konsep dasar meningitis tb.docx

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Konsep Dasar Meningitis TB

Pengertian

Meningitis tuberkulosis adalah infeksi pada meningen yang disebabkan oleh basiltahan asam Mycobacterium tuberculosis (Dewanto, 2!"#

Meningitis tuberkulosis adalah peradangan pada selaput meningen, cairanserebrospinal dan spinal kolumna yang menyebabkan proses infeksi pada sistemsaraf pusat ($arsono, 2%"#

Meningitis tuberkulosis adalah penyebaran tuberkulosis primer dengan fokus infeksiditempat lain (Mans&oer, 2"#

Meningitis tuberkulosis adalah komplikasi infeksi primer dengan atau tanpapenyebaran milier ('ditama, 22"#

tiologiPenyakit meningitis tuberkulosis disebabkan oleh Mycobacterium tuberculosishumanus, sedangkan menurut peneliti yang lain dalam literatur yang berbedameningitis Tuberkulosis disebabkan oleh duamicobacterium yaitu Mycobacteriumtubeculosis dan Mycobacterium bo)is yang biasanya menyebabkan infeksi padasapi dan &arang pada manusia# Mycobacterium tuberculosis merupakan basil yangberbentuk batang, berukuran ,2*,+ m - .,*.m, tidak bergerak dan tidakmembentuk spora# Mycobacterium tuberculosis bersifat obligat aerob, hal inimenerangkan predileksinya pada &aringan yang oksigenasinya tinggi seperti apeksparu, gin&al dan otak#

Mycobacterium tidak tampak dengan pewarnaan gram tetapi tampak denganpewarnaan /iehl*0eelsen# Basil ini bersifat tahan asam, artinya tahan terhadappewarnaan carbolfuchsin 1ang menggunakan campuran asam klorida*etanol# ifattahan asam ini disebabkan karena kadar lipid yang tinggi pada dinding selnya# 3ipidpada dinding sel basil Mycobacterium tuberculosis meliputi hampir +4 dari dindingselnya, dan merupakan hidrokarbon rantai pan&ang yang disebutasam mikolat#Mycobacterium tuberculosa tumbuh lambat dengan doubletime dalam .5*26 &am,maka secara klinis kulturnya memerlukan waktu 5 minggu sebelum dinyatakannegatif#

Pato7siologi

Meningitis tuberkulosis pada umumnya sebagai penyebaran infeksituberkulosisprimer ditempat lain# Biasanya fokus infeksi primer di paru* paru# Tuberkulosissecara primer merupakan penyakit pada manusia# 8eser)oir infeksi utamanyaadalah manusia, dan penyakit ini ditularkandari orang ke orang terutama melaluipartikel droplet yang dikeluarkanoleh penderita tuberkulosis paru pada saat batuk#Partikel*partikel yang mengandung Mycobacterium tuberculosis ini dapat bertahan



lama di udaraatau pada debu rumah dan terhirup masuk kedalam paru*paru orangsehat# Pintu masuk infeksi ini adalah saluran nafas sehingga infeksi pertamabiasanya ter&adi pada paru*paru# Transmisi melalui saluran cerna dan kulit &arangter&adi#

Droplet yang terinfeksi mencapai al)eoli dan berkembang biak dalamruang al)eoli,makrofag al)eoli maupun makrofag yang berasal darisirkulasi# e&umlah kumanmenyebar terutama ke kelen&ar getah beninghilus# 3esi primer pada paru*paruberupa lesi eksudatif parenkimal dankelen&ar limfenya disebut kompleks 9:hon;#Pada fase awal kuman darikelen&ar getah bening masuk kedalam aliran darahsehingga ter&adi penyebaran hematogen# Dalam waktu 2*6 minggu setelahterinfeksi, terbentuklah responimunitas selular terhadap infeksi tersebut# 3imfosit*Tdistimulasi oleha ntigen basil ini untuk membentuk limfokin, yang kemudianmengakti)asi sel fagosit mononuklear dalam aliran darah# Dalam makrofag yang

diakti)asi ini organisme dapat mati, tetapi sebaliknya banyak &uga makrofag yangmati# Kemudian terbentuklah tuberkel terdiri dari makrofag, limfosit dan sel*sel lainmengelilingi &aringan nekrotik dan perki&uan sebagai pusatnya# etelah infeksipertama dapat ter&adi dua kemungkinan, pada orang yang sehat lesi akan sembuhspontan dengan meninggalkan kalsi7kasi dan &aringan 7brotik# Pada orang dengandaya tahan tubuh yang rendah, penyebaran hematogen akan menyebabkan infeksiumum yang fatal, yang disebut sebagai tuberkulosis millier diseminata# Padakeadaan dimana respon host masih cukup efektif tetapi kurang e7sien akan timbulfokus perki&uan yang besar dan mengalami enkapsulasi 7brosa tetapi menyimpanbasil yang dorman# Klien dengan infeksi laten memiliki resiko .4 untukberkembang men&adi tuberkulosis aktif# 8eakti)asi dari fokus perki&uanakan ter&adibila daya tahan tubuh host menurun, maka akan ter&adi pembesaran tuberkel, pusatperki&uan akan melunak dan mengalami pencairan, basil mengalami proliferasi, lesiakan pecah lalu melepaskanorganisme dan produk*produk antigen ke &aringandisekitarnya# 'pabilahal*hal yang di&elaskan di atas ter&adi pada susunan sarafpusat maka akan ter&adi infeksi yang disebut meningitis tuberkulosis# <okus tuberkelyang berlokasi dipermukaan otak yang berdekatandengan ruang sub arakhnoid danterletak sub ependimal disebut sebagai 9<ocus 8ich;# 8eakti)asi dan ruptur darifokus rich akan menyebabkan pelepasan basil Tuberkulosis dan antigennya kedalamruang sub arakhnoidatau sistem )entrikel, sehingga ter&adi meningitis tuberkulosis#

Tanda dan :e&ala:e&ala meningitis diakibatkan dari infeksi dan peningkatan T=K>

akit kepala dan demam adalah ge&ala awal yang sering#

Perubahan pada tingkat kesadaran dapat ter&adi letargi, tidak responsif dan koma



=ritasi meningen mengakibatkan se&umlah tanda sebagai berikut> 8igiditasi nukal(kaku leher" upaya untuk ?eksi kepala mengalami kesukaran karena adanya spasmeotot leher, Tanda kernik positif@ ketika pasien di baringkan dengan paha dalamkeadaan ?eksi ke arah abdomen, kaki tidak dapat diekstensikan sempurna, TandabrudAiki@ bila leher pasien di ?eksikan maka di hasilkan ?eksi lutut dan pinggul# Bila

dilakukan ?eksi pasif pada ekstermitas bawah pada salah satu sisi ekstermitas yangberlawanan#

