BAB 29 ■ MENINGITIS TUBERKULUS
DOROTHEE HEEMSKERK, JEREMY FARRAR, DAN MAXINE CAWS
Ya, saya telah mengetahui peradangan, imposthumes, whelks, tumor scirrhus yang
tumbuh ke Meninges, dengan Tengkorak, dan Penyakit lain dari konformasi yang jahat,
bergairah di dalam Membran Otak; dimana pada awalnya untuk waktu yang lama, sering
sakit kepala, dan paling kejam, dan kemudian setelah itu gangguan mengantuk dan
mematikan telah terjadi; Penyebab Penyakit tidak terdeteksi, tetapi setelah Kematian oleh
Anatomi; dan memang patut dicurigai bahwa rasa sakit yang tak tertandingi dan gigih di
Kepala, yang kembali, dan setiap hari menjadi lebih menyiksa, dalam spekulasi semua
Perbaikan bergantung pada Penyebab yang tak terkalahkan tersebut.
– Thomas Willis (1621 – 1675), from “De Anima Brutorum” (1672) ( 1)
HISTORY
Tuberculosis
Tuberculosis (TB) has been a part of everyday human life since ancient
times. There is evidence of TB in man dating back to 4000 bc, but the
disease may have been present even earlier. Before the discovery of the
causative agent ( Mycobacterium tuberculosis), TB, in its many forms, has
had many different syndromal descriptions: phthisis, consumption, scrofula,
Pott disease, or others less well known such as yaksma ( Indian) and Chaky
Onkay ( Incan). The term “tubercle” was first used by Franciscus de la Boe,
also known as Sylvius of Leyden (1614–1672). He stated that tubercles
were often seen in the lungs of consumptives (2). He was also accredited
with dis- covering a cleft in the brain consequently named the sylvian fissure,
which we now know to be a preferential site for exudates formed in
tuberculous meningitis (TBM).
Asal Mula Tuberculous Meningitis
Deskripsi awal TB intrakranial berasal dari abad ketujuh belas. Dokter sering
menggunakan istilah "hidrosefalus akut" atau "penyakit gembur-gembur otak"
untuk suatu kondisi pada anak-anak yang etiologinya tidak diketahui tetapi
muncul dengan demam, sakit kepala, muntah, dan kematian yang cepat.
Beberapa uraian sejarah dengan jelas menggambarkan keputusasaan baik
pasien maupun dokter; beberapa deskripsi patologis sangat tepat dan sangat
pola dasar.
Nec minus a phlegmone et abcessu quam hujasmodi meningitis et tuberculis,
cephalgiae lethales et incurabiles oriuntur ( Sometimes the headaches, fatal and
incurable, follow abscesses and swellings of the envelopes of the brain, as well as
placques and tubercles of these membranes). ( Willis, 1672 [ 1])
Willis was far ahead of his time as it was not until 150 years later that the
tubercles found upon autopsy were regarded as a distinguishing aspect of the
clinical syndrome, which was only then proposed to be tubercular meningitis.
Attempts were made to define this disease entity based on clinical and
autopsy findings, but due to the multiform presentation both clinically and
pathologically, consensus was not reached until Robert Whytt (1714 to 1766)
lifted the disease out of obscurity with his treatise “Observations on the
dropsy in the brain.” He gives a detailed account of 20 patients, dividing
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penyakit dalam empat tahap yang berbeda, menurut denyut nadi pasien. Ia
menekankan bahwa terminologi “Dropsy atas otak" (
- [hidrosefalus] [di]
[the brain] as described by Hippocrates [460 to 377 bc] in his
De Morbis Popularibus) is in these cases incorrect, because the accumulated
fluid is not found between the skull and the dura mater but most frequently in
the ventricles. The antediluvian technique proposed by Hippocrates to make a
perforation in the upper part of the cranium to evacuate the fluidWhytt
concluded was of no use (3). This publication gave an impetus to scientists to
study this condition systematically and many contributions followed with
different views on the origin of the disease. Some considered the arachnoid
the seat of the pest, others lesions in the brain parenchyma, the ventricles,
until finally Penn in 1825, who thought the origin was in the pia mater, called it
meningitis ( 1). The term tubercular meningitis was first used in 1836 by P.H.
Green in the Lancet. Green introduced the term tu- bercular meningitis to
describe the condition of the cerebral membranes, which were affected by tubercular
lesions in nine tenths of the cases in a series of 45 children, who at the same
time had tubercular deposits in the lungs or the abdomen. Green argued that
these findings were a more essential characteristic of the disease than the
accumulation of cerebro- spinal fluid (CSF) (4,5). The condition was uniformly
lethal.
Elucidating Pathogenesis
Pada akhir abad kesembilan belas, upaya dilakukan untuk meredakan
gejala dari peningkatan tekanan intrakranial dan hidrosefalus. Walter Wynter
(1860 hingga 1945) telah menemukan teknik kasar untuk menusuk ruang
subarachnoid lumbal. Dia secara berturut-turut melakukan bentuk pungsi
lumbal kuno ini pada empat pasien dengan TBM untuk meredakan gejala
tetapi dengan perbaikan jangka pendek (pelebaran pupil dan perbaikan
sensorium sementara), tetapi keempat pasien meninggal (6,7). Morton
(1891) menjelaskan temuan klinis dari serangkaian pasien selama sakit dan
temuan patologis di otak postmortem untuk lebih mengeksplorasi apakah
akan ada alasan untuk prosedur Wynter. Meskipun gagal untuk secara jelas
mengaitkan luasnya hidrosefalus dengan gambaran klinis yang diamati, dia
menyimpulkan:
The operation does no harm, and as the patient is already comatose no
anaesthetic is required. But in any efforts we may make to remove the more
serious symptoms of tuberculous meningitis by draining the intraventricular fluid
we must remember it is nearly always only part of general tuberculosis, which
may, and prob- ably will, prove fatal in other ways, though if in this rapidly fatal
meningitis we can prolong life it may be some time longer before the general
tuberculosis does its deadly work. (8)
Tuberculous meningitis remained universally fatal.
It was not Wynter but Heinrich Quincke who began to popularize the lumbar
puncture for both therapeutic and diagnostic purposes in the late nineteenth and
early twentieth century. With the discovery of M. tuberculosis oleh Robert Koch
pada tahun 1892 dan pengembangan sinar-x oleh Wilhelm Roentgen pada tahun
1895, diagnosis sebelum kematian sekarang dapat dicapai, meskipun pengobatan
yang efektif tetap sulit dipahami.
Penyakit ini masih dianggap berkembang dengan cara yang mirip dengan
meningitis lain sampai otopsi serial yang cermat.
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study of 82 patients by Rich and McCordock (9) in 1933 provided the basis
of what still now is considered to be the establishment of pathogenesis. In
guinea pigs and rabbits, Rich and McCordock (9) could only provoke
inflammation of the meninges by the direct inoculation of bacilli into the
central nervous system (CNS) and not by peripheral injec- tion and
consequent hematogenous spread. In human autopsy studies, they
described that the tubercles found in the brain were seldom of the same
age as those found in other organs and that vasculitis found in the brain
was rather a process originating from the adventitia inward, more likely to
be the result of a focus within the brain rather than caused by di- rect
hematogenous spread of bacilli. These findings led them to form a coherent
hypothesis in which they postulated that, after inhalation of the pathogen, a
short-lived bacteremia fol- lowed, during which bacilli spread throughout the
body and seeded the surface of the brain, forming small granulomas known
as Rich foci. These can exist without causing symp- toms for an unknown
period but may rupture; upon release of the mycobacteria, meninges
become inflamed, giving rise to a multitude of possible pathologic
tuberculous conditions in the CNS (9).
Pengembangan Perawatan
Penemuan patogen penyebab disambut dengan euforia, karena harapan
baru muncul untuk kesembuhan. Pengobatan eksperimental dicoba dengan
tuberkulin, awalnya ekstrak gliserin M. tuberculosis developed by Koch, but
with catastrophic results. Other therapies raised hopes but proved
ineffective, including sanocrysin (gold therapy) (10). In 1944, the first
effective antituberculous agent, streptomycin, was dis- covered by Salman
Waksman, a discovery for which he would win the Nobel Prize for Medicine
in 1950. By 1948, dozens of cases of successfully treated TBM with
intrathecal and intra- muscular streptomycin were reported in the literature.
Rich and Samuels (11) reviewed these cases while giving a striking account
of a case involving a 2-year-old boy who at the height of his disease was in
a vegetative state but within 6 months recovered with residual weakness of
his left arm and minor mental impairment. Many publications followed on
successful streptomycin treatment. However, by 1950, numerous strepto-
mycin resistance reports appeared (12–17). Paraaminosalicylic acid (PAS)
was added to the regimen; although a weak antitu- berculous agent, it
prevented development of resistance. With the introduction of isoniazid
(1952), a major improvement in treatment of all forms of TB was seen. It
became clear that intrathecal administration was no longer necessary. With
the introduction of pyrazinamide (1954) and rifampicin (1963), treatment
regimens for all presentations of drug-susceptible TB could be shortened to
6 to 8 months. The relative con- tributions of the first-line TB drugs to the
efficacy of TBM treatment were comprehensively reviewed by Donald in
2010 (18). Fifty years on these drugs isoniazid, pyrazinamide, rifam- picin,
and streptomycin remain the mainstay of treatment for the vast majority of
patients with TB globally. It is difficult to think of another common infectious
disease whose treatment regimen has remained largely unchanged for over
50 years.
Pengembangan Vaksin
Despite failing to find a cure, Koch continued experimenting with tuberculin
hoping to develop an effective vaccine; how- ever, it proved not to be
effective. Clemens van Pirquet (1874 to 1929), after observing a
hypersensitivity reaction to a sec- ond inoculation with smallpox vaccine,
was led to the idea that Koch’s tuberculin might cause a similar reaction in
patients previously exposed to mycobacteria. Charles Mantoux (1877
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Bab 29: Meningitis Tuberkulosis 475
to 1947) expanded on these ideas and developed the Mantoux diagnostic test
in 1907, which is still in use today. During 1902 to 1920, Albert Calmette and
his assistant Camille Guérin de- veloped a vaccine by serial passage of Mycobacterium
bovis
(which can cause TB in both cattle and humans). After 13 years and 230
passages, the bacille Calmette-Guérin (BCG) strain was considered
attenuated and was first used as a vaccine in humans in 1921 (2).
Prestasi di paruh pertama abad ke-20 dalam diagnosis, pengobatan, dan
pemahaman tentang patogenesis tampaknya menawarkan peluang
pemberantasan. Namun, 60 tahun berikutnya penuh dengan kemunduran dan
TB tetap menjadi masalah kesehatan masyarakat global yang sangat besar.
Kasus AIDS pertama kali terungkap pada awal 1980-an. Sejak saat itu, menjadi
jelas bahwa interaksi TB dan HIV berdampak parah pada kedua pandemi,
sekaligus mempersulit pengelolaan kedua penyakit tersebut. Orang yang
terinfeksi HIV lebih rentan terhadap penyakit TB aktif dan semua bentuk TB di
luar paru. Oleh karena itu, epidemi HIV telah menghasilkan peningkatan yang
signifikan dalam jumlah orang dewasa yang mengalami TBM di daerah
prevalensi HIV yang tinggi. Strain yang resistan terhadap obat M. tuberculosis
prevalensi terus meningkat, termasuk TB yang resistan terhadap beberapa
obat (MDR) dan yang resistan terhadap obat secara luas (XDR), yang
sekarang ada di setiap wilayah di dunia. Kemajuan besar telah dibuat dalam
mengungkap imunologi, dan genetika telah memperdalam pemahaman kita
tentang penyakit yang mendasari imunopatologi; Namun, vaksinasi, diagnosis,
dan pengobatan masih bergantung pada teknik kuno, yang tidak memadai
untuk mengendalikan pandemi lanjutan.
OBAT PENYAKIT
Epidemiologi Tuberkulosis
Pada abad kesembilan belas, TB sangat lazim di Eropa, dengan kejadian
tahunan diperkirakan lebih dari 1.000 per 100.000. Kematian tinggi karena
pasien hanya diobati dengan tirah baring atau terapi yang tidak efektif dan
diperkirakan lebih dari 50% penderita meninggal. Pada masa Robert Koch,
satu dari tujuh orang Jerman meninggal karena TB. Pada akhir abad ke-19
dan awal abad ke-20, insiden menurun di negara yang lebih maju karena
perkembangan ekonomi, kondisi hidup yang lebih baik, kebersihan, dan
pengenalan sanatorium di mana pasien diisolasi dari populasi umum.
Setelah pengenalan pengobatan antimikobakteri, penurunan insidensi dan
mortalitas dipercepat. Tanggapan awal sangat gembira, dan harapan untuk
memadamkan epidemi yang membara ini tinggi.
Despite the initial achievements during the twentieth cen- tury, global TB
burden remains enormous.Worldwide, approx- imately 2.4 billion people are
infected with M. tuberculosis, of whom 10% will develop active disease
during their lifetime. People infected with HIV with latent TB are 20 to 30
times as likely to develop active forms of TB (19).
A systematic analysis for the global burden of disease study in 2010
including mortality data from 187 countries from 1980 to 2010 ranked TB as
the 10th leading cause of death globally. Of the 52.8 million deaths of all
causes globally in
2010, 1,2 juta disebabkan TB (20). Menurut Organisasi Kesehatan Dunia
(WHO), 8,7 juta kasus baru dilaporkan pada 2011 dan diperkirakan 1,4 juta
meninggal (21). Tujuan Pembangunan Milenium bertujuan untuk mencapai
penurunan 50% dalam prevalensi dan tingkat kematian TB dibandingkan
dengan tingkat tahun 1990 pada tahun 2015. Menurut WHO, dari tahun 1990
hingga 2011, penurunan angka kematian sebesar 41% diamati. Menurut
WHO, jika tren saat ini dipertahankan, maka
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 476 Part III: Bacterial and Mycoplasmal Infections
target yang ditetapkan untuk 2015 akan terpenuhi (21). Namun, hal ini
bergantung pada kesinambungan komitmen program TB nasional dan
pembuat kebijakan. Epidemi TB sangat majemuk, dengan 22 negara
berkembang membawa lebih dari 80% beban TB. Faktor demografi seperti
kemiskinan, kepadatan penduduk, dan malnutrisi memegang peranan
penting, begitu pula ketersediaan obat TB yang berkualitas baik. Dampak
pandemi HIV diilustrasikan dengan meningkatnya kontribusi HIV / TB dalam
menyebabkan pola kematian di kalangan remaja pria dan wanita; pada
tahun 2010, gabungan HIV / TB dan cedera menyebabkan lebih dari
setengah kematian di antara pria berusia 20 hingga 39 tahun (20). Bersama
dengan HIV, TB MDR dan XDR terus memicu pandemi (21).
Beban Tuberkulosis Sentral
Sistem saraf
The burden of extrapulmonary TB is tightly associated with the general
pandemic and accounts for more than 10% of all TB cases (21). Of these,
about 5% are forms of TB in the CNS. These estimates are crude because
diagnosis of extrapulmonary TB in general and CNS TB in particular is
challenging, and according to WHO definitions, a patient who has both signs
of pulmonary and extrapulmonary TB should be classified as having
pulmonary TB (21).
In endemic settings, TB is often the leading cause of child- hood
bacterial meningitis (22). In 2009, 7% of all annual cases of bacterial
meningitis and septicemia in the United Kingdom were caused by TB, being
the third leading cause after meningococcal and pneumococcal disease
(23). With the introduction of meningococcal C (1999) and pneumococ- cal
(2006) vaccines in the routine immunization schedule in the United
Kingdom (and in the absence of an effective TB vaccine), TBM may well
become the lead cause.
Di negara-negara dengan beban TB tinggi, anak-anak usia 0 sampai 4 tahun
paling banyak terpengaruh, namun jarang, di bawah usia 3 bulan (24). Rentang usia
5 sampai 15 tahun sering disebut sebagai “usia yang disukai” karena populasi ini
memiliki angka TB terendah dari semua bentuk (25). Di negara dengan prevalensi
TB yang rendah, kasus TBM paling banyak terjadi pada orang dewasa. Faktor risiko
yang sering dilaporkan adalah alkoholisme, diabetes, penggunaan kortikosteroid
baru-baru ini, keganasan, dan imunosupresi (26). Munculnya HIV telah secara
dramatis mengubah dinamika pandemi TB.
Mortalitas dan Morbiditas
Kematian di antara kasus TBM tetap tinggi dan bervariasi tergantung pada usia,
kelompok risiko (HIV), stadium penyakit setelah diagnosis, kepekaan obat dari
organisme yang menginfeksi, waktu antara timbulnya gejala dan permulaan
antibiotik yang efektif, dan kecanggihan pengobatan. infrastruktur dan fasilitas
perawatan kesehatan. Kematian pada anak-anak berkisar antara 10% dan 20%
(24,25,27,28). Gejala sisa neurologis sering terjadi dan dilaporkan pada lebih dari
separuh anak yang masih hidup. Dalam survei retrospektif dari 554 anak di Afrika
Selatan, 74% pasien menderita cacat jangka panjang atau kematian (13%),
termasuk gangguan pendengaran atau penglihatan (masing-masing 14% dan
16%), cacat motorik (44%), dan gangguan kognitif (77%) (29).
Untuk pasien dewasa tidak terinfeksi HIV yang datang lebih awal
(penyakit stadium I), mortalitas kira-kira 20% (30). Kematian meningkat
dengan presentasi tertunda dan penyakit stadium lanjut (Tabel 29.1). Untuk
pasien di tahap II, mortalitas sekitar 30% dan di tahap III, 55%. Seperti pada
anak-anak, dalam
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TABEL 29. 1
TUBERCULOUS MENINGITIS SEVERITY GRADING MENURUT
DEWAN PENELITIAN TOMEDIS 1948
Dini Pasien dengan gejala nonspesifik, dengan
sedikit atau tidak ada tanda klinis meningitis, tanpa paresis,
dalam kondisi umum yang baik, dan sadar sepenuhnya.
Diagnosis ditegakkan terutama pada temuan cairan
serebrospinal (CSF).
Maju Pasien jelas sangat sakit parah
koma, atau dengan pareses kotor
Medium Pasien dalam kondisi antara yang pertama
dua kelompok
Dari Medical Research Council. Pengobatan streptomisin untuk meningitis tuberkulosis. Lanset.
1948; 1: 582–596.
adults, permanent neurologic disability affects over half of the survivors
(30). Co-infection with HIV has a major impact on mortality. In Vietnam,
mortality for the corresponding grade groups in a trial of immediate versus
delayed antiretroviral therapy (ART) for HIV-associated adult TBM was
stage I, 40%; stage II, 52%; and stage III, 75% (31). In HIV-infected children
in India, 6-month mortality has also been reported to be drastically higher
than in HIV-negative children (36% vs. 10%) (32). These mortality figures
are a reflection of the severe immunosuppression in these HIV-infected
patients, illustrating the importance of commitment of policymakers to invest
in accessible integrated TB/HIV care.
Pengaruh HIV
Epidemi HIV tidak diragukan lagi telah memicu epidemi TB. Di seluruh
dunia, diperkirakan 34 juta orang terinfeksi HIV (33). Diperkirakan sepertiga
dari pasien ini dianggap koinfeksi M. tuberculosis. HIV-infected patients with
latent TB have a 50% lifetime risk of progressing to active forms of TB
versus HIV-negative patients with latent TB who have a 10% lifetime risk of
developing disease (34). HIV pa- tients are more likely to develop
extrapulmonary forms of TB, including TBM, and have a higher mortality.
Diagnosis of TB can be more challenging in HIV patients due to a less
specific presentation, wider differential diagnosis, and lower sensitiv- ity of
sputum smear microscopy. However, in contrast, CSF smear is more likely
to be positive in HIV-infected individuals with TBMdue to higher bacillary
loads (35). Patients with low CD4 levels and smear-negative results may
have atypical CSF findings, immunologic tests are not reliable, and
neuroimag- ing may not reveal typical lesions and includes a wider differ-
ential diagnosis (36). Polypharmacy may prove problematic, with higher
toxicity from combined ART and antitubercu- lous regimens and drug
interactions. ART-naive patients who commence ART treatment during their
treatment of TBMmay present with immune reconstitution inflammatory
syndrome (IRIS), which may be particularly detrimental if it presents
intracranially (37).
Resistensi Obat
WHO memperkirakan 20% dari M. tuberkulosis infeksi di seluruh dunia sekarang
resisten terhadap setidaknya satu obat lini pertama (38). MDR TBM resisten terhadap
setidaknya rifampisin dan isoniazid, dua obat lini pertama yang paling efektif. TBM
MDR telah dikaitkan dengan mortalitas yang sangat tinggi pada anak-anak dan orang
dewasa (39-41). Resistensi obat pada TBM jarang didiagnosis pada waktunya
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appropriate treatment adjustments. The difficulties of access to rapid TB
drug susceptibility testing (DST) in much of the world are compounded by
the rarity of a positive isolation of M. tuberculosis from the CSF. Drug
resistance prevalence among TBM cases will generally follow similar
patterns to those observed regionally for pulmonary TB.
Isoniazid resistance in the absence of concomitant rifam- picin resistance is
more prevalent than MDR TB; 7% of M. tuberculosis strain secara global sekarang
resisten terhadap isoniazid (38). Karena isoniazid adalah obat yang paling efektif
dalam menurunkan jumlah bakteri dalam dua hari pertama pengobatan anti-TB,
pengenalan dini terhadap resistansi sangat penting, terutama pada kasus TB di
mana pembunuhan cepat terhadap basil mungkin penting. Di Vietnam, resistansi
isoniazid sendiri atau dikombinasikan dengan resistansi terhadap obat lain
ditemukan pada sepertiga sampel kultur-positif pada pasien HIV dewasa dengan
TBM, dengan 4,3% MDR TBM (40). Dalam kohort dengan sebagian besar pasien
HIV-negatif, resistansi isoniazid ditemukan pada 37,1% sampel di mana 21%
adalah MDR (tingkat MDR keseluruhan adalah 5,6%) (39). Kematian akibat TBM
MDR adalah 100% jika tidak tersedia terapi lini kedua. Pada anak-anak dengan
diagnosis TBM yang terbukti kultur, TB MDR atau monoresistensi rifampisin
diidentifikasi pada 5% kasus di Afrika Selatan. Resistensi multidrug, tidak
mengherankan, dikaitkan dengan mortalitas yang sangat tinggi (83%) (42).
Resistensi isoniazid tanpa resistensi rifampisin juga memiliki dampak yang signifikan
terhadap mortalitas. Analisis awal dari kohort pasien TBM di Vietnam gagal menemukan
dampak yang signifikan dari resistansi isoniazid (/ resistansi streptomisin) pada kematian
(43), tetapi penelitian yang lebih besar pada pasien HIV-positif Vietnam menunjukkan
penurunan yang signifikan dalam kelangsungan hidup ( rasio hazard yang disesuaikan
[HR], 1,78; interval kepercayaan 95% [CI], 1,18 hingga
2.66) di antara pasien yang terinfeksi dengan strain yang resisten terhadap isoniazid, yang
rentan terhadap rifampicin dibandingkan dengan mereka yang memiliki isolat yang sangat
rentan (40). Dalam studi kohort retrospektif di Amerika Serikat, peneliti juga menemukan
peningkatan yang signifikan dalam risiko kematian terkait dengan resistensi isoniazid (rasio
odds [OR],
1,61; 95% CI, 1,08 hingga 2,40) (44). Di antara pasien dewasa HIV-positif Vietnam,
rasio hazard yang disesuaikan untuk mortalitas pasien TBM MDR dibandingkan
dengan pasien dengan isolat yang rentan terhadap semua agen atau streptomisin
monoresisten adalah 5,21 (95% CI, 2,38-11,42) (Gbr. 29.1).
Long-Term Disability
Very little is known about long-term outcome and disability for both children
and adults. Antituberculous chemotherapy has been unsuccessful in
completely preventing long-term sequelae; in many cases, diagnosis may
be too late, but in others, significant neurologic damage occurs subsequent
to initiation of treatment. Especially in children, neurocogni- tive impairment
can jeopardize development, education, and quality of life and place a great
burden on families, schooling, and medical systems. A recent long-term
follow-up study on a South African cohort of pediatric TBM patients who
were severely ill on presentation (stage II or III) reported only 20% of
children to be functionally normal at follow-up (median 6 years after TBM
treatment completion). The main areas of functional deficit were cognitive
impairment (80%), poor scholastic progress (43%), and emotional
disturbance (40%). A smaller proportion of children (25%) had evidence of
motor impairment (45). In a Danish nationwide, population- based cohort
study with up to 30 years follow-up, TBM was associated with an almost
twofold increased long- term risk of dying compared to a background
population (mortality risk ratio [MRR], 1.79; 95%, CI, 1.09 to 2.95). In this
study, the underlying cause of long-term death was most frequently TBM
itself rather than secondary to the most commonly reported neurologic
sequelae (46).
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Bab 29: Meningitis Tuberkulosis 477
Gejala sisa neurologis yang paling sering digambarkan pada orang dewasa adalah
gangguan kognitif, defisit motorik, kelumpuhan saraf kranial, dan atrofi optik (47). Tindak
lanjut 5 tahun pada orang dewasa Vietnam dengan TBM yang mengambil bagian dalam uji
coba terkontrol secara acak tentang efek deksametason pada kelangsungan hidup hanya
dapat menunjukkan manfaat deksametason secara keseluruhan hingga 2 tahun setelah
pengobatan. Lima tahun setelah pengobatan selesai, tidak ada perbedaan dalam hasil
kelangsungan hidup atau kecacatan secara keseluruhan pada kedua kelompok. Pada
kelompok yang menerima deksametason, 48,4% (vs.
52.7% in placebo group) of patients had died at 5 years (31% at 9 months),
6.8% (vs. 7.4% in the placebo group) were se- verely disabled, 17.2% (vs.
14.8% in placebo group) had inter- mediate disability, and only 27.6% (vs.
25.1% in the placebo group) had good outcome (48). However, the beneficial
effect of dexamethasone was preserved at 5 years for patients with stage I
TBM at presentation, demonstrating that, contrary to preceding medical
wisdom, patients with stage I TBM are the group who gain the greatest
benefit from corticosteroids.
Vaccination with Bacilli Calmette-Guerin and Protection
Against Tuberculous Meningitis
Kontroversi seputar perlindungan yang diberikan oleh vaksinasi BCG pada TB
paru dan meningeal dewasa masih ada. Pada orang dewasa, khasiat yang
dilaporkan terhadap semua bentuk berkisar dari 80% sampai 0%. Diusulkan
bahwa vaksin membangun kekebalan dengan menginduksi sel T memori efektor di
paru-paru yang secara bertahap berkurang setelah 10 sampai 15 tahun daripada
membangun "memori pusat" yang lebih tahan lama (49). Berbagai teori telah
dikemukakan untuk perbedaan yang diamati dalam khasiat, termasuk perbedaan
yang beredar M. tuberculosis strain, strain vaksin BCG, atau pajanan pra-imunisasi
terhadap mikokakteri lingkungan. Meskipun demikian, konsensus tentang manfaat
pencegahan bentuk berat TB pada masa kanak-kanak termasuk TBM dan TB
milier ditetapkan. Vaksin ini dianggap 52% sampai 86% protektif terhadap
pengembangan komplikasi berat TB pada masa kanak-kanak seperti TB milier dan
TBM (50). Diperkirakan 100,5 juta vaksinasi BCG yang diberikan kepada bayi pada
tahun 2002 dapat mencegah 29.729 kasus TBM pada anak selama 5 tahun
pertama kehidupannya, atau 1 kasus untuk setiap 3.435 vaksinasi, dan 11.486
kasus TB milier, atau 1 kasus. untuk setiap 9.314 vaksinasi. Berdasarkan data ini,
intervensi ini dianggap sebagai intervensi yang hemat biaya di Asia Tenggara,
Afrika, dan Pasifik Barat, di mana tingkat infeksi TB dan cakupan vaksin tertinggi
(50). Pada anak-anak yang divaksinasi BCG di India yang mengembangkan TBM,
spektrum klinis penyakit tampaknya tidak membaik (51). BCG adalah vaksinasi
yang paling banyak digunakan secara global.
IMUNOPATOGENESIS
Mycobacterium tuberculosis
Penularan TB terjadi ketika seseorang menghirup droplet nuklei yang mengandung
mikobakteri. Satu dari lima basil cukup untuk menyebabkan infeksi. M. tuberculosis merupakan
agen penyebab hampir semua kasus TBM. M. tuberculosis adalah bakteri aerob
obligat intraseluler. Di permukaan sel, ia memiliki lapisan lilin. Kandungan lemak yang
tinggi pada dinding sel membuat basil ini tidak terlihat oleh pewarnaan Gram.
Organisme ini tumbuh lambat dengan waktu generasi 15 sampai 20 jam, berbeda
dengan beberapa organisme lainnya
bakteri piogenik, seperti Streptococcus pneumoniae, Neisseria meningitides, dan Staphylococcus
aureus, dengan waktu generasi
kurang dari satu jam. Struktur antigenik kompleks dari dinding sel meliputi
polisakarida, protein, peptida, lipid, dan glikolipid dengan sifat imunologi
yang spesifik. Lain
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 478 Bagian III: Infeksi Bakteri dan Mikoplasma

