits increase the probability of TBM [15, 16].
Characteristic CSF findings of TBM include the following:
a. lymphocytic-predominant pleiocytosis. Total white
cell counts are usually between 100 and 500 cells/μL.
Very early in the disease, lower counts and neutrophil
predominance may be present,
b. elevated protein levels, typically between 100 and
500 mg/dL,
c. low glucose, usually less than 45mg/dL or CSF: plasma
ratio <0.5.
CSF sample should be sent for acid-fast smear with the important caveat that a single
sample has low sensitivity, on the order of 20%–40% [17]. Several daily large volume (10–15
mL) lumbar punctures are often needed for a microbiologic diagnosis; sensitivity increases to
>85% when four spinal taps are performed [18]. Early studies demonstrated that acid-fast
stains can detect up to 80% [18] although results are highly dependent on CSF volume,
timeliness of sample delivery to the lab and analysis, and the technical expertise of lab
personnel. While culture can take several weeks and also has low sensitivity (∼40–80%), it
should be performed to determine drug susceptibility. Drug-resistant strains have important
prognostic and treatment implications; indeed, TBM due to isoniazid- (INH-) resistant
M.tuberculosis strains have been associated with a twofold increase
in mortality [19].
Given the relatively low sensitivity of acid-fast smear and inherent delay in culture, newer
diagnosticmethods for TBM have been more recently developed [17]. Although ELISA assays
have been developed to detect antibodies directed against specific mycobacterial antigens in
the CSF with varying sensitivities, their limited availability precludes their use as point-of-care
tests in resource-poor countries [17, 20]. A recent study in children aged 6–24 months suggests
that a CSF adenosine deaminase level of ≥10 U/L has >90% sensitivity and specificity of
diagnosing TBM [21]. However, other studies have shown poor specificity of adenosine
deaminase for TBM in certain populations, particularly in HIV-infected adults with concurrent
infections or cerebral lymphomas.
Comparison of microscopy/culture of large CSF volumes to nucleic acid amplification
(NAA) has shown that sensitivity of these methods for the diagnosis of TBM is similar [23].
A meta-analysis determined that commercial NAA assays utilizing polymerase chain reaction
(PCR) for the diagnosis of TBM had an overall sensitivity of 56% and a specificity of 98%
[24]. The surprisingly poor sensitivity is likely due to the fact that most PCR-based studies use
a single target for amplification which can result in false-negative results due to the absence of
the target gene in some TB isolates [25].Newer PCR tests amplify several target genes
simultaneously and have been shown to result in much higher sensitivities in the range of 85%–
95% [26]. Currently, most experts conclude that commercial NAA tests can confirmTBM but
cannot rule it out [27]. Thus, it bears emphasizing that a negative CSF examination for acid-
fast bacilli or M. tuberculosis DNA neither excludes the diagnosis of TBM nor obviates the
need for empiric therapy if the clinical suspicion is high. After starting treatment, the sensitivity
of CSF smear and culture decreases rapidly, while mycobacterial DNA may be detectable in
the CSF for up to a month after treatment initiation.
Diagnosis of TBM can be helped by neuroimaging. Classic neuroradiologic features of TBM
are basal meningeal enhancement and hydrocephalus [17]. Hypodensities due to cerebral
infarcts, cerebral edema, and nodular enhancing lesionsmay also be seen.Magnetic resonance
imaging (MRI) is the imaging test of choice for visualizing abnormalities associated with
TBM, as it is superior to computed tomography (CT) for evaluating the brainstemand spine.
The T2-weighted MRI imaging has been shown to be particularly good at demonstrating
brainstem pathology; diffusion-weighted imaging (DWI) is best at detection of acute cerebral
infarcts due to TBM. However, CT is adequate for urgent evaluation of TBM-associated
hydrocephalus for possible surgical intervention.

8. Tata laksana

TB treatment
Similar to guidelines globally, current SA Department of Health (SADoH) guidelines suggest
RIF, isoniazid, ethambutol and pyrazinamide for 2 months, followed by RIF and isoniazid for
a further 7 months as first-line treatment in adults with CNS TB. However, the principles of
treating TBM are based on those developed for pulmonary TB and not informed by randomised
controlled trials (RCTs) in TBM.[2] RIF is one of the backbone drugs in TBM treatment, but
the evidence for the current recommended dose (10 mg/kg/day) is scant and may be too low.
RIF has poor CSF penetration and TBM patients often present critically ill, vomit and receive
drugs through a nasogastric tube. All these factors may further contribute to suboptimal CNS
TB drug concentrations. Isoniazid and pyrazinamide have good CSF penetration and are
therefore considered critical drugs in TBM treatment. However, the choice of the fourth drug
during the initiation phase of TBM treatment is contentious.[2] Ethambutol crosses the
meninges poorly at the recommended dose. Alternatives such as streptomycin and ethionamide
are of limited use in TBM owing to poor CNS penetration, dose-limiting toxicity and
intolerablegastrointestinal side-effects in adults. Fluoroquinolones such as levofloxacin and
moxifloxacin have high bactericidal activity, are safe and well tolerated and have good CSF
penetration; therefore they are
attractive treatment options for TBM. There is increasing interest in exploring alternative
evidence-based treatment regimens for TBM. RCT findings suggest a mortality benefit from
an ‘intensified’ treatment regimen early during TBM treatment.[10] This study investigated
the safety and pharmacokinetic profiles of higher-than-normal dose, intravenous (IV) RIF and
oral moxifloxacin in HIV-infected and -uninfected TBM patients. Although not powered to
detect a mortality benefit, an improved outcome was observed in patients receiving IV RIF
(~13 mg/kg/d) than in those on the oral standard dose during the initial 2 weeks of TB
treatment. Patients who received IV RIF had a reduced mortality at 6-month follow-up (34%)
compared with those who received oral RIF (65%). A further RCT assessing the use of higher
doses of oral
RIF (15 mg/kg/d) and oral levofloxacin in improving TBM outcome is currently ongoing in
Vietnam (ISRCTN61649292). Results of this trial, which may lead to changes in treatment
guidelines, are expected in 2015.