Mengalami foto fobia atau sensitif yang berlebihan pada cahaya#

Ke&ang akibat area fokal kortikal yang peka dan peningkatan T=K

'danya ruam merupakan ciri menyolok pada meningitis meningokokal#

=nfeksi fulminating dengan tanda*tanda septikemia > demam tinggi tiba*tiba muncullesi purpura yang menyebar, syok dan tanda koagulopati intra)askuler diseminata(metAer et al#, 2."#

:e&ala klinik meningitis berdasarkan stadium adalah sebagai berikiut>

tadium = > tadium prodomal berlangsung lebih kurang 2 sampai bulan#Permulaan penyakit ini bersifat sub akut, sering panas atau kenaikan suhu yangringan atau hanya dengan tanda*tanda infeksi umum, tak ada nafsu makan,muntah*muntah, murung, berat badan turun, tak ada gairah, mudah tersinggung,cengeng, tidur terganggu dan gangguan kasadaran berupa apatis, ge&ala*ge&ala tadilebih sering terlihat pada anak kecil# 'nak yang lebih besar mengetahui nyerikepala, tak ada nafsu makan, obstipasi, muntah*muntah, pola tidur terganggu@ padaorang dewasa terdapat panas yang hilang timbul, nyeri kepala, konstipasi, tak ada

nafsu makan, foto fobia, nyeri punggung, halusinasi, delusi dan sangat gelisah#

tadium == > :e&ala*ge&ala terlihat lebih berat, terdapat ke&ang umum atau fokalterutama pada anak kecil dan bayi# Tanda*tanda rangsangan meningeal mulainyata, seluruh tubuh dapat men&adi kaku dan timbul opistotonus, terdapat tanda*tanda peningkatan tekanan intrakranial, ubun*ubun menon&ol dan muntah lebihhebat# 0yeri kepala bertambah berat dan progresif menyebabkan si anak berteriakdan menangis dengan nada yang khas yaitu meningeal cry# Kesadaran makinmenurun# Terdapat gangguan ner)us kranial antara lain > 0 ==, ===, =C, C=, C== dan C===#Dalam stadium ini dapat ter&adi de7sit neurologis fokal seperti hemiparesis,hemiplegia karena infark otak dan rigiditas deserebrasi# Pada funduskopi dapatditemukan atro7 0# == dan koroid dan ukurannya sekitar setengah diameter papil#

tadium ===> Dalam stadium ini suhu tidak teratur dan semakin tinggi yangdisebabkan oleh terganggunya regulasi pada diensefalon# Pernapasan dan nadi &ugatidak teratur dan terdapat gangguan dalam bentuk cheyne*stokes atau kussmaul#:angguan miksi berupa retensi atau inkontinesia urin# Di dapatkan pula adanyagangguan kesadaran makin menurun sampai koma yang dalam# Pada stadium ini



penderita dapat meninggal dunia dalam waktu minggu bila tidak memperolehpengobatan sebagaimana mestinya#

%# Komplikasi

Peningkatan tekanan intrakranial

$ydrosephalus

De7sit saraf kranial

nsepalitis

yndrome of inapporiate secretion of antidiuretic hormone (='D$"#

'bses otak

Kerusakan )isual

De7sit intelektual

Ke&ang

ndokarditis

Pneumonia (Tarwoto, 2"#

+# Pemeriksaan penun&ang

Pemeriksaan radiologi pada meningitis tuberkulosis meliputi pemeriksaan 8ontgent

thora-, T*scan, M8=# Pada klien dengan meningitis tuberkulosis umumnyadidapatkan gambaran tuberkulosis paru primer pada pemeriksaan rontgen tthoraks,kadang * kadang disertai dengan penyebaran milier dan kalsi7kasi# edangkan padapemeriksaan T*scan dan M8= dapat terlihat adanya hidrosefalus, in?amasimeningen dan tuberkoloma# :ambaran rontgent thoraks yang normal tidakmenyingkirkan diagnosa meningitis tuberkulosis#

Tes Tuberkulin > Tuberkulin hanya mendeteksi reaksi hipersensiti7tas lambat,tidakmenandakan adanya infeksi aktif sehingga penggunaannyauntuk mendiagnosisinfeksi aktif dan meningitis tuberkulosis masih kurang sensitif# 0amun pemeriksaantuberkulin yang positif pada anak memiliki nilai diagnostik, sementara pada orang

dewasa hanya menandakan adanya riwayat kontak dengan antigen tuberkulosis,dan dapat memberikan arah untuk pemeriksaan selan&utnya#

airan erebrospinal > Pemeriksaan cairan serebrospinal merupakan diagnostikyangefektif untuk mendiagnosis meningitis tuberkulosis# :ambaran cairanserebrospinal yang karakteristik pada meningitis tuberculosis adalah> airan &ernihsedikit kekuningan atau -antocrom, Pleositosis yang moderat biasanya antara .*



6 selEmm dengan predominan limfosit, Kadar glukosa yang rendah *6% mgEd3atau kurang dari%4 nilai glukosa darah# Peningkatan kadar protein#

Bakteriologi =denti7kasi basil tuberkulosis pada cairan serebrospinal memilikiakurasiyang sangat tinggi hingga .4 dalam mendiagnosismeningitis tuberkulosis# Fntuk

mendiagnosis basil tersebut dapatdilakukan dengan cara pemeriksaan apuslangsung BT' dengan metode /iehl*0eelsen dan dengan cara kultur pada cairanserebrospinal#

Pemeriksaan Biokimia> Pemeriksaan ini untuk mengukur sifat tertentu darimycobacterium atau respon tubuh penderita terhadap mycobacterium#

Tes =mmunologis1ang mendeteksi antigen atau antibody mikobakterial dalamcairanserebrospinal, metoda yang sering digunakan dalam tesimunologis antara lain>3=' (enAym linked immuno sorbent assay" dan Polymerase hain 8eaction (P8"