SEBUAH Bertahan hidup oleh kelompok perlawanan B Bertahan hidup menurut kategori perlawanan

1.00 1.00

0.75 0.75

Sensitif / SM tahan-tunggal
Sangat sensitif
0,50 0,50

SM tahan mono
Resistensi INH +/- SM
INH tahan mono
0.25 0.25

MDR Tahan INH + SM MDR

0,00 0,00
0 3 6 9 0 3 6 9
Survival Probability

Survival Probability
Bulan Sejak Pengacakan Bulan Sejak Pengacakan
Tidak beresiko Tidak beresiko

Sangat sensitif 98 52 41 35 Peka 126 66 53 47

STR mono-tahan 28 14 12 12 Resistensi INH +/- STR 52 25 11 8
INH mono-resistant 12 6 2 2 MDR 8 0 0 0
Tahan INH + STR 40 19 9 6
MDR 8 0 0 0

C Bertahan hidup berdasarkan garis keturunan D Kelangsungan hidup menurut garis keturunan penderita sangat
rentan terinfeksi M. tuberculosis strain saja

1.00 1.00

0.75 0.75

Asia Timur / Beijing

0,50 Asia Timur / Beijing 0,50

Euro-Amerika Euro-Amerika
0.25 0.25
Indo-Oceanic
Indo-Oceanic

0,00 0,00
0 3 6 9 0 3 6 9
Survival Probability

Survival Probability

Bulan Sejak Pengacakan Bulan Sejak Pengacakan

Tidak beresiko Tidak beresiko

Indo-Oceanic 18 5 3 3 Indo-Oceanic 14 3 2 2
Euro-Amerika 22 10 6 5 Euro-Amerika 14 7 6 5
Beijing 82 43 30 26 Beijing 55 33 26 23

GAMBAR 29.1 Bertahan hidup berdasarkan pola patogen yang resistan terhadap obat dari kohort HIV-positif. SM, streptomisin;
INH, isoniazid; MDR, tahan multidrug. (Tho DQ, Török ME, Yen NT. Pengaruh resistensi obat antituberkulosis dan Mycobacterium
tuberculosis garis keturunan pada hasil pada meningitis tuberkulosis terkait HIV. Agen Antimikroba Chemother. 2012; 56 [6]:
3074–3079.)

antigen terkandung di dalam sitoplasma. Molekul-molekul ini menentukan
respons imun yang khas terhadap infeksi tuberkulosis dan patologi yang
dihasilkannya.
Makrofag dan Formasi Granuloma
Pada TB paru, makrofag alveolar memiliki peran sentral dalam respon imun
bawaan awal M. tuberculosis serta dalam memulai kekebalan sel-T adaptif.
Jika setelah pengenalan dan konsumsi bakteri, makrofag gagal
membasmi M. tuberculosis, Sel T direkrut ke tempat infeksi dan
menghasilkan peradangan kronis dan pembentukan granuloma untuk
menahan infeksi (52). Granuloma sangat penting untuk penyakit
tuberkulosis dan ditandai dengan pembentukan nekrosis sentral lesi, sering
disebut sebagai
kasus. Pada nekrosis padat, pertumbuhan mikobakteri terhambat, dan
infeksi dapat diatasi dan tetap tidak aktif. Granuloma dengan nekrosis sentral
yang berliku-liku menyediakan lingkungan yang optimal untuk mikobakteri
ekstraseluler dan dapat pecah, memungkinkan penyebaran basil ke bagian
lain paru-paru, aliran darah, atau lingkungan luar (53).

