recent advances of tuberculous meningitis therapy

8/16/2019 Recent Advances of Tuberculous Meningitis Therapy

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Dr. Kiking Ritarwan, Sp.S(K), MKT

Dept. of Neurology Medical Faculty, Universitas Sumatera Utara

NEW TRENDS IN VACCINATION AND INFECTION CONTROL- Ruang Seminar FK USU -15 Januari 2011



Major global problem Tuberculosis in Indonesian occupy 3rd rank

from 22 High Burden Countries



4Global tuberculosis contro l : epidemiolo gy, strategy, f inancing : WHO report 2009



Resurgence of tuberculosis in both developingand developed countries:

- Increasing prevalence of HIV infection,

- Over-crowding in the urban population- Poor nutritional status

- Appearance of drug-resistant strains of

tuberculosis

- Ineffective tuberculosis control programmes

Singhi, P. Recent Advances in management of TBM,2010



Estimate approximately of 1.7 billion peopleor one third infected by Mycobacterium tuberculosa .

In the year 1997 amounts of all new cases ofworld is 7.96 million ( range from 6.3 millionuntil 11.1 million people) and estimate 1.87million people die.

Highest Prevalence of Tuberculous Infectionsthere are in nations sub-sahara African andSouth East Asian



9/ 100.000 per year in the USA

110-165/ 100.000 population (in developing countries ofAsia and Africa).

In South East Asian, incidence of Tuberculous 49% from TB

cases in the world

1% cases with active TB have CNS involvement

In developing countries :

* CNS TB- younger age group, usually Childhood (< 3 yo).* In children, dissemination usually occurs early risk of

CNS TB is highest in the first year following infection.* Risk factors: malnutrition, recent measles, HIV



INTRACRANIAL Tuberculous Meningitis (TBM)

TBM with milliary tuberculosis

Tuberculous Encephalopathy

Tuberculous Vasculopathy

Space-occupying lesions: Tuberculoma ( single or multiple), multiple small

tuberculoma with milliary tuberculosis, tuberculous abscess

SPINAL Pott’s spine and Pott’s paraplegia

Tuberculous arachnoiditis (myeloradiculopathy) Non-osseous spinal tuberculoma

Hankey, GJ, Wardlaw JM. Clinical Neurology,2008



Defenition: Infection of the meninges andunderlying brain by the acid-fast organismMycobacterium tuberculosis

The first clinical description of TBM in 18 century:Sir Robert Whytt, even before Robert Koch (1882).

TBM happened at all of age, is increasing with thespread of HIV, and has a high case fatality (30%)and morbidity (30% of patients with neurologicalsequelae).



• Aerob intrasel obligat• Transmisi from droplet

• Alveoli multiply

•

Hematogen disseminasi

2-4 weeks• T limfosit and makrofag

• ‘Rich focus’

• Expanding tubercle



MENINGITISMiliary TB

PRIMARY COMPLEXPRIMARYCOMPLEX

DISSEMINATION to the regional

lymph node

ALVEOLAR MACROPHAGE

DROPLET INHALATION

10% PPT

Bacteremia

Seed to the meninges

Or brain parenchyma

RICH FOCI

Rupture of a rich focus into the

Subarachnoid space

PATHOGENESIS



Innoculation of bacilli into the subarachnoid space

DENSE BASAL MENINGEAL EXUDATE

ADHESION FORMATIONOBLITERATIVEVASCULITIS

Encephalitis/

myelitis

Obstruction of the CSF

Interpendicular fossaInfarction/ stroke syndrome

PATHOGENESIS

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CLINICAL FEATURES

Headache, Lethargy, Confusion, Drowsiness Fever, Stiff Neck, Kernig and Brudzinski signs

ANALYSIS OF CSF

Pressure: increased

Cells: 50-500 white cells/mm3; lymphocytepredominate

Raised Protein: 1-2 gr/l

Glucose: < 2,22 mmol/ l (< 40 mg/dl) FUTURE OF DIAGNOSIS

o History of treatment of TB

o TB extra-organ (clinically and radiology)Thwaites et al, J Infect 2009; 59: 167-187



Lumbar Puncture: the diagnosis is made by

demonstration of acid-fast bacilli by Ziehl-Neelsen(ZN) stain of the CSF. Positive stain 3-6 weeks.Sensitivity :80-85%, spesifisity:98%

Polymerase Chain Reaction (PCR)

- Based approach

- Advantages:positive results after medication

until 1 month

- Estimate PCR is quantitative will hold enoughrole important in inspection of curative

response, and not for diagnostic.

