Tuberculous

Meningitis,
diagnosis
and
Ahmad Rizal
Department
of Neurology
treatment
Hasan Sadikin Hospital
Bandung

TBM, introduction
The most severe extrapulmonary TB
Diagnosis remains difficult
Early recognition is crucial for better
outcome
High mortality rate; sequalae in survivors
Optimal treatment has not been
established
HIV increases, TBM increases

TBM, historical aspects

1836: Six cases of acute
hydrocephalus reported in Lancet
1882: M. tuberculosis stained and
cultured (Koch)
1933: Pathological features (Rich &
McCordock)
2009: too many questions, too few
answers, still

TBM, clinical features

Fever (60 95%)
Anorexia (60 80%)
Headache (50 80%)
Nuchal rigidity (60
80%)
Coma (30 60%)
Vomiting (30 60%)
Thwaites & Hien, TLID, 2005
E. Torok, ASNA Meeting,
March 2007

92.5%
82.5%
90%

TBM, clinical features

Cranial nerve palsies (30 50%)
35%
Hemiparesis (10 20%)
21.6%
Paraparesis (5 10%)
2.5%
Seizure (children 50%, adults 7.5%
5%)
Thwaites & Hien, TLID, 2005

E. Torok, ASNA Meeting,

March 2007

TBM, Clinical Diagnosis

Clinical features not specific
TB exposure
Extra-meningeal TB
50% have abnormal CXR (67% in our
study)
Miliary TB is considered helpful

TBM, when to suspect

(1)

To overcome difficulty in making diagnosis:

Diagnostic algorithm
India study: children
Vietnam study: adults

Clinical scoring system

Diagnostic categories (definite TBM or not)

Using clinical patterns, presence of extraneural
TB and CSF abnormalities
Ogawa: 2 categories (definite, probable)
Thwaites: 3 categories (definite, probable, possible)

Clinical Scoring System

TBM, when to suspect

(2)

Diagnostic algorithms

India study, 110 children (Kumar et al, 1999)

History of illness > 6 days, optic atrophy, focal neuro
deficits, abnormal movements, CSF neutrophils < 50%
Sensitivity 98%, specificity 98% (if > 3 criteria found)

Vietnam study, 143 adults (Thwaites et al, 2002)

Age < 36 years, blood WCC < 15,000, history > 6
days, CSF WCC < 760, CSF neutrophils < 75%
Sensitivity 86%, specificity 79%

Diagnostic categories

TBM, when to suspect

(3)

Diagnostic algorithms
Diagnostic categories
Ogawa (1987)

Definite: AFB in CSF (direct staining, culture), and/or

AFB is found on autopsy
Probable: pleocytosis in CSF, negative culture for
bacteria and yeast with 1 of the followings:

Positive tuberculin test

Evidence of extra-CNS TB, or history of active PTB, or
significant exposure to TB
CSF glucose < 40 mg/dL
CSF protein > 60 mg/dL

Thwaites (2005)

TBM, when to suspect

(4)
Diagnostic algorithms

Diagnostic categories
Ogawa (1987)

Thwaites (2005)
Definite TBM:
Clinical meningitis
and
Abnormal CSF parameters
and
Acid-fast bacilli in CSF (microscopy) and/or
culture positive for M. tuberculosis

TBM, when to suspect

(5)
Diagnostic algorithms

Diagnostic categories
Ogawa (1987)

Thwaites (2005)
Probable TBM:
Clinical meningitis
and
Abnormal CSF parameters
and
At least 1 of the following:
Suspected active pulmonary tuberculosis (chest
radiography)
AFB found in any sample other than from the CSF

TBM, when to suspect

(6)

Diagnostic algorithms

Diagnostic categories
Thwaites (2005)

Possible TBM:

Clinical meningitis
and
Abnormal CSF parameters
and
At least 4 of the following:
History of tuberculosis
MN predominance in the CSF
Illness of > 5 days in duration
CSF:blood glucose ratio < 0.5
Altered consciousness
Yellow (xanthochromic) CSF
Focal neurological signs

TBM, MRC Classification

Grade I
Alert and good orientation without focal
neurological deficit

Grade II
GCS 10 14 + focal neurological deficit
OR
GCS 15 with focal neurological deficit

Grade III
GCS < 10 with or without focal
neurological deficit

TBM, diagnostics
What is expected

Reliable
Easy access
Easy to be done

TBM, diagnostics (2)