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 Bab 29: Meningitis Tuberkulosis 479

Timbulnya respons imun adaptif terhadap M. tuberculosis

tertunda dibandingkan dengan infeksi lain. Penundaan ini memungkinkan pertumbuhan
Central Nervous System Pathology
eksponensial dari mikobakteri sebelum diperlambat atau ditangkap oleh pertahanan inang (54).
Sayangnya, penelitian postmortem saat ini masih sedikit (64,65) tetapi akan
Untuk tanggapan kekebalan adaptif pada TB, sel T CD4 sangat penting. Sel T CD4 mengerahkan
memberikan kontribusi yang besar untuk pemahaman kita tentang penyakit ini.
efek perlindungannya dengan produksi sitokin, interferon utama- (IFN-) dan faktor nekrosis tumor-
Model kelinci dianggap meniru penyakit manusia; Namun, interpretasi
(TNF-). IFN- adalah sitokin pelindung sentral dalam infeksi mikobakteri yang diusulkan untuk
imunologis tidak sempurna. Studi murine tidak digunakan dalam mempelajari
dilindungi dengan memediasi induksi nitric oxide synthase (NOS), meningkatkan sistem mikrobisidal
neuropatogenesis secara langsung pada TBM meskipun digunakan secara luas
di dalam makrofag (55). TNF- memainkan peran kunci dalam pembentukan granuloma dan induksi
dalam memahami kerentanan dan respon protektif terhadap mikobakteri (66).
makrofag dan memiliki properti imunoregulasi (53). Sitokin lain yang terlibat dalam pengendalian
Pengetahuan kami saat ini tentang patogenesis TB SSP didasarkan pada
penyakit mikobakteri adalah interleukin (IL) -1B, IL-6, IL-12, IL-15, IL-18 (proinflamasi) dan IL-10,
hipotesis yang diumumkan lebih dari 70 tahun yang lalu. Meskipun para peneliti
IL-4, dan mengubah faktor pertumbuhan- (TGF-) (antiinflamasi) (53,56). Selain jaringan regulasi
belakangan telah menyatakan kritik (67), pandangan mereka telah dibawa oleh
yang kompleks dari sel dan mediator imun yang mengontrol respon imun bawaan dan adaptif,
para ahli terkini; singkatnya, granuloma intrakranial kecil terbentuk setelah
komponen yang berbeda mungkin dipengaruhi secara negatif oleh faktor virulensi spesifik mikroba.
pembibitan bakteri di otak selama bakteremia berumur pendek. Fokus yang kaya
Virulensi mikobakteri diperkirakan ditemukan dalam kemampuannya untuk mengatur kemotaksis
ini dapat pecah selama periode imunosupresi relatif atau rangsangan lain yang
makrofag, nekrosis, dan apoptosis, memfasilitasi lingkungan yang menguntungkan dalam makrofag
tidak diketahui, melepaskan mikobakteri di ruang subarachnoid atau ruang
atau secara ekstraseluler di granuloma dan akibatnya proliferasinya sendiri dan mungkin juga
ventrikel yang dapat menimbulkan berbagai bentuk TB SSP: meningitis,
memfasilitasi jalan keluar ke situs lain dari infeksi, termasuk SSP (57). komponen yang berbeda
tuberkuloma, abses tuberkulosis, ensefalitis, atau TB sumsum tulang belakang.
mungkin dipengaruhi secara negatif oleh faktor virulensi khusus mikroba. Virulensi mikobakteri
Memasukkan data patologis yang lebih baru, Donald dan rekan (68) telah
diperkirakan ditemukan dalam kemampuannya untuk mengatur kemotaksis makrofag, nekrosis, dan
mengusulkan klasifikasi patogenesis di TBM berikut:
apoptosis, memfasilitasi lingkungan yang menguntungkan di dalam makrofag atau secara
ekstraseluler di granuloma dan akibatnya proliferasinya sendiri dan mungkin juga memfasilitasi jalan
keluar ke situs lain dari infeksi, termasuk SSP (57). komponen yang berbeda mungkin dipengaruhi
secara negatif oleh faktor virulensi khusus mikroba. Virulensi mikobakteri diperkirakan ditemukan
dalam kemampuannya untuk mengatur kemotaksis makrofag, nekrosis, dan apoptosis, memfasilitasi 1. Penyebaran basil secara hematogen dari kompleks primer membentuk
fokus
lingkungan yang menguntungkan dalam makrofag atau secara ekstraseluler di granuloma dan akibatnya proliferasinya kortikal
sendiri ataujuga
dan mungkin meningeal.
memfasilitasiSegera setelah
jalan keluar ke situspembentukannya,
lain dari infeksi, termasuk SSP (57).
proses ini berlanjut ke caseate dan membuang isinya ke ruang
subarachnoid. Pada anak kecil, penyebaran hematogen ini sangat
Respon Kekebalan pada Meningitis Tuberkulosis
mungkin terjadi dalam bentuk TB milier.

TNF- dianggap memiliki peran penting tetapi kontroversial dalam

patogenesis TBM. TNF- adalah sitokin proinflamasi yang diproduksi oleh
monosit, makrofag, dan sel dendritik pada stimulasi dengan mikobakteri
atau produk mikobakteri dan memainkan peran penting dalam
pembentukan dan pemeliharaan granuloma (58). Sedangkan pada TB
paru, obat yang menetralkan TNF dapat menyebabkan perkembangan
penyakit (fatal), pada TBM, peningkatan produksi TNF telah diusulkan
untuk dikaitkan dengan penyakit yang lebih parah, tetapi belum ditetapkan
jika ini hanyalah penanda penyakit lanjut atau jika respons TNF yang tidak
proporsional memediasi perkembangan penyakit.
In vitro infection of microglial cells (macrophages of the brain) results in
the production of robust amounts of TNF-
, IL-6, IL-1B, CCL2, CCL5, and CXCL10 (59). In rabbits infected
intracisternally with M. bovis, oral thalidomide treatment led to reduction of
TNF- levels and clinical improvement (60). In vivo in TBM, TNF- levels
show a peak in the early phase of disease but drop soon after initiation of
treatment (61). Some researchers found an association in disease severity
and CSF levels of IFN- and TNF- in both HIV-positive and HIV-negative
patients (62). This was not supported in a Vietnamese cohort, in which the
only cytokine independently associated with severe disease was IL-6. HIV
co-infection was associated with attenuated levels of several immune
mediators in CSF, in whom low levels of IFN- did show an association with
death, implying a protective role for IFN- . Interestingly, the addition of
dexamethasone to treat- ment was not associated with an attenuation of
inflammatory indices but did lead to a decreased mortality rate (61).
2. Dalam sebagian kecil kasus, penyebaran hematogen dapat membentuk
fokus kaseosa di pleksus koroid atau di dinding ventrikel tempat TBM dapat
berkembang. Penyebaran hematogen pada saat infeksi primer, atau
3. setelahnya, menetapkan fokus kortikal atau meningeal. Ini awalnya
dikendalikan tetapi dapat, kapan saja setelah itu, mengalami kaseasi dan
membuang isinya ke dalam ruang subarachnoid. Proses caseous meluas
dari struktur yang berdekatan seperti vertebra atau telinga tengah hingga
4. melibatkan SSP (sangat jarang).
As a result of this infection, a dense gelatinous fibrinocellular
leptomeningeal exudate is formed.Microscopically, this exudate contains small
and large mononuclear cells, including epitheli- oid cells, which also act as
macrophages. The exudate typically centers around the interpeduncular fossa.
When substantial, the exudate may extend anteriorly to the suprasellar region,
and it may extend through the prepontine cistern and surround the spinal cord
and cerebellum, often into the sylvian fissures. It can envelope and compress
cranial nerves and arteries. Vasculitis may develop, giving rise to ischemic
events. Hydrocephalus can develop by blockage of CSF circulation when
exudates cover the choroid plexus and the basal subarachnoid cisterns around
the midbrain and pons or when tuberculoma cause narrowing of the aqueduct
and third ventricle (66,69). Exudate, vasculi- tis, and hydrocephalus can cause
changes in brain parenchyma. “Border-zone encephalitis” describes a tissue
reaction com- monly seen in brain tissue adjacent to zones of thick adher- ent
exudate. The brain tissue softens, showing signs of edema, perivascular
infiltration, and microglial reaction (66,70). In the following paragraphs, we will
briefly discuss other forms of CNS TB; the rest of the chapter will focus on
TBM.

The brain provides a unique immunologic environment to pathogens. We
know most of the inflammatory mediators are produced locally at the site of
infection. Immunologic studies usually involve cells from peripheral blood or
CSF. Compared to the infected tissue, even in pulmonary TB, lowproportions
of M. tuberculosis –specific effector cells are found in the blood (63).
Tuberculoma in the Central Nervous System
CNS tuberculoma can be encountered separate from TBM, as it is estimated
only 10% of patients with tuberculoma develop meningitis (71,72).
Conversely, in some radiologic studies, tuberculomas were observed either at
presentation or developed

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 480 Part III: Bacterial and Mycoplasmal Infections
selama pengobatan di lebih dari 60% pasien dengan TBM (73). Di daerah
endemik, tuberkuloma merupakan penyebab hingga 30% pasien dengan massa
intrakranial. Tuberkuloma bisa soliter atau multipel, dengan beberapa
melaporkan ratusan lesi pada satu pasien, dijuluki "tuberculomatosis cerebri"
(71). Secara umum, tuberkuloma dalam konteks TBM, meskipun tergantung
pada lokasinya, tidak terkait dengan hasil yang lebih buruk dan akan sembuh
dengan pengobatan antituberkulosis (74). Jarang, tuberkuloma menyatu dan
mencair menyebabkan abses serebral tuberkulosis, yang mungkin memerlukan
pembedahan (75).
Tuberculous Encephalopathy
Tuberculous encephalopathy (TBE) was first described in 1966 in Indian
children who presented with symptoms of a diffuse cerebral involvement
(coma, convulsions, movement disorders) in the context of disseminated TB
but normal cerebrospinal find- ings (76). As there was no clear evidence of TB
infection within the brain, the authors proposed an alternative pathogenetic im-
mune-/hypersensitivity-mediated explanation for this syndrome, pathologically
characterized by white matter, myelin loss with commensurate axonal loss, and
focal necrosis. The principal pathogenetic factor in the groupof caseswas said
tobe an allergic cerebral edema leading to an edematous leukoencephalopathy
similar to acute disseminated encephalomyelitis (ADEM) (77). However, use of
steroids for these patients had proven ineffec- tive. Careful review of the
original publication and the literature of the following 40 years led South African
experts to reappraise this entity in 2007, concluding that the patient population
joined under the umbrella of TBE was clinically and histopathologi- cally
heterogenous. According to the authors, other plausible factors may have
caused the typical findings of TBE, including hypoxic ischemia and toxic or
drug-related complications of TB infection (78). TBE has not been reported in
adults.
Tuberculosis of the Spinal Cord
Tuberculous radiculomyelitis ( TBRM) has been used as a generic
term to include arachnoiditis, intramedullary tuberculoma, and spinal cord
complications of TBM (79). Currently, it is thought that TBRMmay develop in
alternative ways, either (1) as a pri- mary lesion, (2) as an extension from
TBM, or (3) secondary to vertebral TB (80). Intramedullary tuberculomas are
rare. The pathogenesis is parallel to CNS TB: via bloodborne seeding of
bacilli, granuloma formation follows, drainage persists into the subarachnoid
space which may lead to an inflammatory reac- tion in the pia-arachnoid,
which may lead to secondary men- ingitis (81). Clinical presentation may vary,
usually presenting with symptoms of a subacute intramedullary
space-occupying lesion (82). Early recognition of this form of CNS
tuberculoma is important because early surgical intervention and decom-
pression followed by long-term antituberculous chemotherapy may
significantly improve morbidity. Accurate diagnosis can be helped by magnetic
resonance imaging (MRI) (83).
Vascular Events
Secondary to the infection with M. tuberculosis and resultant intracerebral
immunologic response, stroke may develop. In the late nineteenth and early
twentieth century, vascular involvement in TBM was recognized and extensively
studied. Still the vas- cular events in TBM are a pressing subject in TBM
research, because the damage caused by stroke is often irreversible and the
occurrence of stroke is associated with worse outcome (84,85).
Scchhe
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Stroke was reported in 13% to 57% of Indian patients with TBM (85). In Vietnam, serial MRI
revealed stroke in only 9% of patients upon diagnosis, but after 60 days of treatment, 41% of patients
had developed stroke (73). This may be even more prevalent in children, with infarcts reported in
76% of systematically scanned children in South Africa (86). Most in- farcts occur in the region of the arteria
cerebri media ( arteri serebral tengah [MCA]), terutama di pembuluh darah lentikulostrik medial dan
thalamoperforating, menyebabkan infark ganglia basalis yang khas (84). Keterlibatan vaskular ini
diperkirakan mengikuti distribusi eksudat meningeal, yang menyebabkan vaskulitis lokal, terutama di
dasar otak dan di sepanjang tulang sylvian. Mekanisme yang diusulkan dimana pembuluh tersumbat
mengakibatkan iskemia adalah berbagai bentuk. Deskripsi histopatologi yang cermat dari perubahan
vaskular di TBM diterbitkan oleh Hektoen (87) pada akhir abad kesembilan belas. Dia menyimpulkan
bahwa perubahan dapat dijelaskan oleh endarteritis dengan tuberkel subendotel, yang diduga
disebabkan oleh invasi hematogen langsung dari basil di dinding pembuluh darah, atau proliferasi
tuberkulosis mempengaruhi arteri dari adventitia ke dalam untuk mencapai media dan intima (87).
Saat ini, sebagian besar didasarkan pada temuan Rich dan McCordock (9), pandangan yang
diterima secara luas adalah bahwa peradangan menyebar dari luar (adventitia) ke dalam bukan
terbalik. Mekanisme stenosis atau kerusakan lainnya dianggap sebagai proliferasi intimal, nekrosis
dinding pembuluh darah, atau vasospasme. Peran trombosis pembuluh darah tidak jelas. Terdapat
beberapa bukti bahwa stroke pada awal perjalanan penyakit disebabkan oleh vasopasme dan
kemudian stroke melibatkan penyakit intimal proliferatif, meningkatkan kemungkinan intervensi
terapeutik untuk pencegahan stroke terkait trombotik dan vasospasme (9,84). pandangan yang
diterima secara luas adalah bahwa peradangan menyebar dari luar (adventitia) ke dalam daripada
terbalik. Mekanisme stenosis atau kerusakan lainnya dianggap sebagai proliferasi intimal, nekrosis
dinding pembuluh darah, atau vasospasme. Peran trombosis pembuluh darah tidak jelas. Ada
beberapa bukti bahwa stroke di awal perjalanan penyakit disebabkan oleh vasopasme dan kemudian
stroke melibatkan penyakit intimal proliferatif, meningkatkan kemungkinan intervensi terapeutik untuk
pencegahan stroke terkait trombotik dan vasospasme (9,84). pandangan yang diterima secara luas
adalah bahwa peradangan menyebar dari luar (adventitia) ke dalam daripada terbalik. Mekanisme
stenosis atau kerusakan lainnya dianggap sebagai proliferasi intimal, nekrosis dinding pembuluh
darah, atau vasospasme. Peran trombosis pembuluh darah tidak jelas. Ada beberapa bukti bahwa
stroke di awal perjalanan penyakit disebabkan oleh vasopasme dan kemudian stroke melibatkan
penyakit intimal proliferatif, meningkatkan kemungkinan intervensi terapeutik untuk pencegahan stroke terkait trombotik dan vasospasme (9,84).
The Role of Miliary Tuberculosis
Rich and McCordock (9) did not assign a role for miliary TB in the
pathogenesis of TBM as the Rich foci found in their subjects were often
older than the miliary lesions, and there- fore military TB was deemed to be
an incidental occurrence rather than part of the etiology. Even though this is
the view carried forward in most textbooks, some researchers claim that,
particularly in children and possibly in immunocompro- mised patients, t
the likelihood of
(Rich foci) (68)
ciation of TBM
FIGURE 29.2 Chest x-ray showing miliary TB of the lungs.
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prevalence of miliary TB of the leptomeninges is much higher than in adults. TABLE 29 . 2

Younger children most often develop both TBM and miliary TB within 3
months of primary infection. Children with concomitant miliary TB and TBM PRESENTING CLINICAL FEATURES IN ADULTS AND OLDER
are also significantly younger than those with TBM only (24). The immune CHILDREN
system of these young children and the immunocompromised may not be
robust enough to prevent an overwhelming bacteremia, exemplified by the SYMPTOM FREQUENCY/RANGE
miliary character of disease. In these indi- viduals, TBM may be the result of
Headache 50%–80%
a more direct spread of the pathogen to the meninges and subarachnoid
space. Fever 60%–95%
Vomiting 30%–60%
Photophobia 5%–10%

CLINICAL PRESENTATION Anorexia/weight loss 60%–80%

CLINICAL SIGN
General Symptoms on Presentation
Neck stiffness 40%–80%
TBM typically presents in a subacute manner. Presenting signs, symptoms,
Confusion 10%–30%
CSFfindings, and frequencies according to the British Infection Society
guidelines are shown in Table 29.2. In adults, the majority of patients present Coma 30%–60%
with fever, headache, nuchal rigidity, vomiting, meningism, abnormal mental Cranial nerve palsy 30%–50%
stage, and pho- tophobia (75,88,89). Weight loss, night sweats, lethargy, and VI 30%–40%
cough have also be reported (90). The mean duration of symp- toms is typically
III 5%–15%
more than 5 days. A longer duration of history is associated with worse
symptomatology on presentation. VII 10%–20%
Hemiparesis 10%–20%
In 1948, the British Medical Research Council first pub- lished a Paraparesis 5%–10%
classification of TBMpatients according to the severity of disease (see Table
Seizures – adults 5%
29.1). Over the years, these stage groups have been refined and are
published in different formats. In general, both adult and pediatric patients in Children 50%
stage I are fully conscious and may have nonspecific symptoms; in stage II,
patients will have signs of meningitis, lethargy, or cranial nerve palsies; in CAIRAN SEREBROSPINAL
stage III, TBM is accompanied by stupor, severe illness, gross paralysis, or TEMUAN
paresis, convulsions, and or involuntary movements (51). In clinical practice
and research, it would be more useful to have a Glasgow Coma Scale Penampilan yang jelas 80% –90%
(GCS)– guided staging system. An example is shown in Table 29.3. Tekanan pembukaan 25 cm H 2 HAI 50%
Jumlah leukosit ( 10 3 / mL) 5–1.000