G# Penatalaksanaan Medic

Penatalaksanan meningitis tuberculosis adalah H'T

fek samping H'T >

." =soniaAid ($"

fek samping berat yaitu ter&adi hepatitis dan ter&adi pada kira*kira ,%4 dari kasus#Bila ter&adi maka pengobatan dihentikan, dan setelah pemeriksaan faal hati kembalinormal pengobatan dapat dilaksanakan kembali

fek samping ringan berupa

(a" Tanda*tanda keracunan saraf tepi, kesemutan, anastesia dan nyeri otot

(b" Kelainan yang menyerupai syndroma pellagra

(c" Kelainan kulit yang ber)ariasi antara lain gatal*gatal

2" 8ifampisin (8"

feksamping berat &arang ter&adi seperti > sesak nafas yang kadang*kadang disertaikollaps atau syok, anemia hemolitik, purpura dan gagal gin&al# fek samping ringanseperti > gatal*gatal, kemerahan, demam, nyeri tulang, nyeri perut, mual muntah

dan kadang*kadang diare#

" PyraAinamid (/"

fek samping utama adalah hepatitis, dapat ter&adi nyeri sendi dan kadang*kadangserangan penyakit gout#

6" thambutol ("



Dapat menyebabkan gangguan penglihatan, berkurangnya keta&aman penglihatan,kabur dan buta warna merah dan hi&au#

b" teroid

Diberikan untuk>

." Menghambat reaksi in?amasi

2" Mencegah komplikasi

" Menurunkan edema serebri

6" Mencegah perlekatan

%" Mencegah arteritisEinfark otak

=ndikasi>

." Kesadaran menurun

2" De7sit neurologis fokal

Dosis>

Deksametason . mg bolus intra)ena, kemudian 6 kali % mg intra)ena selama 2*minggu selan&utnya turunkan perlahan selama . bulan (Mans&oer et al, 2"#

Tu&uan pengobatan terhadap penderita tuberkulosis adalah menyembuhkanpenderita dari penyakit tuberkulosis yang dideritanya, mencegah kematian akibat

tuberkulosis, mencegah ter&adinya relaps, mencegah penularan dan sekaligusmencegah ter&adinya resistensi terhadap Hbat 'nti Tuberkulosis (H'T" yangdiberikan#

Perawatan

Perawatan penderita meliputi berbagai aspek yang harus diperhatikan dengansungguh*sungguh, antara lain kebutuhan cairan dan elektrolit, kebutuhan nutrisi,posisi klien, perawatan kandung kemih, dan defekasi serta perawatan umumlainnya sesuai dengan kondisi klien#

Pemberian nutrisi melalui 0:T'tur posisi yang nyaman

3.1 Definisi



Meningitis merupakan salah satu infeksi pada susunan

saraf pusat yang mengenai selaput otak dan selaput medulla spinalis yang juga disebut sebagai

meningens. Meningitis dapat disebabkan oleh berbagai jenis mikroorganisme seperti bakteri, virus,

jamur dan parasit. Meningitis Tuberkulosis tergolong ke dalam meningitis yang disebabkan oleh bakteri

yaitu Mycobacterium Tuberkulosa. Bakteri tersebut menyebar ke otak dari bagian tubuh yang lain.

3.2 Epidemiologi

Meningitis TB merupakan salah satu komplikasi TB primer. Morbiditas dan mortalitas penyakit ini tinggi

dan prognosisnya buruk. Komplikasi meningitis TB terjadi setiap 300 TB primer yang tidak diobati. !

melaporkan pada tahun "##0 morbiditas meningitis TB $,%& dari TB ekstrapulmonal. 'nsiden meningitis

TB sebanding dengan TB primer, umumnya bergantung pada status sosio(ekonomi, higiene masyarakat,

umur, status gi)i dan faktor genetik yang menentukan respon imun seseorang. *aktor predisposisi

berkembangnya infeksi TB adalah malnutrisi, penggunaan kortikosteroid, keganasan, cedera kepala,

infeksi +' dan diabetes melitus. -enyakit ini dapat menyerang semua umur, anak(anak lebih sering

dibanding dengan deasa terutama pada / tahun pertama kehidupan. arang ditemukan pada usia

dibaah $ bulan dan hampir tidak pernah ditemukan pada usia dibaah 3 bulan.

3.3 Anatomi Fisiologi

1tak dan sumsum otak belakang diselimuti meningea yang melindungi struktur syaraf yang halus,

membaa pembuluh darah dan dengan sekresi sejenis cairan yaitu cairan serebrospinal. Meningea

terdiri dari tiga lapis, yaitu2

• -ia meter 2 yang menyelipkan dirinya ke dalam celah pada otak dan sumsum tulang belakang

dan sebagai akibat dari kontak yang sangat erat akan menyediakan darah untuk struktur(struktur

ini.

• rachnoid 2 Merupakan selaput halus yang memisahkan pia meter dan dura meter.

• !ura meter 2 Merupakan lapisan paling luar yang padat dan keras berasal dari jaringan ikat

tebal dan kuat.



3.4 Etiologi

Kebanyakan kasus meningitis disebabkan oleh mikroorganisme, seperti virus, bakteri, jamur, atau

parasit yang menyebar dalam darah ke cairan otak.

-enyebab infeksi ini dapat diklasifikasikan atas 2

". Bakteri2

• -neumococcus

• Meningococcus

• +aemophilus influen)a

• 4taphylococcus

• 5scherichia coli

• 4almonella

• Mycobacterium tuberculosis

%. irus 2

• 5nterovirus

3. amur 2

• ryptococcus neoformans

• occidioides immitris



-ada laporan kasus meningitis tuberkulosa ini, mycobacterium tuberculosis merupakan faktor penyebab

paling utama dalam terjadinya penyakit meningitis.

3.5 Patogenesis

Meningitis TB terjadi akibat penyebaran infeksi secara hematogen ke meningen. !alam perjalanannya

meningitis TB melalui % tahap. Mula(mula terbentuk lesi di otak atau meningen akibat penyebaran basilsecara hematogen selama infeksi primer. -enyebaran secara hematogen dapat juga terjadi pada TB

kronik, tetapi keadaan ini jarang ditemukan. 4elanjutnya meningitis terjadi akibat terlepasnya basil

dan antigen TB dari fokus kaseosa 6lesi permulaan di otak7 akibat trauma atau proses imunologik,

langsung masuk ke ruang subarakhnoid. Meningitis TB biasanya terjadi 38$ bulan setelah infeksi primer.

