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

Global tuberculosis control : epidemiology, strategy, financing : WHO report 2009

Resurgence of tuberculosis in both developing

and 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 people

or one third infected by Mycobacterium
tuberculosa.
In the year 1997 amounts of all new cases of
world is 7.96 million ( range from 6.3 million
until 11.1 million people) and estimate 1.87
million people die.
Highest Prevalence of Tuberculous Infections
there are in nations sub-sahara African and
South East Asian

9/ 100.000 per year in the USA

110-165/ 100.000 population (in developing countries of

Asia 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),
tuberculoma with milliary tuberculosis, tuberculous abscess

multiple

small

SPINAL
Potts spine and Potts paraplegia
Tuberculous arachnoiditis (myeloradiculopathy)
Non-osseous spinal tuberculoma

Hankey, GJ, Wardlaw JM. Clinical Neurology,2008

Defenition: Infection
underlying brain by

of the meninges and

the acid-fast organism

Mycobacterium 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 the
spread of HIV, and has a high case fatality (30%)
and morbidity (30% of patients with neurological
sequelae).

11

Aerob intrasel obligat

Transmisi from droplet
Alveoli multiply
Hematogen disseminasi 2-4 weeks
T limfosit and makrofag
Rich focus
Expanding tubercle

PATHOGENESIS

DROPLET INHALATION

ALVEOLAR MACROPHAGE
DISSEMINATION to the regional
lymph node
10% PPT

Miliary TB

PRIMARY
PRIMARY COMPLEX
COMPLEX

MENINGITIS

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

OBLITERATIVE
VASCULITIS

ADHESION FORMATION
Encephalitis/
myelitis

Infarction/ stroke syndrome

Interpendicular fossa
Obstruction of the CSF

CLINICAL FEATURES
Headache, Lethargy, Confusion, Drowsiness
Fever, Stiff Neck, Kernig and Brudzinski signs
ANALYSIS OF CSF
Pressure: increased
Cells: 50-500 white cells/mm3; lymphocyte
predominate
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 enough
role 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 langsung
atau 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 TB
positif

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

Kategori diagnostik
Thwaites
MTB probable:

Gejala klinis meningitis

dan
Gambaran CSS abnormal
dan
Didapatkan setidaknya satu dari 2 hal berikut:
Kecurigaan TB paru aktif (thorax foto)
Didapatkan BTA dari sampel lain selain CSS

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

Kategori diagnostik
Thwaites
MTB possible:

Gejala klinis meningitis

dan
Gambaran CSS abnormal
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

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

Rapid diagnosis of TBM is fundamental to clinical outcome

Current laboratory methods
Neurologic symptoms and signs, CSF finding, and
neuroimaging characteristics
Evidences of Extra-neural TB
H/O recent TB Contact-an important supporting feature
Mx Test- positive in 50%

1948 Relevan British Medical Research

Council (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 multiple

cranial 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 xanthochromic

fluid with pleocytosis, increased protein level and
decreased glucose level
Cell count between 10 500, usually no more than
1000/ mm3, may be predominant lymphocytic, but
not 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 pulmonary

tuberculosis

13-24% have Milliary Pulmonary Tuberculosis

CT Scan/MRI
Enhancement of the basal cisterns 90% of cases
interpeduncular fossa, the ambient cistern & Chismatic
regions are particularly involved
Communicating hydrocephalus in 50-80%
Infarct on CT -20,5-38%, most common basal ganglia and
the territories of the medial striate and thalamoperforating
arteries
MRI more sensitive than CT- meningeal ( basal enhancement)
and parenchymal (infarct) involvement, hydrocephalus
detected equaly by CT and MRI

1. Use of anti tuberculosis drugs

(chemoterapy-TB)
2. Symptomatic and supportive measures
3. Preventing and management of
complication

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 (< 50
kg)
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 or
R+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 antituberculosis

drugs

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

0,4-1,0

Ethambutol

15 - 25

1,0 -7,7

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/ethion
amide 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 with
anti TB Therapy) then tapered over further 3 weeks
may reduce the incidence of sequele in patients
who are culture positive, particularly those who
have a decreased conscious level at presentation.
Prednisolone 60-80 mg/ day tapering after 2
weeks 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 improved
outcome in HIV-negative child and adults with
TBM, 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 like

syndrome/ hemiplegia

Electrolyte
imbalance:hyponatremia

Due to immune reactions

encephalopahty due to brain
edema

Secondary infection: pneumonia

Due to CSF blockage

Hydrochephalus

Urinary tract infection

Malnutration due to
hypercatabolism and inadequate
intake

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 be
tested 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
>200 sel/l

Tindakan yang direkomendasikan

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/l

Mulai terapi ARV setelah kurang lebih 2 bulan

pengobatan TB

<100 sel/l

Mulai terapi ARV dalam 2 minggu pertama

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

Tuberculous meningitis is associated with high

mortality and morbidity
TBM occurs due to infection with human M.

tuberculosis

Airborn droplet nuclei containing M. tuberculosis

reach the alveoli, where the multiply and
disseminate through blood stream to lodge in
different organs including brain and meninges
CSF found in TBM is typically clear
Look and treat complication
The role of corticosteroid in TBM is controversial