Temuan khas pada pemeriksaan neurologis adalah kelumpuhan saraf serabut Neutrofil 10% –70%

VI (terjadi pada hingga 40% pasien) tetapi juga saraf III dan VII sering terlibat (5% Limfosit 30% –90%
sampai 20%). Hemiparesis dan paraparesis dapat muncul saat muncul (pada 5% Protein (g / L) 0,45–3,0
sampai 20% pasien) (75,88) tetapi juga dapat berkembang selama pengobatan
Laktat (mmol / L) 5.0–10.0
sekunder akibat infark. Kejang jarang menjadi gejala yang muncul pada orang
dewasa, namun pada anak-anak dilaporkan terjadi pada sekitar 50% pasien Glukosa CSF / Darah 0,5 95%

(28,29]. Gangguan penglihatan, penurunan penglihatan, dan diplopia mungkin

memiliki berbagai penyebab, termasuk keterlibatan primer saraf optik oleh lesi Thwaites G, Fisher M, Hemingway C, dkk. Pedoman British Infection Society untuk t

tuberkulosis menyebabkan neuritis optik, arachnoiditis optochiasmatic (OCA), dan

sistem saraf
tuberkuloma di daerah kiasmatik atau di jalur optik (91). Lebih sering, gangguan
penglihatan sekunder akibat peningkatan tekanan intrakranial atau toksisitas
etambutol. Penyebab langka kehilangan penglihatan pada TBM adalah
neuroretinitis (92). Tuberkuloma dapat menyebabkan beragam gejala neurologis
yang terkait dengan lesi yang menempati ruang tergantung pada lokasinya di TABEL 29. 3
dalam SSP. Retensi urin sering terjadi yang mungkin mengindikasikan keterlibatan
sumsum tulang belakang. Gangguan pergerakan berhubungan dengan keterlibatan MEDICAL RESEARCH COUNCIL GRADING SYSTEM FOR
ganglia basal, sebagian besar tremor, tetapi juga korea, balismus, dan mioklonus TUBERCULOUS MENINGITIS
telah dilaporkan (88).
TBM Grade Diagnostic Criteria

Grade I Glasgow coma score 15, no focal neurology Glasgow

Gejala awal TBM mungkin tidak spesifik, tetapi dalam konteks gejala yang Grade II coma score 11–14 or
berkepanjangan, riwayat TB sebelumnya, atau rontgen dada yang konsisten Glasgow coma score 15 with focal neurology Glasgow
dengan infeksi TB baru atau sebelumnya, riwayat ini harus meningkatkan
Grade III coma score 10
kecurigaan pada dokter yang merawat. Di banyak buku teks, TBM digambarkan
sebagai meningitis kronis atau subakut; Namun, terminologi ini tidak membantu.
From Heemskerk D, Day J, Chau TT, et al. Intensified treatment with high dose
Setelah pasien TBM mencari perawatan medis, ia harus diperlakukan sebagai
rifampicin and levofloxacin compared to standard treatment for adult patients with
keadaan darurat medis seperti halnya meningitis lainnya. tuberculous meningitis (TBM-IT): protocol for a randomized controlled trial. Trials. 2011;12:25.

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 482 Part III: Bacterial and Mycoplasmal Infections
Anak-anak mungkin memiliki presentasi yang lebih berlarut-larut dan tidak spesifik. Di
rangkaian endemik TB, ini sering menjadi penyebab paling umum dari bentuk meningitis bakteri
pada masa kanak-kanak (22). Gejala prodromal termasuk demam, sakit kepala, anoreksia, dan
muntah pada anak yang lebih besar, sedangkan gagal tumbuh, nafsu makan yang buruk, muntah,
dan gangguan tidur lebih sering terjadi pada anak kecil atau bayi. Batuk dan kelemahan juga dapat
dilaporkan (28,29). Karena gejala-gejala ini tidak spesifik, anak-anak cenderung datang ke rumah
sakit hanya ketika situasi klinis memburuk dan mereka sudah berada di stadium lanjut penyakit (29).
Mirip dengan orang dewasa, ketika gejala awal nonspesifik dikaitkan dengan riwayat kontak
baru-baru ini dengan kasus TB yang didokumentasikan, TBM harus dicurigai. Riwayat
berkepanjangan lebih dari 5 hari, defisit neurologis fokal, dan gerakan abnormal telah ditemukan
secara independen untuk memprediksi TBM (27). Pemeriksaan mungkin menunjukkan tanda-tanda
meningisme yang tidak spesifik, gagal tumbuh, dan pada anak-anak yang lebih kecil, fontanel
membengkak atau lingkar kepala meningkat. Funduskopi dapat menunjukkan tanda-tanda
papilledema atau keterlibatan retinal. Dalam sebuah penelitian retrospektif terhadap 554 anak Afrika
Selatan, 97% muncul pada stadium II atau III, dengan durasi rata-rata gejala 9 hari. Iritasi meningeal
adalah yang paling sering ditemukan (98%). Kejang (47%) dan mono- / para- / quadri- / hemiplegia
(63%) juga sering diamati. Kelumpuhan saraf kranial lebih jarang terjadi (27%) dibandingkan pada
orang dewasa, seperti peningkatan tekanan intrakranial (23%) (29). ubun-ubun menonjol atau
lingkar kepala bertambah. Funduskopi dapat menunjukkan tanda-tanda papilledema atau
keterlibatan retinal. Dalam sebuah penelitian retrospektif terhadap 554 anak Afrika Selatan, 97%
muncul pada stadium II atau III, dengan durasi rata-rata gejala 9 hari. Iritasi meningeal adalah yang
paling sering ditemukan (98%). Kejang (47%) dan mono- / para- / quadri- / hemiplegia (63%) juga
sering diamati. Kelumpuhan saraf kranial lebih jarang terjadi (27%) dibandingkan pada orang
dewasa, seperti peningkatan tekanan intrakranial (23%) (29). ubun-ubun menonjol atau lingkar
kepala bertambah. Funduskopi dapat menunjukkan tanda-tanda papilledema atau keterlibatan
retinal. Dalam sebuah penelitian retrospektif terhadap 554 anak Afrika Selatan, 97% muncul pada stadium II atau III, dengan durasi rata-rata gejala 9 hari. Iritasi meningeal adalah yang paling sering ditemukan (98%). Kejang (47%) dan mono- / para- / quadri- / hemiplegia (63%) ju
Munculnya HIV telah mengubah epidemiologi TB dan terutama hasil klinis penyakit. Pasien
yang terinfeksi HIV lebih mungkin mengembangkan bentuk penyakit di luar paru. TBM dianggap
sebagai kondisi terdefinisi AIDS. Studi penelitian tidak memberi kesan bahwa HIV sangat mengubah
gambaran klinis TBM, terutama pada pasien dengan jumlah CD4 yang lebih tinggi; presentasi klinis
mungkin mencerminkan apa yang terlihat pada orang HIV-negatif. Pasien dengan jumlah CD4 yang
lebih rendah mungkin memiliki perjalanan penyakit yang lebih atipikal, dengan tanda yang kurang
spesifik dan lebih halus serta diagnosis banding yang lebih luas, membuat diagnosis menjadi lebih
menantang (36). Oleh karena itu, pasien yang terinfeksi HIV dapat muncul kemudian selama
perjalanan penyakit, dengan kesadaran yang berubah, dan akibatnya lebih sering pada stadium
lanjut penyakit (35). Pasien HIV lebih mungkin mengalami gangguan kognisi, limfadenopati umum,
dan hepatosplenomegali (32). Sebuah penelitian retrospektif yang membandingkan presentasi klinis
dan hasil pada anak dengan dan tanpa infeksi HIV secara mengejutkan menemukan bahwa anak
yang tidak terinfeksi HIV lebih mungkin untuk hadir dengan tingkat kesadaran yang menurun; ini
mungkin terkait dengan respon imun yang buruk pada anak-anak dengan gangguan sistem imun.
Mirip dengan orang dewasa, anak-anak yang terinfeksi HIV memiliki riwayat penyakit yang lebih
lama, status gizi yang lebih buruk, lebih sering menyertai hepatosplenomegali, limfadenopati, dan
otorrhea (93). Terlepas dari kemiripan dalam presentasi, hasilnya secara signifikan lebih buruk untuk
orang dewasa yang terinfeksi HIV dan anak-anak dengan TBM. Sebuah penelitian retrospektif yang
membandingkan presentasi klinis dan hasil pada anak dengan dan tanpa infeksi HIV secara
mengejutkan menemukan bahwa anak yang tidak terinfeksi HIV lebih mungkin untuk hadir dengan
tingkat kesadaran yang menurun; ini mungkin terkait dengan respon imun yang buruk pada
anak-anak dengan gangguan sistem imun. Mirip dengan orang dewasa, anak-anak yang terinfeksi
HIV memiliki riwayat penyakit yang lebih lama, status gizi yang lebih buruk, lebih sering menyertai
hepatosplenomegali, limfadenopati, dan otorrhea (93). Meskipun kemiripan dalam presentasi, hasil
secara signifikan lebih buruk untuk orang dewasa yang terinfeksi HIV dan anak-anak dengan TBM.
Sebuah penelitian retrospektif yang membandingkan presentasi klinis dan hasil pada anak dengan dan tanpa infeksi HIV secara mengejutkan menemukan bahwa anak yang tidak terinfeksi HIV lebih mungkin untuk hadir dengan tingkat kesadaran yang menurun; ini mungkin terka
Progression During Treatment
Respon paradoks selama pengobatan antituberkulosis sering dilaporkan
meskipun telah dilakukan kemoterapi yang tepat dengan basil yang rentan. Ini
dapat ditemukan di semua jaringan tetapi paling sering di paru-paru, kelenjar
getah bening, dan otak (94). Di otak, tuberkuloma bisa berkembang atau
membesar selama pengobatan untuk TB paru, TBM, atau TB milier. Baik
ditemukan pada pencitraan otak rutin atau disertai dengan gejala yang
memburuk, tanda-tanda lesi yang menempati ruang, atau kejang. Ini
umumnya terjadi dalam 1 sampai 4 bulan setelah memulai pengobatan,
seringkali setelah perbaikan awal. Terapi antituberkulosis harus dilanjutkan;
penambahan kortikosteoid sistemik dapat dipertimbangkan (95). Dalam
konteks diagnosis yang baik dan konfirmasi mikrobiologis yang rentan
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patogen, respon paradoks dapat didiagnosis secara klinis; Namun,
diagnosis yang salah, resistensi obat, dan infark serebral mungkin menjadi
penyebab alternatif kerusakan meskipun pengobatan. Pengenalan dini
penyebab alternatif ini penting karena memerlukan intervensi segera.
In TBM, vascular events are most often ischemic in nature. Vascular
involvement is more frequently seen in chronic men- ingitides than in treated
acute bacterial forms of meningitis (96). Other infective causes of stroke in
tropical regions may include malaria, syphilis, Chagas disease, cysticercosis.
Events can go unnoticed, as they occur silently or in severely ill pa- tients
already in deep coma. The most common signs of TBM- associated stroke
are mono- or hemiplegia but also may present as lowered consciousness,
disorders of movement, seizures, cranial nerve palsies, papilledema, and
decerebration (84). Clearly, neurologic deterioration also can have its origin in
a tu- berculoma, cerebral edema, or infiltrating exudate (97). Unlike
hypertensive or atherothrombotic stroke, transient ischemic at- tacks (TIAs)
and lacunar lesions are rare in TBM (84). Patients may present with
symptoms of stroke but more often develop stroke later in the course of
disease, typically during the first weeks of treatment (73,84). It is not currently
possible to pre- dict which patients will develop stroke and it is associated with
higher mortality and morbidity. Initial imaging studies may not be sensitive
enough to detect the early changes of an ischemic event. Antithrombotic
therapies such as aspirin and dipyridam- ole which prevent or reduce the
incidence of stroke may im- prove outcomes in TBM and warrant further
clinical study.
DIAGNOSIS
Clinical Case Definition
Early recognition of TBM is pivotal, because prompt initiation of treatment
greatly increases chances of survival and reduces disability. However, early
symptoms are nonspecific and diagnostic confirmation has hardly improved
since the early twentieth century. Ziehl-Neelsen smear for acid-fast bacilli is
central to diagnosis because it gives rapid results; however, the reported
sensitivity is low. Sensitivity estimates depend on the criteria used for gold
standard and range widely from 10% to 60%. This wide variation is likely to
depend on many fac- tors including laboratory performance, workload,
technician diligence and experience, time from taking the sample to stain-
ing in the laboratory, and volume of CSF examined. Liquid culture of M.
tuberculosis is considered the gold standard for diagnosis, but due to the
slow growing nature of mycobacteria, the time to a positive result may range
from 2 to 8 weeks. This renders the test ineffective for clinical decision
making regard- ing treatment initiation, although a positive result can confirm
the decision to continue therapy (although a negative result should not
automatically lead to stopping) and provides an isolate for drug susceptibility
evaluations. A suggestive history must raise clinical suspicion. A clinical
diagnostic algorithm based on prospective data and validated against a
second data set is available based on clinical and laboratory features
(98,99). Different clinical algorithms are published through- out the literature;
those of most use are based on simple clinical and laboratory criteria and
can be used in resource- limited settings, where disease burden is highest.
Table 29.4 shows an example.
In order to address the heterogeneity in clinical diagno- sis among
published research studies of TBM, a consensus score-based case
definition, based on expert opinion, has been published for use in the
research context, with an alternative scoring if imaging is not available. This
case definition is not
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TABLE 29 . 4 In children, CSF modifications are similar to adults; however, smear and culture
are less sensitive.
DIAGNOSTIC CRITERIA OF TUBERCULOUS MENINGITIS In HIV-positive patients, atypical findings are encoun- tered in a
USED IN CLINICAL TRIALS considerable proportion of patients, which may lead to delay in diagnosis
and treatment. Normal levels of lactate, glucose, protein, and WCC are
Classification Diagnostic Criteria more often reported in HIV; even completely normal CSF findings can be
found particularly in patients with severe immunosuppression (CD4 count
Definite TBM Clinical meningitis plus acid-fast bacilli seen
50 cells/ L). In the context of HIV, neutrophils often predominate in the CSF
in the CSF or
cell population (37).
Mycobacterium tuberculosis cultured from
the CSF
Essential to the search for acid-fast bacilli is the volume of the CSF
Probable TBM Clinical meningitis plus one of the following sample, the time spent on microscopic examination, and the efficiency with
criteria: which the microbiology, biochemistry, and hematology laboratories use the
■ Radiographic evidence of pulmonary precious CSF sample. Increasing the volume (to a minimum of 6 mL) and
tuberculosis slide examination time to a standard time (preferably 30 minutes) can
■ Acid-fast bacilli seen in sputum or gastric improve the yield to more than 60% of clinically diag- nosed cases (101).
fluid Particularly for pediatric patients, it can be difficult to obtain large volumes of
■ Evidence of extrapulmonary tuberculosis CT or MRI CSF, but drawing of larger volumes should be encouraged to improve the
■ brain scan features confirmation rate, where not contraindicated. It should be remembered that
consistent with TBM the major safety issue relates to the decision on whether to perform a
Possible TBM Clinical meningitis plus 2 of the following lumbar puncture; the volume of CSF then taken is of secondary
criteria: consequence. Hence having made the decision to perform a CSF, it is only
■ History of previous tuberculosis ethical to then take a volume of CSF that will give a good chance of
■ Illness duration 5 days improving the care of the patient. The CSF should be concentrated prior to
■ Glasgow coma score 15 Focal examina- tion of the deposit, either by centrifugation or filtration (102). Direct
■ neurologic signs smear examination of CSF is rarely positive.