Kebanyakan bakteri masuk ke cairan serebro spinal dalam bentuk kolonisasi dari nasofaring atau secara

hematogen menyebar ke pleksus koroid, parenkim otak, atau selaput meningen. ena(vena yang

mengalami penyumbatan dapat menyebabkan aliran retrograde transmisi dari infeksi. Kerusakan

lapisan dura dapat disebabkan oleh fraktur , paska bedah saraf, injeksi steroid secara epidural,

tindakan anestesi, adanya benda asing seperti implan koklear, - shunt, dll. 4ering juga kolonisasi

organisme pada kulit dapat menyebabkan meningitis. 9alaupun meningitis dikatakan sebagai

peradangan selaput meningen, kerusakan meningen dapat berasal dari infeksi yang dapat berakibat

edema otak, penyumbatan vena dan memblok aliran cairan serebrospinal yang dapat berakhir dengan

hidrosefalus, peningkatan intrakranial, dan herniasi

Skema patofisiologi meningitis tuberkulosa

BT masuk tubuh

↓

Tersering melalui inhalasi

arang pada kulit, saluran cerna

↓

Multiplikasi

↓

'nfeksi paru : focus infeksi lain

↓

-enyebaran hematogen

↓

Meningens

↓

Membentuk tuberkel

↓



BT tidak aktif : dormain

Bila daya tahan tubuh menurun

↓

;upture tuberkel meningen

↓

-elepasan BT ke ruang subarachnoid

↓

M5<'<='T'4

3.6 anifestasi !linis

=ejala klinis meningitis TB berbeda untuk masing(masing penderita. *aktor(faktor yang bertanggung

jaab terhadap gejala klinis erat kaitannya dengan perubahan patologi yang ditemukan. Tanda dan

gejala klinis meningitis TB muncul perlahan(lahan dalam aktu beberapa minggu.

Keluhan pertama biasanya nyeri kepala. ;asa ini dapat menjalar ke tengkuk dan punggung. Tengkuk

menjadi kaku. Kaku kuduk disebabkan oleh mengejangnya otot(otot ekstensor tengkuk. Bila hebat,

terjadi opistotonus, yaitu tengkuk kaku dalam sikap kepala tertengadah dan punggung dalam sikap

hiperekstensi. Kesadaran menurun.tanda Kernig>s dan Brud)insky positif.

=ejala meningitis tidak selalu sama, tergantung dari usia si penderita serta virus apa yang

menyebabkannya. =ejala yang paling umum adalah demam yang tinggi, sakit kepala, pilek, mual,

muntah, kejang. 4etelah itu biasanya penderita merasa sangat lelah, leher terasa pegal dan kaku,

gangguan kesadaran serta penglihatan menjadi kurang jelas.

=ejala pada bayi yang terkena meningitis, biasanya menjadi sangat reel muncul bercak pada kulit

tangisan lebih keras dan nadanya tinggi, demam ringan, badan terasa kaku, dan terjadi gangguan

kesadaran seperti tangannya membuat gerakan tidak beraturan.

=ejala meningitis meliputi 2



• =ejala infeksi akut

v -anas

v <afsu makan tidak ada

v nak lesu

• =ejala kenaikan tekanan intracranial

v Kesadaran menurun

v Kejang(kejang

v ?bun(ubun besar menonjol

• =ejala rangsangan meningeal

v kaku kuduk

v Kernig

v Brud)inky ' dan '' positif

=ejala klinis meningitis tuberkulosa dapat dibagi dalam 3 stadium 2%

4tadium ' 2 4tadium aal

• =ejala prodromal non spesifik 2 apatis, iritabilitas, nyeri kepala, malaise, demam, anoreksia

4tadium '' 2 'ntermediate

• =ejala menjadi lebih jelas

• Mengantuk, kejang,• !efisit neurologik fokal 2 hemiparesis, paresis saraf kranial6terutama <.''' dan <.'', gerakan

involunter

• +idrosefalus, papil edema

4tadium ''' 2 dvanced

• -enurunan kesadaran

• !isfungsi batang otak, dekortikasi, deserebrasi

3." Diagnosis

!iagnosa pada meningitis TB dapat dilakukan dengan beberapa cara 2@

". namnese 2 ditegakkan berdasarkan gejala klinis, riayat kontak dengan penderita TB

%. Aumbal pungsi

=ambaran A4 pada meningitis TB 2

• 9arna jernih : antokrom

• umlah 4el meningkat M< C -M<

• Aimfositer



• -rotein meningkat

• =lukosa menurun D/0 & kadar glukosa darah

-emeriksaan tambahan lainnya 2

• Tes Tuberkulin

• Eiehl(<eelsen 6 E< 7• -; 6 -olymerase hain ;eaction 7

3. ;ontgen thora

• TB ape paru

• TB milier

F. T scan otak

• -enyengatan kontras 6 enhancement 7 di sisterna basalis

• Tuberkuloma 2 massa nodular, massa ring(enhanced

• Komplikasi 2 hidrosefalus

/. M;'

!iagnosis dapat ditegakkan secara cepat dengan -;, 5A'4 dan aglutinasi Aate. Baku emas diagnosis

meningitis TB adalah menemukan M. tb dalam kultur 44. <amun pemeriksaan kultur 44 ini

membutuhkan aktu yang lama dan memberikan hasil positif hanya pada kira(kira setengah dari

penderita

3.# Penatalaksanaan

Terapi *armakologis yang dapat diberikan pada meningitis TB berupa 2

• ;ifampicin 6 ; 7 5fek samping 2 +epatotoksik

• '<+ 6 + 7 5fek samping 2 +epatotoksik, defisiensi vitamin B$

• -yra)inamid 6 E 7 5fek samping 2 +epatotoksik

• 4treptomycin 6 4 7 5fek samping 2 =angguan pendengaran dan vestibuler

• 5thambutol 6 5 7 5fek samping 2 <euritis optika

;egimen 2 ;+E5 : ;+E4

$ama %bat D%S&S

'<+ !easa 2 "0("/ mg:kgBB:hariGpiridoksin /0 mg:hari

nak 2 %0 mg:kgBB:hari

4treptomisin %0 mg:kgBB:hari i.m selama 3 bulan

5tambutol %/ mg:kgBB:hari p.o selama % bulam pertama!ilanjutkan "/ mg:kgBB:hari;ifampisin !easa 2 $00 mg:hari nak "0(%0 mh:kgBB:hari

!i samping tuberkulostatik dapat diberikan rangkaian pengobatan dengan deksametason untuk

menghambat edema serebri dan timbulnya perlekatan(perlekatan antara araknoid dan otak.