- Pai et al (2003): PCR sensitivity : 56%, spesifisity

98%.

Pai et al, Lancet Infect Dis 2003; 3(10): 633-43



TBM is a difficult disease to diagnose Several diagnostic categorical:

- Scorring system

- Ogawa criteria (definite, probable)- Thwaites criteria (definite, probable,possible)



Scoring system (Twaithes, lancet Neurol 2005;4:160-70)



Kategori diagnostik◦ Ogawa (1987)

Definite : BTA ditemukan di CSS (pewarnaan langsungatau kultur), dan/atau didapatkan BTA pada otopsi

Probable : Pleositosis di CSS

Hasil kultur bakteri dan jamur negatif

Ditambah satu dari hal-hal berikut:

Tuberkulin tes positif

Adanya TB ekstraneural, atau riwayat TB aktif, atau paparan

terhadap TB Glukosa CSS < 40 mg/dL

Protein CSS >60 mg/dL

Ogawa et al, Medicine 1987; 66(4): 317-27



Kategori diagnostik◦ Thwaites

MTB definite : Gejala klinis meningitis

dan

Gambaran CSS abnormal

dan

Didapatkan BTA di CSS (mikroskopi) dan/atau kultur TBpositif

Thwaites et al, J Infect Dis 2005; 192: 2134-41




MTB probable : Gejala klinis meningitis

dan


dan

Didapatkan setidaknya satu dari 2 hal berikut:

Kecurigaan TB paru aktif (thorax foto)

Didapatkan BTA dari sampel lain selain CSS





MTB possible : Gejala klinis meningitis

dan


dan

Didapatkan setidaknya 4 dari 7 hal berikut:

Riwayat menderita TB Predominansi MN di CSS Lama sakit > 5 hari

Rasio glukos CSS; darah < 0.5 Penurunan kesadaran Warna CSS kuning / xanthochrom

Didapatkan defisit neurologi fokal




Rapid diagnosis of TBM is fundamental to clinical outcome Current laboratory methods

Neurologic symptoms and signs, CSF finding, andneuroimaging characteristics

Evidences of Extra-neural TB

H/O recent TB Contact-an important supporting feature

Mx Test- positive in 50%



1948 Relevan British Medical ResearchCouncil (MRC) Staging System

Stage I◦ Fully conscious and no deficite neurologic sign

Stage II◦ Grade 2a: GCS 15 with deficite neurologic focal◦ Grade 2b: GCS 10 – 14 (Confused) with hemiparesis

or single cranial nerve palsy Stage III

◦ Comatose or Stuporous, GCS < 10 with multiplecranial nerve palsies or complete hemiplegi



Singhi P, Singhi S. Current Treatment Options in infectious Disease 2001.



Misra UK (2001) Educational Course Literatur



Mean Duration of illness 2 weeks 2 weeks

History of TB Contact 56 (45-70%) 28 (2 -80%)

Positive Tuberculin skin test 72 (50-95%) 51 (40-70%)

Abnormal chest-x ray 61 (35-75%) 45 (25-55%)

Neurologic clinics vol 17;4: Nov 1999



Characteristically, we find a clear or xanthochromicfluid with pleocytosis, increased protein level anddecreased glucose level

Cell count between 10 – 500, usually no more than

1000/ mm3, may be predominant lymphocytic, butnot always

Protein content 100-500mg%, in Supartini (2002)and Mulyono (2002) studies average 283-498 mg%

Definite diagnosis must be based on presence of M.tuberculosis in CSF.



50-60% has sign of active pulmonarytuberculosis

13-24% have Milliary Pulmonary Tuberculosis



CT Scan/MRI- Enhancement of the basal cisterns 90% of cases

interpeduncular fossa, the ambient cistern & Chismaticregions are particularly involved

- Communicating hydrocephalus in 50-80%

- Infarct on CT -20,5-38%, most common basal ganglia andthe territories of the medial striate and thalamoperforatingarteries

- MRI more sensitive than CT- meningeal ( basal enhancement)and parenchymal (infarct) involvement, hydrocephalusdetected equaly by CT and MRI



1. Use of anti tuberculosis drugs(chemoterapy-TB)

2. Symptomatic and supportive measures

3. Preventing and management ofcomplication



DRUGS Dosage Child Dosage Adult Route

Isoniazid 10 – 20 mg/kg( max 500 mg)