and 2 of the following criteria: Yellow

■ CSF
■ 50% lymphocytes in the CSF CSF
■ glucose 50% blood glucose

From Heemskerk D, Day J, Chau TT, et al. Intensified treatment with high dose
rifampicin and levofloxacin compared to standard treatment for adult patients with
tuberculous meningitis (TBM-IT): protocol for a randomized controlled trial. Trials. 2011;12:25.
dimaksudkan untuk menentukan keputusan pengobatan dan mungkin kurang praktis
dalam pengaturan klinis. Secara khusus, ini tidak boleh digunakan untuk menyingkirkan
diagnosis TBM (100) (Tabel 29.5).
Tanpa konteks riwayat klinis yang sugestif, TBM dapat menyerupai
meningoencephalitides kronis lainnya. Khususnya, pada pasien yang
terinfeksi HIV, kendala utama dalam praktik klinis adalah perbedaan dari
bentuk meningitis kronis lainnya, terutama meningitis kriptokokus,
toksoplasmosis serebral, ensefalitis cytomegalovirus, dan limfoma SSP.
Karena hasil diagnostik dari apus umumnya rendah, eksklusi yang hati-hati
dari diagnosis lain sangat penting. Segera setelah kecurigaan muncul,
anamnesis dan penyelidikan tambahan harus diarahkan ke pajanan terhadap
TB dan menyingkirkan penyebab lain yang dapat diobati.
Cerebrospinal Fluid Analysis
Chest X-Ray
The chest x-ray may reveal active or previous infection with
M. tuberculosis. In children, signs of primary infection may be noted on
chest x-ray. In adults, the chest x-ray is often normal, but all typical lesions
can be found including apical scarring, calcified Ghon complex, upper lobe
infiltration, and nodular and cavitating disease. Miliary TB is frequently
asso- ciated with TBM (see Fig. 29.2) found on chest x-ray in 25% to 50%
of adults and 15% to 25% of children with TBM (103,104).
Kultur Mikobakteri
As for CSF smear, sensitivity of culture of M. tuberculosis
from the CSF is increased by using a larger volume of CSF, which should
be concentrated prior to inoculation of the deposit wherever possible.
Previously, Lowenstein-Jensen (LJ) media and later agar media
(Middlebrook 7H10, 7H11) were recommended; however, liquid culture
techniques show increased sensitivity and more rapid turnaround times for
the isolation of mycobacteria and should be used where possible.
Commercial liquid culture systems include BACTEC MGIT 960 system
(Becton Dickinson Microbiology Systems, Sparks,

Fundamental to diagnosis is the lumbar puncture and conse- MD) and MB/BacT system (BioMérieux, Durham, NC) and have reduced the
quent CSF analysis. CSF pressure is raised ( 20 cm H 2 O) in approximately time to results for both isolation and DST of mycobacteria (105). CSF
50% of adults and 40% to 75% of children cultures generally become positive between 10 and 21 days on commercial
( 10 cm H 2 HAI). Biasanya, CSF berwarna “jerami”. Hasilnya bisa jadi liquid culture systems, although late positives may occur after 35 days due to
samar-samar. Jumlah sel darah putih (WCC) umumnya the low bacillary load (106,107).
lebih rendah (10 hingga 1.000 10 6 sel / mL) dibandingkan pada meningitis bakterial,
terutama limfositik, dengan serum rendah rasio glukosa LCS (50%). Laktat The microscopically observed drug susceptibility
biasanya meningkat, yang mencerminkan gangguan metabolisme intraserebral (MODS) assay is a noncommercial liquid culture technique with minimal
atau proses iskemik. Kadar protein total yang meningkat (0,5 g / L) merupakan technical requirements that can detect both mycobacteria and drug
indikasi gangguan sawar darah-otak atau peningkatan produksi imunoglobulin resistance (108). In TBM, MODS culture has shown comparable sensitivity
intraserebral. to mycobacteria

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TABEL 29. 5

DEFINISI KASUS SERAGAM

KRITERIA KLINIS SKOR DIAGNOSTIK

Skor kategori maksimum 6

Durasi gejala lebih dari 5 hari 4

Gejala sistemik yang mengarah pada tuberkulosis (satu atau lebih dari yang berikut): 2
penurunan berat badan (atau kenaikan berat badan yang buruk pada anak-anak), keringat malam, atau batuk terus-menerus selama

lebih dari 2 minggu

Sejarah kontak dekat baru-baru ini (dalam tahun lalu) dengan seseorang dengan 2
tuberkulosis paru atau TST atau IGRA positif (hanya pada anak-anak di bawah usia 10 tahun)

Defisit neurologis fokal (tidak termasuk kelumpuhan saraf kranial) Kelumpuhan saraf 1

kranial 1

Kesadaran yang berubah 1

KRITERIA CSF Skor kategori maksimum 4

Penampilan yang jelas 1

Sel: 10–500 / L 1

Dominasi limfositik (50%) Konsentrasi protein lebih 1

besar dari 1 g / L 1
Rasio glukosa CSF-ke-plasma kurang dari 50% atau glukosa LCS absolut 1
konsentrasi kurang dari 2 2 mmol / L

KRITERIA PENCITRAAN SEREBRAL Skor kategori maksimum 6

Hidrosefalus 1

Peningkatan meningeal basal 2

Tuberkuloma 2

Infark 1

Hyperdensitas basal prakontras 2

BUKTI TUBERKULOSIS DI TEMPAT LAIN Maximum category score 4

Rontgen dada sugestif tuberkulosis aktif: tanda tuberkulosis 2; 2/4

tuberkulosis milier 4
CT/ MRI/ultrasound evidence for tuberculosis outside the CNS 2

AFB identified or Mycobacterium tuberculosis cultured from another source—that 4

is, sputum, lymph node, gastric washing, urine, blood culture

Positive commercial M. tuberculosis NAAT from extraneural specimen 4

Exclusion of alternative diagnoses

An alternative diagnosis must be confirmed microbiologically (by stain, TST, tuberculin skin test. IGRA, interferon-
culture, or NAAT when appropriate), serologically (e.g., syphilis), or histopathologically (e.g., release assay; NAAT, nucleic acid amplification test. AFB,
lymphoma). The list of alternative diagnoses that should be considered, dependent on age, immune acid-fast bacilli. The individual points for each criterion (1, 2,
status, and geographical region, include pyogenic bacterial meningitis, cryptococcal meningitis, or 4 points) were determined by consensus and by
syphilitic meningitis, viral meningoencephalitis, cerebral malaria, parasitic or eosinophilic meningitis ( Angiostrongylus
considering their quantified diagnostic value as defined in
cantonensis, Gnathostoma spinigerum, toxocariasis, cysticercosis), cerebral toxoplasmosis and studies.
bacterial brain abscess (space-occupying lesion on cerebral imaging), and malignancy (e.g.,
lymphoma)

(continued)

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 TABLE 29 . 5

UNIFORM CASE DEFINITION (CONTINUED)

Clinical entry criteria

■ Symptoms and signs of meningitis include one or more of the following: headache, irritability, vomiting, fever, neck stiffness, convulsions, focal neurologic deficits,
altered consciousness, or lethargy.

Tuberculous meningitis classification

Definite tuberculous meningitis
■ Patients should fulfill criterion A or B:
A. Clinical entry criteria plus one or more of the following: acid-fast bacilli seen in the CSF, Mycobacterium tuberculosis
cultured from the CSF, or a CSF-positive commercial nucleic acid amplification test.
B. Acid-fast bacilli seen in the context of histologic changes consistent with tuberculosis in the brain or spinal cord with suggestive symptoms or signs and
CSF changes or visible meningitis (on autopsy).

Probable tuberculous meningitis

■ Clinical entry criteria plus a total diagnostic score of 10 or more points (when cerebral imaging is not available) or 12 or more points (when cerebral imaging is
available) plus exclusion of alternative diagnoses. At least 2 points should either come from CSF or cerebral imaging criteria.

Possible tuberculous meningitis

■ Kriteria masuk klinis ditambah skor diagnostik total 6-9 poin (ketika pencitraan otak tidak tersedia) atau 6-11 poin (ketika pencitraan serebral tersedia)
ditambah pengecualian diagnosis alternatif. Kemungkinan tuberkulosis tidak dapat didiagnosis atau disingkirkan tanpa melakukan pungsi lumbal atau
pencitraan otak.

Meningitis nontuberkulosis
■ Diagnosis alternatif ditegakkan, tanpa diagnosis pasti meningitis tuberkulosis atau tanda-tanda penyakit ganda yang meyakinkan

Dari Marais S, Thwaites G, Schoeman JF, dkk. Meningitis tuberkulosis: definisi kasus seragam untuk digunakan dalam penelitian klinis. Lancet Infect Dis.
2010; 10 (11): 803–812.

growth indicator tube (MGIT) for CSF culture, however with a median
turnaround time of 6 days versus 15.5 days (106). This study did not
evaluate direct DST using MODS or MGIT. MODS is increasingly used in
low-resource countries for the diagnosis of pulmonary MDR TB; however, it
is still not widely used for TBM, although that should change. WHO has
endorsed both commercial and noncommercial liquid culture systems for
TB diagnosis (109).
obat untuk regimen yang gagal ”harus diterapkan. Pengalaman dari TB paru dan data
farmakokinetik mendukung penggunaan uoroquinolone (levo ac oxacin, gati fl oxacin,
atau moxi fl oxacin) (113,114). Siprofloksasin sebaiknya tidak digunakan karena
kurang aktif melawan M. tuberculosis; resistensi berkembang dengan cepat dan dapat
menyebabkan seleksi strain yang resisten terhadap fluorokuinolon yang lebih aktif
(113).

MDR TB is defined as M. tuberculosis with resistance to at least

rifampicin and isoniazid. XDR TB is defined as
M. tuberculosis with resistance to at least isoniazid and rifam- picin, any
fluoroquinolone, and at least one of three injectable second-line drugs
(amikacin, capreomycin, or kanamycin). Whereas MDR pulmonary TB can
be effectively treated with second-line antituberculous drugs, evidence on
effective treat- ment of MDR TBM is limited to small series or single case
reports and mortality is extremely high (39). The majority of deaths from
TBM occur within the first month of treatment (30,31,110). If the CSF is
culture positive for mycobacteria, molecular diagnostic tests can be used to
establish resistance to rifampicin or isoniazid (111,112). If only conventional
pheno- typic DST is available, the results of the drug susceptibility test will
be returned to the treating physician at the earliest after 4 to 6 weeks but
more often after at least 8 weeks of treat- ment. The majority of TBM
patients infected with rifampicin- resistant strains will have succumbed
before the decision can be made to change to a second-line regimen; for
this reason, molecular tests for rifampicin resistance should be applied in all
cases of TBM, but especially where there is a high suspicion of MDR TBM
(previous treatment history, known exposure to an MDR or chronic TB case,
HIV patient, or failure to respond to first-line therapy). Currently, there is no
evidence base to support treatment regimens for patients with MDR TBM,
but the principle of TB treatment to “never add a single
Pengujian Kulit Tuberkulin
The Mantoux tuberculin skin test (TST) is performed by intracutaneously
injecting a small dose of purified protein derivative (PPD). After 48 to 72
hours, an induration of 15mm or more is considered positive in all persons
(115). The value of this diagnostic test is highly dependent on the
background prevalence of TB, age of the patient, and the co-infection with
HIV. Up to 10% to 15% of immunocompetent children with
culture-documented TB do not initially show TST reactivity. Sensitivity can
be decreased by host factors, such as young age, poor nutrition,
immunosuppression, other viral infections (such as measles, varicella, and
influenza), recent TB infec- tion, and disseminated TB diseases (116). In
culture-proven TBM patients in Egypt, only 19% of patients had tubercu- lin
positivity on admission. The yield improved when the test was repeated
after 60 days, with 62% positivity (117). Severe immunosuppression will
also suppress skin test reactivity (118). False-positive TST results may also
occur in BCG- vaccinated individuals and those exposed to environmental
nontuberculous mycobacteria (116). In the United Kingdom, Heaf testing
was preferred to Mantoux. It follows the same principles as the Mantoux
test, however a special “Heaf gun” with multiple small needles is used,
which is thought to be less painful in children and has an easier readout
(119).

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 486 Part III: Bacterial and Mycoplasmal Infections
Developments in Diagnostics
Biochemical tests
Biochemical tests can detect features of the infecting organism or products of
the host immune response. Of the biochemical tests, adenosine deaminase
(ADA) assays are still of interest world- wide, particularly in low-income
settings. The test is relatively cheap and easy to perform. It is an attractive
candidate for the diagnosis of TBM because it has been shown to be of value
in the distinction of tuberculous pleural effusions (120). ADA is re- leased by T
cells during cell-mediated immune response to bacilli (121). A recent
metaanalysis reviewed 10 publications on ADA for the diagnosis of TBM and
concluded that the mean values of the sensitivity and specificity of the ADA
assays were respectively 79% and 91% compared to culture as the gold
standard, with an inability particularly to distinguish TBM from bacterial men-
ingitis (122). However, publication bias and spectrum bias in included cases
may have resulted in overestimation of diagnostic accuracy. Inclusion of
inappropriate controls will result in an overestimation of diagnostic accuracy,
particularly if the test is poor at discriminating the common differential
diagnoses; raised levels may also be seen in sarcoidosis, meningeal
lymphoma, subarachnoid hemorrhage, and neurobrucellosis. Although
ADAmay be of use within diagnostic algorithms, the probability that a patient
has TBMwith a negative result is still too high to rule out the diagnosis using
ADA values. Furthermore, in HIV- infected individuals, the test is not of use
(123).
Immunoassays
Berbagai immunoassay telah dievaluasi untuk diagnosis TBM, dengan sensitivitas dan spesifitas
yang sangat bervariasi di antara penelitian, biasanya karena bias spektrum di antara kontrol.
WHO mengeluarkan rekomendasi kebijakan negatif pertama yang melarang penggunaan tes
serologi komersial yang ada untuk diagnosis TB paru pada tahun 2011, setelah evaluasi
sistematis (124). Imunoasai mungkin tidak membedakan antara infeksi akut dan paparan
sebelumnya, dan reaktivitas silang antibodi selanjutnya dapat menurunkan spesifisitas. Deteksi
lipoarabinomannan (LAM) telah dievaluasi untuk diagnosis TB dan minat saat ini meningkat
sejak pengembangan alat tes aliran urin lateral di titik perawatan, yang telah menunjukkan nilai
dalam diagnosis TB paru pada pasien HIV dengan imunosupresi parah ( CD4 100 sel / L)
(125.126). Namun, ini adalah subset pasien yang relatif berbeda dan tes CD4 pertama-tama
diperlukan untuk menentukan apakah tes LAM dapat diterapkan. LAM adalah komponen dinding
sel M. tuberculosis, memiliki efek imunoregulasi dan antiinflamasi, dan berfungsi sebagai faktor
virulensi dari mikobakteri (127). Penelitian sebelumnya tentang ELISA yang diarahkan untuk
mendeteksi antibodi IgG terhadap antigen LAM telah melaporkan sensitivitas dan spesifisitas
yang menjanjikan dalam penelitian kecil, tetapi hasil yang sangat bervariasi dipublikasikan untuk
populasi klinis TB yang berbeda, yang mencerminkan bias spektrum dalam evaluasi tes serologi
untuk TB. Tes ELISA deteksi antigen LAM standar, menunjukkan hasil dalam 2 sampai 3 jam
(Clearview TB ELISA, Inverness Medical Innovations, Waltham, MA), telah dinilai pada CSF dari
150 pasien dalam pengaturan prevalensi HIV tinggi. Dengan sensitivitas yang sangat rendah
yaitu 31%, tetapi spesifikasinya 94%, ini memiliki potensi untuk menjadi tes aturan cepat untuk
TBM untuk pasien terinfeksi HIV dengan imunosupresi lanjut bila digunakan dalam kombinasi
dengan aturan prediksi klinis (128), tetapi hapusan cairan serebrospinal yang dioptimalkan
kemungkinan memiliki diagnosis yang lebih tinggi. menghasilkan. Tes imunologi lain yang telah
dievaluasi adalah tes pelepasan interferon (IGRA), termasuk respon IgGELISPOT darah perifer
terhadap PPD, CFP-10, dan ESAT-6; namun, semua menunjukkan sensitivitas yang buruk pada
pasien TBM (129.130). Salah satu tes IGRA yang tersedia secara komersial, QuantiFERON-TB
Gold semua menunjukkan sensitivitas yang buruk pada pasien dengan TBM (129.130). Salah
satu tes IGRA yang tersedia secara komersial, QuantiFERON-TB Gold semua menunjukkan
sensitivitas yang buruk pada pasien dengan TBM (129.130). Salah satu tes IGRA yang tersedia
secara komersial, QuantiFERON-TB Gold
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In-Tube test (QFT-GIT) uses enzyme-linked immunosorbent assay (ELISA)
technique tomeasure cell-mediated immunity in response to proteins specific for M.
tuberculosis complex. When assessed for TBMin India, thewhole blood IGRAhad
sensitivity of 44.4% and specificity of 62.5% for diagnosing TBM with positive
pre- dictive value (PPV) of 72.7%. IGRA on CSF had 88% indetermi- nate results
in TBMpatients (131).
Nucleic Acid Amplification Tests
Amplification of mycobacterial DNA by polymerase chain reaction (PCR) has
turned away attention from immunologic techniques. Systematic review on
commercial nucleic acid amplification tests (NAATs) for TBM summarized
the perfor- mance as having potential to rule in or confirm diagnosis (speci-
ficity 98%), but low sensitivity (56%) precludes the use of these tests to rule
out (132). NAAT should be used as an adjunct to conventional microscopy,
culture, and clinical algorithms.
Themost recent advance in diagnosis is theGeneXpertMTB/ RIF (Cepheid,
Sunnyvale, CA), an easy-to-use desktop machine that simultaneously detects
the presence of M. tuberculosis dan resistensi rifampisin menggunakan PCR
real-time, memberikan hasil dalam 2 jam. Risiko kontaminasi dan akibatnya
hasil positif palsu dikurangi dengan penggunaan kartrid sekali pakai yang
tertutup rapat. Waktu pergantian yang cepat dapat mengarah pada perbaikan
penting dalam pengelolaan TB MDR. Tes ini telah didukung oleh WHO pada
tahun 2010 untuk digunakan pada TB paru (112). GeneXpert lebih sensitif
daripada noda, dibandingkan dengan kultur. Dalam sampel dahak
BTA-negatif, kultur-positif, deteksi M. tuberculosis showed 76.9% sensitivity
and 99.0% speci- ficity in a decentralized low-income setting. Sensitivity for
rifampicin resistance was 94.4% and specificity 98.3%, regard- less of HIV
infection (133). These results are clearly promis- ing and roll out of the
GeneXpert MTB/RIF test has been impressive globally
(http://who.int/tb/laboratory/mtbrifrollout/ en/). The GeneXpert test has been
shown to be more sensitive than smear on extrapulmonary samples in reports
combining analysis of all extrapulmonary samples with a small number of CSF
samples (134–137). In June 2013, the WHO Strategic and Technical Advisory
Group (STAG) reviewed the evidence for use of GeneXpert on extrapulmonary
samples. 15 pub- lished and 7 unpublished studies, involving 5,922 samples,
were included in the review which endorsed GeneXpert for use on
extrapulmonary samples, including CSF. The report recom- mended “Xpert
MTB/RIF should be used in preference to con- ventional microscopy and
culture as the initial diagnostic test in testing cerebrospinal fluid specimens
from patients presumed to have TB meningitis (strong recommendation given
the ur- gency of rapid diagnosis, very low quality of evidence).” Pooled
sensitivity and specificity against a clinical gold standard were estimated to be
55.6% and 98.8%, respectively (138).
Data from 265 consecutive patients with suspected TBM presenting at
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam showed GeneXpert
detected M. tuberculosis in 56.7% (n
97/171 [95%CI, 48.9; 64.2%]) of pretreatment CSF sam- ples of
patients clinically diagnosed with TBM (specificity was 100%, n
94/94). Detection was only marginally lower than MGIT
culture at 60.8% (n 104/171) and similar to detection
rates in CSF reported for other commercial nucleic acid ampli- fication tests,
with the advantage that rifampicin resistance is also detected by GeneXpert
(139). Three cases of rifampicin re- sistance were detected and confirmed by
MGIT DST. Although the numbers of MDR cases are too small to draw robust
conclu- sions regarding accuracy in CSF, rifampicin resistance detection by
GeneXpert MTB/RIF has been shown to be accurate in spu- tum samples. For
MDR TBM, this test will be of great impor- tance, as detection of drug
resistance within hours rather than days will allow research into optimal
treatment of MDR TBM.
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Further multicenter evaluation of this novel GeneXpert assay may lead to