4teroid diberikan untuk2

• Menghambat reaksi inflamasi



• Mencegah komplikasi infeksi

• Menurunkan edema serebri

• Mencegah perlekatan

• Mencegah arteritis:infark otak

'ndikasi 4teroid 2

• Kesadaran menurun

• !efisit neurologist fokal

!osis steroid 2

!eksametason "0 mg bolus intravena, kemudian F kali / mg intravena selama % minggu selanjutnya

turunkan perlahan selama " bulan.

Bagan -enatalaksanaan Meningitis

ika dijumpai tanda klinis meliputi 2

"7 -anas

%7 Kejang

37 Tanda rangsang meningeal

F7 -enurunan kesadaran

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3.' Prognosis

-rognosis meningitis tuberkulosa lebih baik sekiranya didiagnosa dan diterapi seaal mungkin. 4ekitar

"/& penderita meningitis nonmeningococcal akan dijumpai gejala sisanya. 4ecara umumnya, penderita

meningitis dapat sembuh, baik sembuh dengan cacat motorik atau mental atau meninggal tergantung 2

• umur penderita.

• enis kuman penyebab

• Berat ringan infeksi

• Aama sakit sebelum mendapat pengobatan• Kepek

Tuberculosis 8esearch and Treatment

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Tuberculous Meningitis> Diagnosis and Treatment H)er)iew

:race # Mar-. and dward D# han.,2,,6,%

.Department of Medicine, Fni)ersity of olorado Den)er 'nschutA Medical ampus,'urora, H 56%, F'

2Di)ision of Pulmonary ciences and ritical are Medicine, Fni)ersity of oloradoDen)er 'nschutA Medical ampus, 'urora, H 56%, F'

Den)er Ceterans 'Iairs Medical enter, Den)er, H 522*55, F'

6Department of Medicine, 0ational Jewish $ealth, Den)er, H 52+, F'

%Program in ell Biology, 0ational Jewish $ealth, Den)er, H 52+, F'

8ecei)ed eptember 2..@ 8e)ised .+ 0o)ember 2..@ 'ccepted .5 0o)ember2..

'cademic ditor> arlo :arAelli

opyright 2.. :race # Mar- and dward D# han# This is an open access articledistributed under the reati)e ommons 'ttribution 3icense, which permitsunrestricted use, distribution, and reproduction in any medium, pro)ided the

original work is properly cited#

'bstract

Tuberculous meningitis (TBM" is the most common form of central ner)ous systemtuberculosis (TB" and has )ery high morbidity and mortality# TBM is typically asubacute disease with symptoms that may persist for weeks before diagnosis#

haracteristic cerebrospinal ?uid (<" 7ndings of TBM include a lymphocytic*predominant pleiocytosis, ele)ated protein, and low glucose# < acid*fast smearand culture ha)e relati)ely low sensiti)ity but yield is increased with multiple, large)olume samples# 0ucleic acid ampli7cation of the < by P8 is highly speci7c butsuboptimal sensiti)ity precludes ruling out TBM with a negati)e test# Treatment for TBM should be initiated as soon as clinical suspicion is supported by initial <studies# mpiric treatment should include at least four 7rst*line drugs, preferablyisoniaAid, rifampin, pyraAinamide, and streptomycin or ethambutol@ the role of



?uoroLuinolones remains to be determined# 'd&uncti)e treatment withcorticosteroids has been shown to impro)e mortality with TBM# =n $=C*positi)eindi)iduals with TBM, important treatment considerations include drug interactions,de)elopment of immune reconstitution in?ammatory syndrome, unclear bene7t ofad&uncti)e corticosteroids, and higher rates of drug*resistant TB# Testing the ecacy

of second*line and new anti*TB drugs in animal models of e-perimental TBM isneeded to help determine the optimal regimen for drug*resistant TB#

.# =ntroduction

Tuberculous meningitis (TBM" is caused by Mycobacterium tuberculosis (M#tuberculosis" and is the most common form of central ner)ous system (0"tuberculosis (TB"# TBM is associated with a high freLuency of neurologic seLuelae

and mortality if not treated promptly N.O%# TBM is rare in de)eloped countries withabout . to .% cases occurring annually in the F, less than 4 of the estimated6,. annual cases of bacterial meningitis N+, G# The disease occurs whensubependymal or subpial tubercles, also known as 98ich foci; seeded duringbacillemia of primary infection or disseminated disease, rupture into thesubarachnoid space N5# =ndi)iduals with increased risk for TBM include youngchildren with primary TB and patients with immunode7ciency caused by aging,malnutrition, or disorders such as $=C and cancer N!, .# The use of antitumornecrosis factor*alpha (T0<Q" neutraliAing antibody has also been associated withincreased risk of e-trapulmonary TB including TBM N..# Most ha)e no known

history of TB, but e)idence of e-trameningeal disease (e#g#, pulmonary" can befound in about half of patients N, 6# The tuberculin skin test is positi)e in onlyabout %4 of patients with TBM# =n low TB pre)alence areas, TBM is most commonlyseen with reacti)ation TB#

2# Hb&ecti)e and Method

The goal of this o)er)iew is to describe e)idence*based diagnostic and treatment

approaches of TBM# This paper was written for clinicians seeking a practicalsummary of this topic# Rhile this paper focuses on these aspects of TBM, a briefo)er)iew of the clinical manifestations of TBM as well as past and current animalmodels of TBM treatment will be discussed#



3iterature in this 7eld was systematically identi7ed on PubMed using the key words9tuberculous meningitis,; 9tuberculosis cerebrospinal ?uid,; and 9tuberculosisner)ous system,; as well as combing through the bibliography of rele)ant papers#More recent articles describing new 7ndings in the 7eld were gi)en particularattention#