Corticosteroids
Corticosteroid treatment is associated with improved survival in HIV-uninfected patients with
TBM and is recommended in all affected patients, regardless of HIV status.[11] In an RCT of
adjunctive dexamethasone in TBM, this medication was associated with a reduced risk of death
compared with placebo, which was significant in all patients at 9-month follow-up (relative
risk: 0.69; p=0.01),[12] but only a trend for mortality benefit with dexamethasone was
observed in subgroup analysis of HIV-infected patients (p=0.08). Of note, corticosteroid
treatment was associated with a decrease in severe adverse events, in particular hepatitis (0/274
v. 8/271 cases in the placebo group; p=0.004).

Treatment of HIV infection in TBM patients

A large proportion of HIV-infected patients are antiretroviral therapy (ART)-naive or have
defaulted ART at TBM presentation. Starting ART during TB treatment improves outcome in
HIV/TB co-infected patients, and one large RCT from Vietnam has provided guidance on
the timing of ART in such patients.[13] In this study of patients with HIV-associated TBM,
there was no difference in 9-month mortality between severely immunosuppressed TBM
patients (median CD4+ count = 41 cells/μL) who started ART immediately (within 7 days of
TB treatment) and those who started later (2 months after TB treatment initiation). Grade 4
adverse events were significantly more frequent in the ART group who started treatment
immediately (80 v. 69%; p=0.04), suggesting that delayed treatment may be preferable. In view
of these findings and the risk of CNS TB-IRIS, current SA DoH ART guidelines recommend
starting ART 4 - 6 weeks after TB treatment in TBM patients, regardless of CD4+ count.

Paradoxical TBM-IRIS
TB-IRIS occurs owing to an exaggerated immune response against TB antigens in HIV-
infected patients after ART initiation. Paradoxical TB-IRIS occurs in patients who typically
show clinical improvement after starting appropriate TB treatment, and subsequently present
with new, recurrent or worsening TB symptoms after ART initiation in the context of a
recovering immune system. Neurological TB-IRIS is the most life-threatening form of TB-
IRIS, with an associated mortality of 13 - 75%. Neurological IRIS may present as meningitis,
intracerebral tuberculoma(s), tuberculous brain abscess, radiculomyelitis or spinal epidural
abscess. Patients frequently present with atypical inflammatory features such as focal
meningeal enhancement on brain imaging (Fig. 2). In an observational study from Cape Town,
47% of TBM patients developed TBM-IRIS at a median of 14 days after ART initiation, while
mortality due to TBM-IRIS was 12.5% (2/16).[14] Factors at TBM presentation associated
with subsequent TBM-IRIS
included high CSF neutrophil count and high CSF bacillary load (reflected by M. tuberculosis
culture positivity). Corticosteroids are the only evidence-based treatment currently available
for TB-IRIS. In an RCT of prednisone for the treatment of non-life-threatening paradoxical
TB-IRIS, significant benefit was demonstrated with prednisone compared with placebo.The
combined endpoint was days hospitalised and outpatient therapeutic procedures. Additionally,
there was also significant symptomatic improvement associated with prednisone.[15] Based
on these findings and anecdotal evidence of the benefit of corticosteroids in neurological TB-
IRIS, our practice is to treat all patients with neurological TB-IRIS with prednisone 1.5
mg/kg/d orally (or IV dexamethasone) for at least 2 weeks, after which the dose is reduced
gradually according to clinical response. Temporary interruption of ART should only be
considered in patients with a severe or persistently depressed level of consciousness and in
those with severe neurological disability unresponsive to corticosteroid therapy.[16] A vital
component of the management of HIV-associated TBM patients who will start ART is a
comprehensive discussion
with the patient, and preferably also with a family member, about the risk of developing
neurological TB-IRIS, the typical symptoms that could be expected and the need to return to
hospital should any of these develop.

8)
9. Prognosis
Some studies have assessed the clinical and laboratory indices that might predict outcome.
The early trials used univariate analysis—assessing prognostic variables without adjusting
for the effect of covariables. From these studies, some poor prognostic indicators arose—
extremes of age, advanced stage of disease, concomitant extrameningeal TB, and evidence
of raised intracranial pressure. Studies employing multivariate analyses that adjust for the
influence of other variables are scarce. One such study in children found that the age of the
patient and stage of disease were two independent variables associated with prognosis. A
more recent study looked at clinical, laboratory, and CT features in adults and children
with TBM. A multivariate logistic regression model showed that the most significant
variables for predicting outcome in TBM were age, stage of disease, focal weakness,
cranial nerve palsy, and hydrocephalus. The message for clinicians is simple: children with
advanced disease with neurological complications have poor outcomes. The intervention
required is rapid diagnosis and treatment.