significant improvement in the diagnosis and treat- ment of TBM in general
and MDR TBM in particular.

Central Nervous System Imaging

Radiologic results can add additional evidence for diagnosis while also potentially
serving as the missing link between epidemiol- ogy, etiology, and
pathophysiology, especially given the paucity of postmortem studies. Presenting
findings are pluriform and during treatment, progressive changes may appear.
Contrast-enhanced MRI is the modality of choice because it has a higher
resolution over computed tomography (CT) scanning. However, in many endemic
settings, MRI is too expensive or not readily available.

The typical initial findings are hydrocephalus, basal menin- geal

enhancement, and tuberculoma. Hydrocephalus (Fig. 29.3) is the most
common finding. Hydrocephalus is also seen in bacte- rial meningitis, although
less frequent (140). Generally, in TBM, hydrocephalus is of the communicating
type (141). Occasionally, obstructive hydrocephalus can be diagnosed by
imaging, when narrowing of the aqueduct of Sylvius is noted or when a
parenchymal mass is demonstrated obstructing the flow of CSF. If
neurosurgical interventions (shunting, endoscopic third ven- triculostomy) are
available and contemplated, air encephalogra- phy can be helpful in excluding
patients with communicating hydrocephalus from undergoing unnecessary
procedures (142). GAMBAR 29.4 Peningkatan meningeal basal pada orang dewasa dengan TBM. Gambar
resonansi magnetik T1-weighted yang diperkuat dengan Gadolinium menunjukkan peningkatan
meningeal basal terkait TBM yang meluas ke arah gambar sylvian.
Peningkatan meningeal basal (Gbr. 29.4) pada stadium lanjut dapat,
meskipun jarang, dapat ditunjukkan pada CT scan nonkontras, ketika obliterasi
dari tangki interpeduncular diamati. Setelah pemberian kontras, biasanya ada
peningkatan difus dari tangki subarachnoid basal; kadang-kadang,
telah dilaporkan terjadi pada 5% sampai 40% pasien dengan TBM (74,144).
peningkatan meningeal terlihat di atas cembung serebral, fisura sylvian, dan
Fitur khas pada pencitraan MRI bergantung pada apakah granuloma tidak
tentorium (143). Pada tahap awal, pencitraan CT atau MRI tanpa penggunaan
berkaseasi, berkaseasi dengan pusat padat, atau kaseasi dengan pusat
c
cairan. Noncaseat-
erculoma biasanya hipointens pada gambar T1-weighted perintense
Tuberkulom
pada gambar T2-weighted dan menunjukkan homogenitas setelah
melibatkan par
pemberian kontras. Kasease loma dengan kaseasi padat terlihat
dan subdural o
hipointens atau gambar T1-weighted isoinn dan isointense ke hipointens
pada gambar berbayang, dengan peningkatan rim pada pemberian
kontras
n. Caseating granulomawith a liquid center looks hypoin- n T1-weighted
images and hyperintense on T2-weighted with rimenhancement after
contrast administration (74). ging, a (tubercular) abscess may be
difficult to distinguish ubercular granulomas with a liquid center.
Tuberculous es are generally more rapidly progressive, larger, have a
wall, and can be loculated and irregular in shape.

ng treatment, tuberculoma may develop paradoxically;

r, in a prospective serial MRI study, this phenomenon was d in 60%of
patients, suggesting that it is part of the natural of disease on treatment
rather than being discordant (73). emic events most commonly occur
during treatment rather ing a presenting sign, mostly located in the basal
ganglia
. 6), which is in line with the severe basal infection, exu- rmation, and
consequent vasculitis. In a serial MRI study, thasone reduced the
proportion of patientswho developed during treatment; however, the
difference was not statisti- nificant, possibly due to insufficient sample size
(73). Using contrast-enhanced MRI in children in Turkey, pre- senting
findings were meningeal enhancement (90.9%), hydro- cephalus (63.6%),
infarction (45.5%), tuberculomas (27.2%), cranial nerve involvement
(27.2%), and severe cortical atro- phy (9.1%) (145). Retrospectively,
miliary involvement of the leptomeninges was present in a very large (88%)
propor- tion of young South African children scanned for TBM (146).
However, raremiliaryCNS involvement is also reported in some adult
patients (Fig. 29.7). This discrepancy between adults and
FIGURE 29.3 Hidrosefalus terkait dengan TBM. Gambar resonansi magnetik T1-weighted
yang disempurnakan Gadolinium yang menunjukkan hidrosefalus kotor terkait dengan
TBM.

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GAMBAR 29.5 Tuberkuloma pada orang dewasa dengan TBM. MRI berbobot T1 yang diperkuat dengan Gadolinium menunjukkan beberapa
tuberkuloma di batang otak yang meluas ke hipotalamus.

anak kecil mungkin merupakan indikasi bahwa penyebaran hematogen langsung ke meninges in HIV patients (36). Infarcts, tuberculous abscess, tubercu- lous
memainkan peran yang lebih besar pada anak-anak, kemungkinan karena imunitas bawaan dan encephalitis, and optochiasmatic arachnoiditis on imag- ing have all been
adaptif yang belum matang. associated with poor outcome.
Kriteria pencitraan diagnostik yang sama berlaku untuk anak-anak dengan infeksi With the advent of newer more sensitive imaging tech- niques, our
HIV, namun atrofi kortikal adalah temuan yang lebih umum (86) (Gambar 29.8). Pada ability to detect abnormalities will improve. Magnetic resonance
orang dewasa dengan AIDS, temuan radiologis dilaporkan serupa dengan pasien tanpa angiography (MRA) may have a role in predicting the chance of infarction in
HIV; bagaimanapun, perbedaannya TBM (148). 3-Tesla
ic reso
infeksi dan ity and
(32,37,147). S e. Still
meningkatkan meningeal apid d

FIGURE 29.6 Basal ganglia infarct in an adult with TBM. CT image without contrast FIGURE 29.7 Miliary lesions in an adult with TBM. Gadolinium- enhanced
showing infarction of the left capsula interna and caudate head. T1-weighted MRI showing multiple miliary lesions and small tuberculoma in an adult
patient with TBM.

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 lous

G H I

FIGURE 29.8 Temuan MRI yang umum pada anak dengan TBM. SEBUAH: Gambar T1-weighted aksial dengan kontras menunjukkan
peningkatan leptomeningeal yang tebal di tangki suprasellar yang meluas ke tangki interpeduncular. B: Citra koronal T1-weighted dengan
kontras menunjukkan peningkatan leptomeningeal dengan peningkatan leptomeningeal basal yang ditandai. C: Gambar aksial T1-weighted
menunjukkan beberapa nodul yang meningkat di parenkim. D: Gambar axial T2-weighted menunjukkan infark pada kepala ekor dan
putamen kanan. E: Pencitraan aksial T1 yang ditingkatkan dengan gadolinium menunjukkan peningkatan leptomeningeal basal yang luas di
tangki suprasellar, interpeduncular, dan ambien. F: Gambar T1-weighted sagital yang tidak disempurnakan menunjukkan adanya
hidrosefalus masif. G: Contrast-enhanced axial T1-weighted image reveals thick leptomeningeal enhancement in suprasellar cistern
extending into interpeduncular and ambient cisterns and small tu- berculoma in left brainstem. H: Contrast-enhanced axial T1-weighted
image reveals basal meningeal enhancement and both dilated temporal horns. I: Contrast-enhanced coronal T1-weighted image reveals
thick leptomeningeal enhancement of interhemispheric fissure. ( continued)

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 490 fecti

J K L

FIGURE 29.8 ( continued) J: Contrast-enhanced axial T1-weighted image shows tuberculoma in the left temporal lobe. K: Contrast-enhanced
axial T1-weighted image shows small tuberculomata in brainstem and basal meningeal enhancement of both sylvian fissures. L: Gambar
dengan pembobotan T1 aksial dengan kontras yang ditingkatkan menunjukkan tuberkuloma kecil di gagang otak kiri dan lobus temporal,
keduanya dilatasi tanduk temporal dan peningkatan meningeal dari gambaran sylvian kiri. (Atas kebaikan Dr. Nguyen Duc Bang, Rumah Sakit
PhamNgoc Thach untuk Tuberkulosis dan Penyakit Paru-paru, Kota Ho Chi Minh, Vietnam.)

PENGOBATAN
The treatment of TBM may be divided into four comple- mentary areas:
specific antituberculous therapy, adjunctive immunomodulatory therapy,
anticoagulant therapy, and man- agement of intracranial pressure. In
addition, treatment of HIV-associated TBM requires consideration of drug
interac- tions and IRIS.
Specific Antituberculous Treatment
serupa; namun, untuk anak-anak, sering kali dosis yang lebih tinggi digunakan (Tabel 29.6).
In this section, we would like to put emphasis on the statement that the
CNS “should be regarded as a unique therapeutic compartment” (152) and
pharmacokinetic and pharmacodynamic data should be considered in the
construc- tion of more effective treatment schedules. The majority of deaths
from TBM occur in the first 2 months of treatment, indicating that effective
antimycobacterial killing is most critical in the intensive phase. However,
prevention of relapse and the prevention of emerging resistance are
additionally im- portant principles of effective multidrug treatment.

Treatment guidelines for TBM treatment are not uniform. In general, global
guidelines recommend 9 to 12 months treatment with rifampicin, isoniazid,
pyrazinamide, and strep- tomycin (or ethambutol) in the intensive phase,
followed by a combination of rifampicin and isoniazid in the continuation
phase (75,149–151). These treatment regimens are based on the early
trials in pulmonary TB involving the introduction of the new first-line
antituberculous drugs. The drug dos- ages and dura
The ability of the different first-line antituberculous drugs to penetrate
the CSF is variable and few of the second-line drugs are effective in
reaching the brain. A summary of antimycobacterial activity and CSF
penetration of the first-line drugs used in the intensive phase is appropriate.
We will also briefly review some of the second-line agents with favorable
CSF levels. Of note, little is known about the levels of antimy- cobacterial
drugs in the brain tissue. Drugs may need to over-

ng of the choroid plexus

derived from p ood–brain barrier, made
macokinetic p llaries and surrounding

TABEL 29. 6

DOSIS HARIAN YANG DIANJURKAN DARI OBAT-OBATAN ANTITUBERKULUS GARIS PERTAMA PADA ANAK-ANAK DAN
ORANG DEWASA DENGAN TUBERKULUS MENINGITIS

Obat Dosis Harian Anak (12 tahun) Dosis Harian Dewasa

Isoniazid (INH) 10 mg / kg (kisaran 6-15 mg / kg) 15 mg / 5 mg / kg (kisaran 4–6 mg / kg) 10 mg / kg

Rifampisin (RIF) kg (kisaran 10-20 mg / kg) 35 mg / kg (kisaran 8–12 mg / kg) 25 mg / kg (kisaran

Pyrazinamide (PZA) (kisaran 30-40 mg / kg) 20–30 mg / kg) 15 mg / kg (kisaran 12–18

Streptomisin (SM) 17,5 mg / kg (kisaran 15-20 mg / kg) 20 mg / mg / kg) 15 mg / kg (kisaran 15-20 mg / kg)

Etambutol (EMB) kg (kisaran 15-25 mg / kg)

Dari Donald PR. Kemoterapi meningitis tuberkulosis pada anak-anak dan orang dewasa. Tuberkulosis (Edinb). 2010; 90 (6):
375–392.