# linical Manifestations

TBM is typically a subacute disease# =n one seminal re)iew, symptoms were presentfor a median of . days (range, one day to nine months" prior to diagnosis N6# 'prodromal phase of low*grade fe)er, malaise, headache, diAAiness, )omiting, andEorpersonality changes may persist for a few weeks, after which patients can thende)elop more se)ere headache, altered mental status, stroke, hydrocephalus, and

cranial neuropathies# eiAures are uncommon manifestations of TBM in adults andwhen present should prompt the clinician to consider alternate diagnoses such asbacterial or )iral meningitis or cerebral tuberculoma@ in contrast, seiAures arecommonly seen in children with TBM, occurring in up to %4 of pediatric cases N.2# The clinical features of TBM are the result of basilar meningeal 7brosis and )ascularin?ammation N.# lassic features of bacterial meningitis, such as stiI neck andfe)er, may be absent# Rhen allowed to progress without treatment, coma and deathalmost always ensue# =n sur)i)ors of TBM, neurologic seLuelae may occur thatinclude mental retardation in children, sensorineural hearing loss, hydrocephalus,cranial ner)e palsies, stroke*associated lateraliAing neurological de7cits, seiAures,

and coma N.6#

6# Diagnosis

The diagnosis of TBM can be dicult and may be based only on clinical andpreliminary cerebrospinal ?uid (<" 7ndings without de7niti)e microbiologiccon7rmation# ertain clinical characteristics such as longer duration of symptoms(Ssi- days", moderate < pleiocytosis, and the presence of focal de7cits increase

the probability of TBM N.%, .+# haracteristic < 7ndings of TBM include thefollowing>

(i" lymphocytic*predominant pleiocytosis# Total white cell counts are usuallybetween . and % cellsE3# Cery early in the disease, lower counts andneutrophil predominance may be present,

(ii" ele)ated protein le)els, typically between . and % mgEd3,



rapidly, while mycobacterial D0' may be detectable in the < for up to a monthafter treatment initiation N25#

Diagnosis of TBM can be helped by neuroimaging# lassic neuroradiologic features

of TBM are basal meningeal enhancement and hydrocephalus N.G# $ypodensitiesdue to cerebral infarcts, cerebral edema, and nodular enhancing lesions may alsobe seen# Magnetic resonance imaging (M8=" is the imaging test of choice for)isualiAing abnormalities associated with TBM, as it is superior to computedtomography (T" for e)aluating the brainstem and spine# The T2*weighted M8=imaging has been shown to be particularly good at demonstrating brainstempathology@ diIusion*weighted imaging (DR=" is best at detection of acute cerebralinfarcts due to TBM N2!# $owe)er, T is adeLuate for urgent e)aluation of TBM*associated hydrocephalus for possible surgical inter)ention#

%# Treatment

%#.# 'ntimicrobial Therapy

Timely treatment dramatically impro)es the outcome of TBM# Thus, empirictreatment is warranted when clinical features and < 7ndings are suggesti)e of

TBM e)en before microbiologic con7rmation# The recommended treatment regimenfor presumed drug*susceptible TBM consists of two months of daily =0$, rifampin(8=<", pyraAinamide (P/'", and either streptomycin (M", or ethambutol (MB",followed by GO. months of =0$ and 8=< (Table ." N.G, O6# =0$ is considered themost critical of the 7rst*line agents due to its e-cellent < penetration and highbactericidal acti)ity (Table 2" N%O!# Rhile 8=< penetrates the < less freely, thehigh mortality of TBM due to 8=<*resistant strains has con7rmed its importance N6#P/' has e-cellent penetration into the < and is a key drug in reducing the totaltreatment time for drug*susceptible TB N6.# $ence, if P/' cannot be tolerated, thetreatment course for TBM should be lengthened to a total of .5 months# Rhile M orMB are traditionally used as the fourth anti*TB agent in TBM, neither penetrates

the < well in the absence of in?ammation and both can produce signi7cantto-icity with long*term use N6.# =t bears emphasiAing that not only the choice ofantimicrobials, but also the dose used and duration of treatment are empiric in TBMand largely based on the treatment of pulmonary TB#

tab.



Table .> 8ecommended standard treatment regimen for drug*susceptible TBM#

tab2

Table 2> Pharmacokinetic acti)ity and < penetration of anti*TB drugs#

:i)en that the newer generation ?uoroLuinolones (<Y0", for e-ample, le)o?o-acinand mo-i?o-acin, ha)e strong acti)ity against most strains of M# tuberculosis andha)e e-cellent < penetration and safety pro7les, <Y0 would appear to ha)e greatpotential as part of 7rst*line therapy for TBM# =n a randomiAed controlled study for TBM treatment, addition of an <Y0 to standard regimen enhanced anti*TBperformance as measured by )arious clinical parameters# 'lthough there was nosigni7cant diIerence in mortality, the study was likely not adeLuately powered todemonstrate such an eIect N5# =t is important to note that serum <Y0concentrations are lowered by concurrent 8=< use@ furthermore, the optimal area*under*the*cur)e to minimum inhibitory concentration ratio for <Y0 as anti*TB agentshas not been well described# 'nother randomiAed controlled study is currentlyunderway to e)aluate treatment of TBM with high*dose 8=< and le)o?o-acincompared to standard treatment N62@ if they ha)e positi)e results, therecommended standard treatment may change in the near future#

0o controlled trials ha)e been published to date for the treatment of multidrugresistant (MD8" TBM, de7ned as resistance to at least =0$ and 8=<# <urthermore,)ery few studies ha)e been published on the < penetrance of many of thesecond*line and newer anti*TB agents# linicians of patients with MD8*TBM are leftto e-trapolate from guidelines for the treatment of pulmonary MD8*TB# The Rorld$ealth HrganiAation recommends for pulmonary MD8*TB the use of a minimum offour agents to which the M# tuberculosis strain has known or suspectedsusceptibility including use of any 7rst*line oral agents to which the strain remainssusceptible, an in&ectable agent (i#e#, an aminoglycoside or capreomycin", an <Y0,and then adding other second*line agents as needed for a total of at least fourdrugs N6# < penetration of the 7rst* and second*line anti*TB drugs are shown in Table 2 N%, 6O6!#

'mong new anti*TB agents, bedaLuiline (TM2G, a diarylLuinoline" and delamanid(HP*+G+5, a nitro*dihydroimidaAo*o-aAole" appear most promising, as they areboth in phase === clinical trials N%# Three additional no)el agents, sudoterb (335%5,a pyrrole deri)ati)e", P'*526 (a nitroimidaAo*o-aAine", and Y.! (an analogue ofMB" are currently in phase == trials N%, %.# Their ability to penetrate the < hasyet to be adeLuately studied (Table 2"#