300 mg Oral

Rifampicine 10 – 20 mg/kg(max 600 mg)

450 mg (< 50kg)600 mg (> 50

kg)

Oral

Pyrazinamide 30 – 35 mg/kg(max 2gr)

1,5 gr (< 50 kg)2,0 gr (> 50 kg)

Oral

Ethambuthol 15 – 20 mg/kg(max 1 gr)

15 mg/kg Oral

WHO recommended Combination ATD, Initial Treatment ( 2 month) :INH+R+PZA+E orR+PZA+S; Continued ( 7 month):INH+ R.

ATS recommended Combination ATD, Initial ( 2month):

INH+R+PZA or S;Continued ( 9 month): INH+ R



CSF Consentration of certain antituberculosisdrugs

DRUGS Daily

Dose

Mg kg

Serum

Ug dl

Normal

Meningens

Ug ms

Inflammated

menigens

ug ms

Isoniazid 5 - 10 3 - 5 0,6- 1,6 2,0 – 3,2

Rifampicine 10 - 20 0,4 – 1,2 0 0,4-1,0

Ethambutol 15 - 25 1,0 -7,7 0 0,5-2,5

Pyrazinamide 25 - 30 15 - 50 10 30 – 50

Streptomycine 15 - 40 25 – 50 trace 2.0 – 9.0

Misra ,UK. Tuberculous meningitis. XVII World Congress of neurology, London,(2001)



Good penetration in CSF Treatment: Isoniazid,Rifampicine,Pyrazinamide,prothianamide/ethionamide and cycloserine.

Only in the presence of meningeal inflamation:

kanamycin, amikacin and capreomycin

Poor or no penetration: PAS and ethambutol



Thwaites et al, J Infect 2009; 59: 167-187



Dexamethasone (adults 12 mg/ day, child < 25 kg,8 mg/ day) given for 3 weeks ( in conjuction withanti TB Therapy) then tapered over further 3 weeksmay reduce the incidence of sequele in patients

who are culture positive, particularly those whohave a decreased conscious level at presentation.

Prednisolone 60-80 mg/ day tapering after 2weeks to finish 4-6 weeks, is an alternative.

Hankey GJ, Wardlaw, JM. Clinicl neurology,2008



Meta-analysis of 7 RCT involving 1140 participant(with 411 death) concluded that CS improvedoutcome in HIV-negative child and adults withTBM, but the benefit in HIV infected individuals

remains uncertain CS were effective in reducing the risk of death in

children (RR,0,77; 95% CI, 0,62 to 0,96)

Cochrane Database Syst Rev, 2000;3: CD00224



INTRACRANIAL EXTRACRANIAL

Due to arteritis Stroke likesyndrome/ hemiplegia

Electrolyteimbalance:hyponatremia

Due to immune reactions encephalopahty due to brain

edema

Secondary infection: pneumonia

Due to CSF blockage Hydrochephalus

Urinary tract infectionMalnutration due tohypercatabolism and inadequateintake



Comorbidity with HIV/ AIDS is important CNS involvement in 10-20% of AIDS related TB

Is associated high mortality

All patient with suspected CNS TB shoul betested for HIV

Infection with atypical mycobacteria is common

Antiretroviral treatment probably shoul not be

delayed in those with severe immune response( CD 4 count < 100 cell/ul).



Rekomendation B, II

Kadar CD4 Tindakan yang direkomendasikan

>200 sel/μl

Tunda pemberian ARV selama mungkin, kalau

bisa sampai selesai pengobatan TB. Mulai

pemberian ARV jika didapatkan penurunan CD4

hingga< 200 selama terapi TB

100-200 sel/μl Mulai terapi ARV setelah kurang lebih 2 bulan

pengobatan TB

<100 sel/μl Mulai terapi ARV dalam 2 minggu pertama

pengobatan TB

Thwaites et al, J Infect 2009; 59: 167-187



Tuberculous meningitis is associated with highmortality and morbidity

TBM occurs due to infection with human M.tuberculosis

Airborn droplet nuclei containing M. tuberculosis reach the alveoli, where the multiply anddisseminate through blood stream to lodge indifferent organs including brain and meninges

CSF found in TBM is typically clear

Look and treat complication

The role of corticosteroid in TBM is controversial

recent advances of tuberculous meningitis therapy

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