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sel glia. Tingkat obat di dua kompartemen, CSF dan jaringan otak, mungkin
tidak sama. Rintangan ketiga mungkin penetrasi dan kerja obat dalam
kondisi yang relatif anaerobik di dalam tuberkuloma.
Streptomycin and Ethambutol
The initial drug to be introduced for TBM treatment was streptomycin. This
aminoglycoside must be given intramus- cularly. Streptomycin is a protein
synthesis inhibitor. The minimal inhibitory concentration (MIC) in fully
susceptible clinical isolates is in the range 0.5 to 2.0 g/mL (153). With the
commonly used dosages in adults, the early bactericidal activity (EBA;
generally defined as the fall in counts per mil- liliter sputum per day during
the first 2 days of treatment) of
streptomycin, however, is low ( 0.1 log 10 colony-forming unit [CFU]/mL
sputum per day) (154). With a poor penetration in
CSF, kontribusi streptomisin pada rejimen multidrug untuk TBM mungkin
sangat terbatas. Jika tidak ada peradangan meningeal, penetrasi tidak
terjadi. Namun, pada menin- gitis, penetrasi bisa mencapai 20% dari level
serum simultan. Pada awal perjalanan penyakit, ketika gangguan sawar
darah-otak menonjol, kadar di atas MIC dapat ditemukan di CSF (3 sampai
16 g / mL). Namun, ketika perbaikan klinis dicatat, kadar CSF hampir tidak
mencapai MIC (0 hingga 1,25 hingga 4 g / mL) (155). Karena TBM mungkin
mencerminkan keadaan umum TB yang menyebar, tampaknya tepat untuk
mempertahankan streptomisin dalam jadwal pengobatan, namun dengan
biaya toksisitas yang meningkat. Untuk pasien HIV, etambutol harus diganti
dengan streptomisin karena injeksi harus dihindari bila memungkinkan
pada orang yang terinfeksi HIV. Etambutol bersifat bakteriostatik terhadap
basil TB yang tumbuh secara aktif dengan menghalangi pembentukan
dinding sel bakteri. Etambutol sedikit lebih efisien dalam menembus cairan
serebrospinal, dengan kadar dibandingkan dengan serum dalam kisaran
0% sampai 54%. Pada orang dewasa sehat, meskipun dosis oral 50 mg /
kg yang merupakan dua kali dosis terapeutik biasa, dan dengan adanya
kadar darah yang tinggi secara proporsional, etambutol tidak muncul di
CSF orang dewasa yang sehat. Setelah dosis oral kadar 18,6 sampai 25
mg / kg, etambutol muncul di CSF pasien dengan meningitis aktif (0,74
sampai 1,98 g / mL) (155). Namun, dengan MIC 0,5 sampai 2,0 g / mL,
peran etambutol dalam pengobatan TBM mungkin terbatas. Baik
streptomisin dan etambutol terbukti tidak efektif dalam mensterilkan dahak
pada TB paru, jadi perannya dalam TBM mungkin terbatas pada
pencegahan resistensi.
Isoniazid
After the introduction of isoniazid, a major improvement was seen in the
outcome for patients with all grades of TBM. Isoniazid exerts its
antimycobacterial activity by inhibiting the synthesis of mycolic acid required
for the mycobacterial cell wall. It is the most bactericidal TB drug and kills
ap- proximately 95% of rapidly multiplying organisms in sputum samples
within 48 hours (156). Isoniazid has the highest EBA
of the first-line TB drugs ranging from 0.4 to 0.8 log 10 CFU/ mL sputum per
day (154). MIC in liquid media is low: 0.02
to 0.04 g/mL (153). A C max of 3 to 5 g/mL is needed for optimal action
against sensitive M. tuberculosis and isoniazid-
resistant strains with relatively low MICs (157). It has good penetration in the
CSF in both children and adults. Peak levels are reached at approximately 6
hours after dose (155). With an oral dosage of about 9 mg/kg, isoniazid
rapidly diffused into the CSF. By 4 hours, mean CSF isoniazid
concentrations measured were 3.2 g/mL, well over the MIC and in the range
of optimal C max for sensitive strains (158). Isoniazid is effective
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Bab 29: Meningitis Tuberkulosis 491
dalam mencegah resistensi bila digunakan dengan obat pendamping. Ini kurang
efisien dalam membasmi organisme yang tumbuh lambat. Beberapa menganjurkan
pemberian dosis yang lebih tinggi karena resistensi semakin melimpah dan
intraserebral yang lebih tinggi
C maks dapat menyebabkan pembunuhan strain dengan resistensi tingkat rendah, yang
tidak membawa mutasi pada gen katG. Selain itu,
itu N- acetyltransferase-2 genotipe individu (NAT2) mempengaruhi EBA isoniazid
pada dosis tertentu, dan asetilator isoniazid yang lebih cepat secara konsisten
memiliki EBA yang lebih rendah (154). Sebaliknya, asetilator lambat mungkin
meningkatkan kerentanan terhadap hepatotoksisitas (159).
Rifampisin
Rifampicin is a key drug in the treatment for TBM, illustrated by the high
mortality in MDR TBM patients compared to isolated isoniazid resistance. In
contrast, in a review of the lit- erature, Donald (18) found little effect on
mortality in adults after the introduction of rifampicin and pyrazinamide to the
TBM treatment schedule but a significant effect on survival in children. Still,
based on the drug resistance data, rifampicin seems to have a pivotal role in
treatment; it may well be that doses in adults are not sufficient to reach
adequate levels in the CSF. An Indonesian phase 2 clinical trial, establishing
the safety of high-dose intravenous (13 mg/kg/day) rifampicin with or without
(high dose) moxifloxacin, did not show increased tox- icity and moreover
showed a 50% reduction in mortality for patients receiving high-dose
rifampicin (160). However prom- ising, this trial was not powered for a
clinical outcome, and the results of a current randomized controlled trial
comparing an intensified 2-month regimen of high-dose (15 mg/kg/day) oral
rifampicin and levofloxacin are awaited (161).
Rifampicin inhibits bacterial RNA synthesis by inhibiting RNA polymerase.
Rifampicin is highly bound to plasma pro- teins, which leaves only 20%of total
drug freely diffusible. This is reflected in the ability of rifampicin to penetrate
the CSF, with a CSF/plasma ratio of maximally 20% found in early TBMand
no drug detectable in CSF in the absence of meningeal inflam- mation (155).
After an oral dosage of approximately 11 mg/kg,
serum C max averaging 11.5 g/mL were obtained at 2 hours. Rifampicin
penetrated very slowly into the CSF, and concentra-
tions only slightly in excess of its MIC against M. tuberculosis
(sekitar 0,3 g / mL) dipertahankan selama periode (158). Secara umum, kadar
rifampisin dalam serum yang rendah dilaporkan, terutama pada pasien
HIV-positif, yang penyerapan semua obat TB mungkin terganggu (162).
Disarankan bahwa konsentrasi serum fampisin 2 jam setelah dosis antara 8
dan 24 g / mL diperlukan untuk pengobatan TB paru yang optimal. Tingkat
serum di bawah 4 g / mL didefinisikan sebagai sangat rendah (163). Di
Indonesia, 70% pasien TB menjalani plasma 2 jam
konsentrasi (C maks) di bawah 4 g / mL (164). Peningkatan dosis rifampisin dari 10
mg / kg menjadi 13 mg / kg menyebabkan dis-
Peningkatan kadar plasma secara proporsional (65%) dan secara signifikan
meningkatkan proporsi pasien dengan konsentrasi plasma puncak rifampisin
di atas nilai referensi 8 g / mL (165). EBA dan aktivitas bakterisidal dari
rifampisin (0,2 hingga
0,6 log 10 CFU/mL sputum per day) may be enhanced with an increased dose.
Pyrazinamide
The mechanism of action of pyrazinamide is not completely understood. It
is known for its ability to kill semidormant
M. tuberculosis bacilli in low pH milieu that are not killed by the other
TBdrugs, possibly by disruptingmembrane energetics and inhibiting
membrane transport function in M. tuberculosis
(166). Pada TB paru, penambahan pirazinamid ke rejimen 6 bulan secara signifikan
mengurangi tingkat kekambuhan menjadi kurang dari
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5% (18.156). Pyrazinamide sangat efisien dalam menembus CSF. Umumnya
tingkat tinggi ditemukan sebanding dengan serum (167). EBA dalam
beberapa hari pertama pengobatan rendah tetapi pada hari ke 4 sampai 14
cocok dengan rifampisin dan isoniazid dan mungkin juga aktif melawan basil
ekstraseluler (18). Karena penetrasi rifampisin dalam CSF terbatas dan sering
terjadi resistensi isoniazid, peran pirazinamid pada TBM tidak boleh
diremehkan.
Meningitis Tuberkulosis yang Tahan Obat
The general principles for treating multidrug-resistant TB are as follows: (a)
use at least three previously unused drugs, one of which should be a
fluoroquinolone; (b) streptomycin resistance does not confer resistance to
other aminoglycosides, therefore amikacin or kanamycin can be used; and
(c) treat for at least 18 months (168). There is no uniform guideline for
treatment of drug-resistant TBM. No clinical trials have been conducted.
Our ability to diagnose drug-resistant TBM more rapidly with PCR-based
techniques will warrant an expeditious introduction of protocols for
practitioners in all settings. Such guidelines should be based on our existing
pharmacokinetic and pharmacodynamic knowledge in order to minimize
toxicity and maximize efficacy. Most second-line TB drugs have limited
bactericidal capacity and do not diffuse easily to the CSF (41).
Second-Line Agents
Of the second-line drugs, fluoroquinolones are an attractive option for the
treatment of TB meningitis because of their demonstrable in vitro activity,
intracellular penetration, toler- ability, good bioavailability, and ease of
administration. With the exception of ciprofloxacin, the mycobactericidal
activity is comparable to that of isoniazid. The EBA of levofloxacin, gati-
floxacin, and moxifloxacin in pulmonary TB were compared to that of
isoniazid by Johnson and colleagues (169). This study reported levofloxacin
to have the greatest EBA, compa-
rable to that of isoniazid. “The EBA 0–2 of INH (0.67 log 10
cfu/ml/day) was greater than that of moxifloxacin and gati-
floxacin [both 400 mg daily] (0.33 and 0.35 log 10 cfu/ml/day,
respectively), but not of levofloxacin 1000 mg daily (0.45 log 10
cfu/ml/day)” (169). The diffusion to the cerebral compartment
is excellent. A pharmacokinetic study comparing ciprofloxa- cin,
levofloxacin, and gatifloxacin in patients with TBM found levofloxacin to
have excellent CSF penetration, with a ratio of area under the curve (AUC)
in CSF to AUC in plasma of 75%. This compared favorably with gatifloxacin
(35%) and ciprofloxacin (14%) (170). For moxifloxacin, the penetration has
been reported to be 71% and 82% of plasma levels with doses of 800 mg
and 400 mg, respectively (171).
In serum, median free AUC 0–24/ actual MIC 90 in plasma was
180.99 for levofloxacin, 179.77 for gatifloxacin, and 58.35 for
moxifloxacin. C max was 15.55 g/mL for levofloxacin, 4.51 g/ mL for
gatifloxacin, and 6.13 g/mL for moxifloxacin (172).
Data farmakokinetik ini menunjukkan bahwa fluoroquinolones, levofl oxacin
dan moxifl oxacin khususnya, berpotensi menjadi agen sterilisasi yang
sangat efektif dalam pengobatan TBM.
Dari obat lini kedua yang tersisa, hanya etionamida dan sikloserin yang memiliki
kemampuan yang cukup untuk berdifusi ke CSF. Pada TBM, rasio penetrasi serum
ke CSF dari 40% sampai 100% dilaporkan, dengan konsentrasi puncak CSF
berkisar dari 1,0 sampai
2,6 g / mL dicapai 3 jam setelah pemberian dosis 250 mg (155). MIC yang
dilaporkan adalah 0,25 sampai 0,5 g / mL (157).
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Ethionamide may be a valuable drug for the management of both
susceptible and drug-resistant TBM. Ethionamide is a structural analog of
isoniazid. If isoniazid resistance is con- ferred by mutations in the KatG
gene, these isolates may still be sensitive to ethionamide; however, inhA
mutations for isoniazid resistance confer cross-resistance to ethionamide
(173,174). Cycloserine is only moderately bactericidal and has an MIC of 25
to 75 g/mL; however, penetration in CSF is good (157). None of the
second-line drugs have been sub- jected to clinical trials for the use in TBM
treatment with the exception of moxifloxacin and levofloxacin (160,161).
Of the newagents, a diarylquinoline (bedaquiline or Sirturo, previously
known as TMC207) was approved for the treat- ment of MDR TB by the U.S.
Food and Drug Administration in December 2012. It has a novel mode of
action specifically in- hibiting mycobacterial adenosine triphosphate (ATP)
synthase (175). When added to a background regimen of second-line drugs
in patients with MDR pulmonary TB, TMC207 led to more rapid sputum
culture conversion and possibly prevented resistance formation in
companion drugs without adding to toxicity of the regimen (176). Its MIC
against M. tuberculosis
sangat rendah (0,06 g / mL) (177). EBA dalam 3 hari pertama pengobatan tidak
optimal, tetapi dari hari ke 4 sampai 7, TMC207 menginduksi penurunan serupa pada
CFU menjadi rifampisin dan isoniazid selama periode yang sama (178). Kemampuan
senyawa baru ini untuk melewati sawar darah-otak belum ditetapkan; namun, obat ini
memiliki sifat farmakokinetik yang menguntungkan dan merupakan kandidat yang
menarik untuk penelitian di masa depan pada pasien TBM.
Mengingat keparahan TBM, umumnya, toksisitas pengobatan yang
lebih tinggi dapat diterima jika disertai dengan hasil klinis yang lebih baik.
Alasan paling umum untuk penghentian pengobatan adalah
hepatotoksisitas. Terutama isoniazid, rifampisin, dan pirazinamid yang
terlibat dalam hepatitis yang diinduksi obat (DIH); namun, jika dipantau
dengan cermat, kerusakan hati yang parah dapat dicegah. Streptomisin
dapat menyebabkan oto- dan nefrotoksisitas, dan neuritis optik etambutol.
Takiaritmia jantung dilaporkan untuk fluorokuinolon, khususnya
moxifloksasin, tetapi sangat jarang. Kunci untuk hasil yang baik adalah
mulai pengobatan anti-TB yang efektif. Uji klinis diperlukan untuk
mengembangkan pedoman pengobatan yang lebih efektif untuk TBM yang
rentan dan resistan terhadap obat.
Pengobatan Tambahan
Kortikosteroid
Pedoman global sekarang merekomendasikan penggunaan kortikosteroid sebagai
tambahan untuk pengobatan. Penambahan deksametason ke dalam regimen
antibiotik yang digunakan pada TBM telah terbukti menurunkan mortalitas pada TBM
pada orang dewasa dan anak-anak (30.179). Sebuah tinjauan Cochrane
menyimpulkan bahwa penggunaan tambahan kortikosteroid mengurangi risiko
kematian (rasio risiko [RR], 0,78; 95% CI, 0,67-0,91; 1140 peserta, 7 percobaan) pada
pasien dengan TBM. Data tentang menonaktifkan defisit neurologis residual
menunjukkan bahwa kortikosteroid juga mengurangi risiko kematian atau
menonaktifkan defisit neurologis sisa (RR, 0,82; 95%
CI, 0,70 hingga 0,97; 720 peserta, 3 percobaan) (180). Ini belum dibuktikan
atau dibantah untuk pasien HIV-positif. Efek menguntungkan dari steroid
mungkin tidak terdistribusi secara homogen di antara populasi pasien yang
berbeda. Di seluruh kelompok tingkat keparahan yang berbeda, efek manfaat
deksametason mungkin lebih jelas pada kelas yang kurang parah (30,48).
Baru-baru ini, dilaporkan bahwa tanggapan kekebalan dapat
dimodulasi melalui leukotrien A 4 hidrolase (LTA 4 H)
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 494 Bagian III: Infeksi Bakteri dan Mikoplasma

gen. Secara tidak langsung, gen ini mengatur tingkat-tingkat TNF, dan Pemulihan Kekebalan Tubuh dengan Terapi Antiretroviral
polimorfisme pemicu dapat mengarah ke keadaan hiperinflamasi, peradangan
Themortality forHIV-infected patients withTBMis alarmingly high. CD4
yang tidak adekuat, atau respons antara.
counts of patients with TBM are characteristically very low (35). For these
Pasien dengan TBM, yang homozigot untuk LTA 4 H- polimorfisme tinggi (T /
patients, the question of timing of initi- ation of ART is critical. Initiation
T), memiliki kadar TNF lebih tinggi dan tinggi
should be as early as possible to support the immune response; however,
leukosit di CSF. Di antara pasien yang tidak menerima glukokortikoid, kematian
toxicity, pharmaco- kinetic interactions, IRIS, and pill burden may complicate
tertinggi di antara pasien dengan genotipe T / T. Namun, pasien ini menunjukkan
early treatment. Two recent clinical trials on initiation of ART in
penurunan kematian terbesar pada kelompok yang diobati dengan deksametason
HIV-associated TB showed that severely immunocompromised (CD4 200
tambahan, menunjukkan bahwa deksametason dapat mengurangi respons
cells/ L) patients with (mostly pulmonary) TB may benefit from early initiation
peradangan yang berlebihan pada kelompok ini. Sebaliknya, pasien yang
of ART with lower rates of AIDS-defining illnesses or death, but at the cost
homozigot untuk polimorfisme menyebabkan ekspresi rendah
of a higher oc- currence of IRIS (187,188). In TBM, mortality is much higher
and intracranial IRIS may be detrimental (189). A randomized controlled trial
sion dari LTA 4 H (C / C) menunjukkan peningkatan mortalitas saat diobati dengan
in Vietnam showed no reduction in mortality with immediate initiation of
deksametason, mungkin karena penekanan lebih lanjut
ARTs; instead, the study suggested that it may be safer to defer the
respon imun yang tidak memadai. Para pasien yang heterozigot pada lokus ini (C /
initiation of ART to 8 weeks of TBM treatment in patients with TBM, as
T) memiliki mortalitas terendah dan penggunaan deksametason tampaknya tidak
delayed treatment was associated with fewer adverse events (31). TBM
mempengaruhi mortalitas pada kelompok ini (181).
IRIS has been reported to be a frequent occurrence in ART-naive pa- tients
who started ART treatment 2 weeks after initiation of TBM treatment (16/34,
Hasil ini menunjukkan bahwa keparahan penyakit pada manusia dapat disebabkan
47%). High CSF neutrophil counts, culture positivity, and a combination of
oleh respon imun yang berlebihan atau defisiensi dan, mungkin yang lebih penting,
high CSF TNF- and low IFN- concentrations on presentation was associated
bahwa pengobatan dengan kortikosteroid mungkin hanya bermanfaat bagi mereka
with development of IRIS (190). For a more elaborate review and guideline
yang memiliki kecenderungan tertentu untuk mengalami hiperinflamasi dan dapat
of ART and TB drug interactions, we refer to the National Institutes of Health
merugikan mereka yang mengalami defisiensi. respons imun. Hal ini membutuhkan
(NIH) guidelines (191).
penilaian prospektif dan jika terbukti mungkin memerlukan penggunaan kortikosteoid
yang lebih disesuaikan menurut genotipe individu atau fenotipe respon imun di masa
depan.