%#2# 'd&uncti)e orticosteroid Therapy

Much of the neurologic seLuelae of TBM is considered to be due to ano)ere-uberant host*in?ammatory response that causes tissue in&ury and brain

edema N%2# ince the middle of the 2th century, systemic corticosteroids ha)ebeen used as ad&uncti)e treatment for TBM on the basis of the notion thatdampening of the in?ammatory response can lessen morbidity and mortality, areasonable hypothesis as the brain is con7ned to a 7-ed space# =ndeed, ad&uncti)ecorticosteroid treatment of pyogenic bacterial meningitis has shown ecacy incertain groups of patients N%, %6 although this is contro)ersial N%%, %+# =nattempting to determine the cell type responsible for inciting the in?ammatoryresponse, 8ock et al# N2 found that M# tuberculosis was much more likely to infectbrain tissue macrophages (microglial cells" with marked increases in production ofproin?ammatory cytokines and chemokines than stromal brain cells (astrocytes"# =n

this in )itro study, coincubation of TB*infected microglial cells with de-amethasonesigni7cantly inhibited production of in?ammatory mediators N2# 'lthough there haslong been concern that corticosteroids may reduce < penetration of anti*TB drugsN., one small study demonstrated that corticosteroids had no eIect on <penetrance of 7rst*line anti*TB agents N6+# ' ochrane meta*analysis of se)enrandomiAed controlled trials comprised a total of ..6 participants concluded thatcorticosteroids impro)ed outcome in $=C*negati)e children and adults with TBM (88#G5" N%G# These results were strongly in?uenced by a study of %6% adults with TBMin Cietnam showing that treatment with de-amethasone was associated withsigni7cantly reduced mortality at nine months of followup N%5# Hne possiblee-planation for the sur)i)al bene7t in the Cietnamese study is that the anti*in?ammatory eIects of corticosteroids reduced the number of se)ere ad)ersee)ents (!#%4 )ersus .+4", particularly hepatitis, pre)enting the interruption of the7rst*line anti*TB drug regimen N%5#

ince there are no controlled trials comparing corticosteroid regimens, treatmentchoice should be based on those found to be eIecti)e in published trials# Hnerecommended regimen for children is de-amethasone .2 mgEday =M (5 mgEday forchildren weighing Z2% kg" for three weeks, followed by gradual taper o)er the ne-tthree weeks N%!# =n the large study in Cietnam, patients with mild disease recei)edintra)enous de-amethasone # mgEkgEday [ . week, #2 mgEkgEday [ . week, andthen four weeks of tapering oral therapy N%5# <or patients with more se)ere TBM,intra)enous de-amethasone was gi)en for four weeks (. week each of #6mgEkgEday, # mgEkgEday, #2 mgEkgEday, and #. mgEkgEday", followed by fourweeks of tapering oral de-amethasone therapy N%5#



Rhile neutraliAation of T0<Q predisposes indi)iduals to TB including TBM N.., T0<Qis also considered to play an important role in contributing to the pathogenesis of TBM N+O+, consistent with the aforementioned deleterious eIects of the 0in?ammatory response# =ndeed, Tseno)a et al# showed that the addition ofthalidomide, a potent inhibitor of T0<Q, to antibiotics was superior to antibiotics

alone in protecting rabbits from dying (%4 reduction in mortality" in their model of TBM N+2# =n addition, there was marked reduction in T0<Q le)els in both < andblood as well as a decrease in leukocytosis and brain pathology in rabbits thatrecei)ed thalidomide N+2#

%## <luid Management in TBM

=n patients with TBM, there may be nonosmotic stimuli for antidiuretic hormone

('D$" e-pression, resulting in a syndrome of inappropriate 'D$ (='D$" release#Rhile 'D$ itself may not aggra)ate cerebral edema, acute de)elopment ofsigni7cant hyposmotic hyponatremia may worsen cerebral edema due to watershifting from the intra)ascular compartment into the e-tra)ascular (intracellular ande-tracellular" space of the brain# Rhile restriction of water intake is a mainstay of='D$ treatment, hypo)olemia should be a)oided, since it may decrease cerebralperfusion as well as ser)e as a stimulus for further 'D$ release# =n a comprehensi)ere)iew of this issue, it was noted that ?uid restriction to pre)ent cerebral edema in TBM is un&usti7ed N+6# =nstead, it was recommended that a eu)olemic state shouldbe the goal to maintain cerebral perfusion as well as to pre)ent hypo)olemia*

induced 'D$ release# =f symptomatic, acute hyponatremia does not respond to anti* TB treatment and appropriate ?uid restriction (while maintaining eu)olemia", use ofC2 ('D$" receptor antagonist should be considered although, to the best of ourknowledge, this has not been studied in TBM# are must be taken, howe)er, topre)ent too rapid of correction of chronic hyponatremia due to the risk ofprecipitating osmotic demyelination syndrome#

%#6# urgical =nter)ention in TBM $ydrocephalus

$ydrocephalus is a common complication of TBM@ pre)alence has been documentedin SG%4 of patients in se)eral published series N+%, ++# Centriculoperitoneal shuntplacement and endoscopic third )entriculostomy are surgical techniLues which ha)ebeen demonstrated to relie)e ele)ated intracranial pressure (=P" in TBM, leading toimpro)ed neurological outcomes N+G, +5# hildren are at particularly high risk forhydrocephalus and ele)ated =P# =n a study of 2.G children with TBM in outh 'frica,



4 reLuired )entriculoperitoneal shunting for either noncommunicatinghydrocephalus or failure of medical therapy with diuretics in communicatinghydrocephalus N+!# $istorically, surgical inter)ention was only recommended withgrade 2 or TBM hydrocephalus (normal or mildly altered sensorium@ easilyarousable" due to increased mortality and risk of poor surgical outcome in patients

with grade 6 disease (deeply comatose"# $owe)er, a retrospecti)e analysis of !%patients with grade 6*associated hydrocephalus who underwent shunt placementdemonstrated fa)orable outcomes in 4O6%4 of patients, suggesting that theremay be a role for surgical inter)ention e)en in ad)anced TBM hydrocephalus NG# =nthis study, poor neurological outcomes after shunt placement were associated withage V three years and S three days in duration of symptoms#