Thalidomide
Aspirin dan Dipiridamol
Thalidomide adalah obat dengan sifat imunomodulator melalui penghambatan
Stroke dikaitkan dengan hasil yang buruk pada TBM. Vaskulitis infiltratif
TNF- (182). Dalam penelitian pada hewan, kadar TNF dalam cairan serebrospinal
dan proliferatif serta patologi pembuluh nekrotikans telah terlibat dalam
yang dihasilkan selama TBM terbukti berkorelasi dengan tingkat patogenesis,
patogenesis. Kontribusi relatif trombosis terhadap perkembangan kejadian
meskipun hal ini sulit untuk ditiru pada manusia dengan TBM (84). Pada kelinci
iskemik tidak diketahui. Tromboflebitis tuberkulosis telah dijelaskan dalam
yang terinfeksi TB secara intrakranial, rejimen antituberkular yang termasuk
studi patologis sebelumnya (64,87). TB paru parah ditandai dengan
thalidomide menyebabkan penurunan kadar TNF di CSF dan mencegah kematian
fibrinolisis yang rusak dan keadaan hiperkoagulasi (192). Pada anak-anak
(183). Kelompok yang sama telah menggunakan analog thalidomide (IMiD3) untuk
dengan TBM, perubahan ditemukan pada prokoagulasi, faktor
pengobatan hewan percobaan yang terinfeksi TBM sebagai tambahan untuk
antitrombotik, fibrinolisis, jumlah trombosit, dan fungsi endotel vaskular,
pengobatan antituberkulosis standar. IMiD3 memiliki aksi imunodulasi yang
semuanya berkontribusi pada peningkatan risiko trombosis (193). Aspirin
sebanding dengan thalidomide, tetapi tidak seperti thalidomide, IMiD3 tidak
telah menjadi sasaran uji klinis pada TBM karena antitrombotik dan
teratogenik. Penggunaan tambahan IMiD3 pada kelinci menghasilkan peningkatan
mungkin pelindung saraf. Namun, sebuah uji klinis pada 146 anak-anak
yang nyata dalam kelangsungan hidup, mengurangi leukositosis CSF,
dengan TBM tidak menunjukkan efek yang signifikan pada mortalitas atau
menurunkan kadar TNF, dan peradangan meninges yang berkurang pada
defisit neurologis dengan dosis rendah atau dosis tinggi aspirin (194). Satu
pemeriksaan histologis. Efek menguntungkan pada kelangsungan hidup dan
studi acak label terbuka pada 118 orang dewasa tentang peran aspirin
keparahan gejala IMiD3 secara nyata lebih besar daripada thalidomide pada
menunjukkan efek menguntungkan pada kematian dan hasil MRI (195).
model hewan ini (184).
Dalam studi ini, beberapa pasien secara selektif menerima kortikosteroid,
yang mungkin memiliki hasil yang bias. Penelitian acak yang lebih besar
dan tepat diperlukan untuk menetapkan peran aspirin (dan dipyridamole)
dalam pengelolaan kejadian iskemik terkait TBM. Dalam pengaturan
Conversely, increases of TNF- concentrations have been reported
perawatan bedah saraf intensif di Afrika Selatan, oksigenasi jaringan otak
during thalidomide treatment, raising more ques- tions about the interaction
dipantau pada dua anak. Penurunan oksigenasi dibalik dengan terapi
between TNF- and thalidomide. A clinical study in 15 adults with TB,
agresif dengan oksigen, resusitasi cairan, dukungan inotropik, dan transfusi
including HIV-positive and HIV-negative patients, showed a reduction in
darah, yang mungkin mencegah infark (196).
disease severity with the use of thalidomide, which was correlated with an
increase in TNF- levels. By contrast, those patients with poor outcome who
were not designated to receive thalidomide continued to demonstrate
clinical progression of the disease and remained with low levels of TNF-
and type 1 cytokines (185).

In children with TBM, a randomized placebo controlled study of

adjunctive thalidomide was stopped early because of an increased risk of
death and adverse events in the treatment arm (186). The role of TNF- in Peningkatan Tekanan Intrakranial dan
TB is complex and has yet to be fully elucidated. Currently, there is no role Hidrosefalus
of TNF- inhibition in the treatment for TBM; however, the potential role for
IMiD3 in the management of TBM in patients may be a subject of future Furosemide dengan atau tanpa acetazolamide dapat digunakan untuk mengobati
pharmacokinetic research. hidrosefalus yang berkomunikasi pada TBM untuk menurunkan produksi CSF oleh
pleksus koroid. Beberapa institusi menyukai

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daily lumbar punctures with intracranial pressure monitoring through
manometry to assess the response to medical therapy. An external
ventricular drain, ventriculoperitoneal shunting, or endoscopic third
ventriculostomy may be indicated for patients not responding to conservative
measures and noncom- municating hydrocephalus (197). Patients for these
procedures should be carefully selected, as the success rate depends on the
correct diagnosis, the severity of disease, and the expertise of the
neurosurgical teams. Outcome is better in patients with early intervention in
the better grades (198). Some institutions use osmotic agents, such as
mannitol or hypertonic saline, however there have been no studies
establishing the effective- ness in TB of the CNS.
Hyponatremia
TBM yang disertai dengan hiponatremia dikaitkan dengan hasil yang lebih buruk.
Sebagian besar disebabkan oleh sindrom sekresi hormon antidiuretik yang tidak
tepat (SIADH) atau sindrom pemborosan garam otak (CSW). CSW mungkin
kurang terdiagnosis pada TBM, dan perbedaan antara kedua entitas seringkali
sulit di rangkaian endemik. Perawatan harus diarahkan untuk menghindari
hipoosmolalitas dan hipovolemia. Pembatasan cairan dapat merugikan dan tidak
dianjurkan. Umumnya, disarankan untuk merawat semua pasien hiponatremia
dengan hati-hati dengan larutan garam hipertonik dengan atau tanpa
udrokortison (197,199). Koreksi harus dilakukan secara bertahap untuk
menghindari mielinolisis pontine.
Genetika Patogen dan Virulensi
M. tuberculosis strains were shown to vary in virulence in the 1960s when
Mitchison et al. conducted experimental infection of Guinea pigs with strains
from South India and Britain (200,201). Many epidemiologic in vitro and in
vivo stud- ies have since attempted to establish differences in virulence with
regard to dissemination and disease severity but no consensus has yet
been established due to often contradic- tory findings and the difficulty of
interpretation (202,203). There is wide variation in experimental technique
in vitro or the comparative strains in both laboratory and epidemio- logic
studies. Evolutionarily, TBM represents a dead end for the pathogen and
therefore propensity to cause TBM is not directly advantageous but may be
a by-product of increased pulmonary virulence causing greater transmission
(204). The standard laboratory strain, H37Rv, which was the first M.
tuberculosis strain sequenced in 1997 (205), is laboratory adapted and
exhibits low virulence in vitro and in animal models in comparison with
almost all clinical strains (206), therefore demonstration of increased
virulence in comparison with H37RV does not represent a “hypervirulent”
strain.
Analysis of large sequence polymorphisms within the
M. tuberculosis genome has defined six major global lineages, which are
largely geographically restricted within the eponymous region; Indo-Oceanic,
Euro-American, East Asian, East African-Indian, and two Mycobacterium
africanum garis-garis. Dalam garis keturunan Asia Timur "modern", genotipe
Beijing telah ditentukan oleh spoligotipe karakteristiknya dan diselidiki secara
ekstensif, karena telah dikaitkan dengan peningkatan virulensi dan resistensi
obat di beberapa wilayah (207-212). Pengenalan genotipe Beijing ke
beberapa daerah juga mengakibatkan peningkatan cepat dalam prevalensi
strain ini (212). Di Vietnam, di antara kasus TBM, hal itu menunjukkan
hubungan yang signifikan dengan status HIV, resistansi obat, dan resistansi
multidrug (213) dibandingkan dengan Euro-American.
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Bab 29: Meningitis Tuberkulosis 495
and Indo-Oceanic strains. HIV-negative patients infected with the
Beijing-strain had shorter duration of illness before presentation to hospital
and fewer CSF leukocytes, suggesting that mycobacterial genotype may
affect disease progression and the nature of the intracerebral inflammatory
response (214). Studies in South African children have also shown an
association between Beijing genotype and extrapulmonary TB (208). A
recent retrospective cohort study of TBM patients in Thailand supported the
theory that the Beijing genotype is the most pathogenic strain of M.
tuberculosis and associated with TBM, whereas the Euro-American lineage
was much less commonly linked with TBM. Results showed that modern
sublineages of Beijing genotype were associated with higher CSF WCC and
more severe (stage III) disease but not with mortality rate (215). Conversely,
among HIV-positive patients in Vietnam, those infected with the modern
Beijing lineage strains had lower mortality than patients infected with the
ancient Indo-Oceanic lineage (HR, 0.29; 95% CI, 0.14; 0.61) (214). This
contradictory finding might be explained by the proinflammatory properties
of the modern Beijing lineages, which although detrimental to the
immunocompetent host may be conversely protective in the
immunocompromised. It is known that protective immunity in TB disease is
a delicate bal- ance of pro- and antiinflammatory cascades. However,
studies in other regions have found no association between Beijing
genotype and dissemination (216–218). Within each region, the M.
tuberculosis genotypes circulating vary significantly as do the genotyping
divisions applied to analysis and therefore the pathogen populations being
compared are not identical. Wider studies synthesizing global data are
required to estab- lish definitive interpretation.
Genetika-Host
Telah lama diketahui bahwa ada unsur genetik pada kerentanan TB. Dari
mereka yang terpapar M. tuberculosis, approxi- mately 10% establish an
infection and, of those, 10% will develop active disease while the remaining
individuals will harbor a latent infection. Approximately 1% of active TB
cases develop into TBM. Susceptibility to the different forms of TB (latent,
active, disseminated) is a complex interplay between host genetics,
pathogen genetics, and environmental factors (such as smoking,
malnutrition, comorbidities).
Protective immunity to TB depends on innate immunity
and an effective TH 1 response, as evidenced by the dramatic increase in
susceptibility shown by HIV-infected individuals.
Many candidate genes have been proposed to be associated with
susceptibility to pulmonary TB (219–222), but fewer studies have looked at
the association between host genetics and susceptibility to severe and
disseminated disease. The toll-like (TLR) receptor pathway has been
implicated in TB progression. The human TLR family has 12 members that
can recognize pathogen-associated molecular patterns (PAMPs) and upon
activation initiate an innate immune response, cytokine production, and the
formation of the adaptive immune response. The TLRs known to be
involved in M. tuberculosis recognition are TLR2, TLR4, TLR9, and possibly
TLR8 (223). One of the few host genetic studies to investigate susceptibility
factors for TBM as distinct from pulmonary TB showed an association
between a polymorphism in the TLR2 gene (SNP T597C) and the
development of TBM and miliary TB, indicating the TLR2 pathway plays a
role in the ability to disseminate of M. tuberculosis ( 214). However, this
polymor- phism is itself synonymous, and the causative single nucleotide
polymorphism (SNP) in linkage disequilibrium has not yet been identified.
Further studies investigating the interaction
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 496 Part III: Bacterial and Mycoplasmal Infections
between host and pathogen in TBM susceptibility have shown that
individuals with the TLR2 polymorphism are more likely to be infected with
the Beijing genotype of M. tuberculosis
and that this association is strongest in those with TBM (214).
Polymorphisms in the toll-interleukin 1 receptor domain-con- taining adaptor
protein (TIRAP) gene have also been shown to be associated with
susceptibility to TBM in Vietnam and South Africa (224,225). TIRAP is a
protein further down the TLR pathway, which mediates signals from the TLR
receptors, activating macrophages and dendritic cells.
Recently a SNP in the promoter region of the LTA 4 H gene has been
identified to play a role in susceptibility to myco-
bacteria which is discussed in more detail in the section on corticosteroid
treatment. Future research on host genetic susceptibility to TB and TBM will
need to explore the poten- tial of genetically tailored adjunctive therapies.
CONCLUSION
CNS TB is a devastating form of TB. In resource-limited settings, it places a
high burden on patients, their fami- lies, society, and health care systems.
Disease incidence is a direct reflection of the TB epidemic and complicated
by the MDR/XDR TB and HIV epidemic. The current develop- ments in
TBM research have advanced our understanding of the disease; however,
they have not led to acceptable im- provements in clinical outcomes. Early
diagnosis and treat- ment initiation are essential to a good outcome. The
recent endorsement of the GeneXpert test for pulmonary TB may impact
the management of MDR TBM in particular, which is highly lethal, and
offers the potential for improved diag- nostics for TBM. However, more
robust evidence must be generated to validate the specificity for rifampicin
resistance on CSF, because withholding rifampicin from treatment regi-
mens for sensitive strains may be detrimental. Little is known about the
optimal second-line treatment regimen for MDR TBM and this may pose TB
programs and clinicians with a problem when confronted with a
rifampicin-resistant positive result on GeneXpert, without an elaborate drug
sensitivity spectrum. Both first- and second-line treatment will need to be
optimized for TBM according to the ability of antimyco- bacterial drugs to
penetrate the brain. Still, there is a pressing
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relief of fluid pressure. Lancet. 1891;1:981–982. Morton CA. The pathology of tuberculous
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need for the development of a rapid, sensitive, point of care diagnostic that
can be used in decentralized settings. This will lead to a reduction in
frequently encountered disastrous treat- ment delays.
Currently, the TB drug pipeline has 10 compounds in the clinical
development phase for both MDR and drug-sensitive TB
(http://www.newtbdrugs.org/pipeline.php). Because the pipeline is aimed to
create affordable, tolerable, active new antimycobacterials for pulmonary
TB, CSF penetration is not necessarily an attribute that these candidate
compounds have been developed for. Assessing any new drug that
emerges from the pipeline will need to be subjected to well-designed,
adequately powered clinical trials for TBM, which are resource consuming
and difficult to achieve and will require multisite involvement. Other areas of
future research for TBM treatment should include the benefit of adjunctive
drugs such as aspirin or immune-modulating drugs, which may reduce
sequelae. In general, future trials should be aimed at efficiency by using
innovative trial designs, making more efficient use of existing drugs, and by
basing the trial rationale on existing pharmacokinetic/pharmacodynamic
data, in particular, the ability to penetrate the brain. Protection conferred by
BCG vaccine is insufficient. The TB vaccine pipeline has 11 vac- cine
candidates entered in clinical trials. (http://www.tbvi
. eu/fileadmin/user_upload/Documenten/News/TB_Vaccine_
Pipeline_2011_FINAL03042012.pdf). Most are preexpo- sure vaccines
aimed to prevent TB disease intended to either replace BCG (recombinant
live vaccines) or to be given after BCG prime as boosters (either protein
adjuvant formulations or recombinant viral carriers) (226). Recently,
MVA85A, a booster vaccine for BCG, was subjected to the first efficacy trial
since BCG; however, it failed to prove a statistically sig- nificant effect
(227). The development of an effective vaccine has the potential to greatly
influence the TB epidemic, how- ever requiring renewed funding incentives,
appropriately structured trials, and eventually government commitment to
support vaccination strategies. It is a less popular notion, but fundamental
to the control of both the TB and HIV pandemics is the commitment of
policymakers to address socioeconomic issues, such as poverty, crowding,
lack of education, failing health care infrastructure, and lack of access to
health care— factors significantly contributing to the perpetuation of these
epidemics.
14. Kwapinski J. [Streptomycin resistance of Mycobacterium tuberculosis
cultured in cerebro-spinal fluid]. Gruzlica. 1950;18(3–4):437–447. Long ER. [Resistance of Mycobacterium
15. tuberculosis to streptomycin]. Rev Bras Tuberc Doencas Torac. 1950;18(130):440–454.
16. Muratore A. [Study of streptomycin resistance of the bacterial flora of the tuberculous
meningitis departments and its relation with the insurgence of supervening meningitis
during streptomycin therapy]. Riv Clin Pediatr.
1950;48(5):291–304.
17. Pothmann FJ, Fehr KO. [Resistance of the tubercle bacillus to streptomycin and to
streptomycin in combination with TB I in tuberculous meningitis].
Beitr Klin Tuberk Spezif Tuberkuloseforsch. 1950;103(5):422–430. Donald PR. The
18. chemotherapy of tuberculous meningitis in children and adults. Tuberculosis (Edinb). 2010;90(6):375–392.
Centers for Disease Control and Prevention. HIV and TB Factsheet.
19.
Atlanta: Centers for Disease Control and Prevention; 2011:2.
20. Lozano R, Naghavi M, Foreman K. Global and regional mortality from 235 causes of death for
20 age groups in 1990 and 2010: a systematic anal- ysis for the Global Burden of Disease
Study 2010. Lancet. 2012;380(9859): 2095–2128.
21. World Health Organization. Global Tuberculosis Control: WHO Report
2011. Geneva: World Health Organization; 2011:258.
22. Wolzak NK, Cooke ML, Orth H, et al. The changing profile of pediatric meningitis at a
referral centre in Cape Town, South Africa. J Trop Pediatr.
2012;58(6):491–495.
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