%#%# Treatment =ssues of TBM in Patients with oncurrent $=C =nfection

TB is the most common opportunistic infection in $=C*infected persons, and $=Cinfection is an independent risk factor for e-trapulmonary TB including meningitisNG.# <or these reasons, diagnosis of TBM should automatically trigger testing for$=C infection# =n general, the diagnosis and treatment of TBM in $=C*infectedindi)iduals is similar in principle to non*$=C infected sub&ects although there are afew notable ca)eats, including the potential de)elopment of immune reconstitutionin?ammatory syndrome (=8=", drug interactions and to-icities with concomitantanti*TB and antiretro)iral ('8C" therapy, Luestionable ecacy of ad&uncti)ecorticosteroids, and higher pre)alence of drug*resistant TB in $=C*positi)e

populations#

Treatment of $=C with '8C therapy can result in =8=, causing clinical e-acerbationof TBM# =ndeed, in high $=C pre)alent settings, 0 TB complicated by =8= has beenshown to be the most freLuent cause for neurological deterioration in patientsnewly starting '8C therapy NG2# 8isk factors for =8= include a high pathogen load(e#g#, miliary TB", )ery low D6 T*cell count (V% cellsE3" when '8C therapy isinitiated NG, and concurrent initiation of '8C and anti*TB therapy NG6#

oncurrent '8C and anti*TB therapy carries the risk of drug interactions andto-icities# $owe)er, delaying '8C therapy in patients coinfected with $=C and TBhas been associated with higher mortality NG%# 0e)ertheless, due to the possibilityof =8= with '8C initiation, most guidelines do not recommend simultaneousinitiation of '8C and anti*TB medications# ' recent randomiAed controlled trialcomparing mortality in patients started on immediate '8C at the time of diagnosis



of TBM and $=C )ersus patients started on '8C two months after diagnosis foundsigni7cantly more serious ad)erse e)ents in the immediate arm NG6# Mortality didnot diIer signi7cantly, but there was a trend towards greater all*cause mortality inthe immediate '8C group at nine months followup# The Rorld $ealth HrganiAationrecommends that anti*TB therapy be started 7rst, followed by '8C treatment within

eight weeks N6# The enter for Disease ontrol and Pre)ention recommends thatfor patients with D6 counts V. cellsE3, '8C therapy be started after two weeksof anti*TB therapy NG+#

The bene7t of ad&uncti)e corticosteroid treatment for TBM in patients coinfectedwith $=C has not been demonstrated NG.# =n the large study of Cietnamese adultswith TBM, no mortality bene7t from de-amethasone was found in the subgroup of!5 patients who were coinfected with $=C N%5# Thus, at the present time, thebene7t of ad&uncti)e corticosteroid treatment in $=C*infected indi)iduals remains

uncertain N%G although the theoretical bene7t of corticosteroids to decrease TB*associated =8= has led some e-perts to prescribe them to this population#

There is also e)idence that a particularly )irulent strain of TB, the R*Bei&inggenotype, is associated with $=C infection and high le)els of resistance in TBM NGG#Multiple studies ha)e shown MD8*TB to be more commonly found in $=C*infectedpatients with concurrent TBM NG5O5, often leading to treatment failure and )eryhigh mortality# =n high $=C pre)alence settings and in all $=C*infected patients, dailyanti*TB treatment as directly obser)ed therapy should be gi)en in order to reduce

relapse and treatment failure N6, 5.# =t is important to note that $=C coinfectionalone, e)en without TB drug resistance, confers worse outcomes in TBM# $=Ccoinfection was shown to be associated with #% times higher mortality in aretrospecti)e cohort study of TBM patients in the Fnited tates from .!!O2%N.!#

+# Prognosis

Prognosis of TBM largely depends on neurologic status at the time of presentation,and time*to*treatment initiation# Rhile the course of TBM is generally not as rapid orfulminant as meningitis due to pyogenic bacteria, empiric treatment should beinitiated as soon as the diagnosis is suspected as any delay in treatment canworsen outcome# Carious case series indicate a mortality rate of G4O+%4 inde)eloped countries, and up to +!4 in underde)eloped areas NO%# Mortality risk ishighest in those with comorbidities, se)ere neurologic in)ol)ement on admission,



rapid progression of disease, and ad)anced or )ery young age# 0eurologic seLuelaeoccur in up to %4 of sur)i)ors N%#

G# 'nimal Models 're 0eeded to 'd)ance Hur Fnderstanding and Treatment of TBM

'nimal models are critically important in testing the ecacy of new drugs and)accines against TB N52# The challenge of animal models of TBM is that TBM inhumans is considered to typically occur a certain period of time after a primaryinfection through the respiratory tract, a condition that would be dicult to mimic ine-perimental animals# =ndeed, all animal models of TBM resort to direct inoculationof M# tuberculosis into the 0# The rabbit model of TBM, in which mycobacteria areinoculated directly into the cisterna magna, is perhaps the most well*establishedanimal model of TBM N5, +2# Therapeutic studies e-amining ecacy of antibiotics,

)accines, and ad&uncti)e agents such as thalidomide in the conte-t of TBM ha)ebeen studied in the rabbit model N+2, 5, 56# Rhile the murine model of TB is moretractable than rabbits due to the greater )ariety of mouse reagents a)ailable andlower cost in conducting the studies, the immunologic and clinical responses of miceto e-perimental TBM do not mimic as well as rabbits to human TBM N5%#

Despite the fact that B: )accination is suboptimal in protecting against pulmonary TB N5+, 5G, it is considered to be relati)ely ecacious in protecting againstchildhood TBM N55# Tseno)a et al# showed in a rabbit model of TBM that while B:

pro)ided protection against the laboratory strain M# tuberculosis $G8), it aIordedsigni7cantly less protection against a hyper)irulent clinical strain (R*Bei&ing $05G5",particularly against 0 disease N56# =n B:*)accinated mice challenged with R*Bei&ing $05G5, there was signi7cantly greater in7ltration of the subarachnoid spaceby lymphocytes and macrophages, coincident with greater bacterial burden andworse 0 pathology score N56# 'n important lesson from this study is that in thesearch for more ecacious TB )accines, it is important to test the )accine inanimals challenged with rele)ant, clinical strains of M# tuberculosis#

5# onclusion

Meningitis is the most deadly form of TB, particularly in persons coinfected with $=C#arly diagnosis and treatment can dramatically reduce the high mortality associatedwith this disease# =n general, treatment should be at least nine months in durationand should be comprised of at least four agents to which the M# tuberculosis strain



has known or suspected susceptibilities# 'd&uncti)e corticosteroid treatment shouldbe considered, particularly in persons without concurrent $=C infection# =n order toguide therapy, it is optimal to base treatment on TB resistance patterns, especiallyin $=C*coinfected persons who carry high risk for drug*resistant TB# More studies areneeded to e)aluate < penetration of newer TB agents to facilitate de)elopment of

better treatment regimens for both drug*susceptible and drug*resistant TBM#'dditionally, randomiAed controlled trials to optimiAe treatment for MD8*TBM areimportant to 7nd the best possible combination of drugs a)ailable and tostandardiAe treatment#

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