What we have now
Worldwide:
Yield of several techniques: ZN, Ogawa, liquid culture
Means to increase positivity rate of diagnostic
modalities
Ongoing large studies:

TBM immunology study (immunol. marker in blood and CSF)

Host genetic susceptibility to TB
Rapid culture
Molecular drug resistance

Indonesia, particularly Bandung

TBM, diagnostics (3)

What we have now
Worldwide
Indonesia, particularly Bandung
Efforts to gain more positive result:
Ongoing study on clinical, lab. and radiological
features (Indonesian setting)

Clinical pattern, bacteriological pattern

Outcome (HIV vs. non-HIV)

TBM, diagnostic pitfalls

Low positivity rate
Volume of LCS, among others, seems
to be the most significant factor in
AFB finding

Thwaites (Vietnam): > 5 mL

Zainuddin (Bandung): > 7 mL

THE MORE, THE BETTER

TBM, treatment
Optimal TBM treatment has not
been established in clinical trials
Same drug
Different pharmacokinetics

Various guidelines
Intensive phase of 4 drugs (RHZ+S or E
or ethionamide)
Continuation phase of 2 drugs (RH)
Treatment duration 9 12 months

TBM, treatment pitfalls

Controversy about choice of drugs
H and Z good penetration
CSF conc. of R ~ 10% plasma concentration
Neither E nor S penetrates uninflammed
meninges
Increasing S resistance

Optimal duration : 6, 9, or 12 months?

Drug resistance
MDR-TB

TBM, adjunctive steroids

Steroids reduce case fatality but not morbidity
Meta-analysis in children: steroids probably
improves survival (Prasad, 2000)
Dexamethasone trial in Vietnam (Thwaites et
al, 2004)
Randomized, double blind, placebo-controlled trial
(n=545)
Outcome: death or severe neuro sequalae at 9 month
Dexamethasone is associated with reduced risk, but
not prevent severe neurological disability
Fewer adverse events in dexamethasone group

TBM, adjunctive steroids

Latest Cochrane Review (Prasad,
2008)
Helps reduce the risk of death or
disabling residual neurological deficits
ALL HIV-negative cases of TBM should
receive corticosteroids
Still need more trials in HIV-positive

HIV and TBM

HIV ~ extrapulmonary TB
Increasing incidence of TBM
HIV infection is 1 risk factor of
developing TBM

Two chronic meningitis:

TBM
Cryptococcal meningitis

Natural Course of HIV

Infection

Co-administration of ART
and OAT
HIV infection significantly
complicates the treatment of TB

High prevalence of drug side effects

High risk of drug-drug interaction
Reduced drug absorption
The risk of developing IRIS
Overlap toxicity

Recommendation: initiate one line of

treatment at a time

Co-administration of ART
and OAT
Recommended guideline
CD4 > 100:
ART starts after 2 months of OAT

CD4 < 100

ART starts earlier (2 weeks is acceptable)

HIV-associated TBM
Thwaites et al (JID, 2005)
96 HIV-infected and 432 HIV-uninfected
patients
No difference in clinical presentation
HIV ~ more EPTB
No differences in relapses or adverse
events
HIV reduces survival rates

Survival in HIVassociated TBM

Thwaites et al, JID,

2005

Meningitis, HIV+ vs HIVTotal

population
(n=152)

HIV-positive
(n=41)

HIV-negative
(n=111)

27 (65.9%)

96 (86.5%)

123 (80.9%)

Definite TBM

59

66

Probable TBM

20

37

57

12 (29.3%)

1 (0.9%)

13 (8.6%)

10 (9%)

10 (6.6%)

2 (4.8%)

4 (3.6%)

6 (3.9%)

Diagnosis

Tuberculous meningitis

Cryptococcal meningitis
Probable bacterial meningitis
Unknown cause

Factors Associated with 1month death

Dead
(n=61)

Alive
(n=91)

28 / 61 (45.9)

13 / 91 (14.3)

Altered consciousness (GCS < 14)**

33 / 55 (60)

27/89 (30.3)

Fever on presentation*

27/56 (48.2)

25/86 (29.1)

Focal neurological sign*

35 (57.4)

37 (40.7)

CSF leukocyte count > 70/mm3

30 (49.2)

45 (49.4)

Peripheral leukocyte > 10,000/ mm3

32/56 (57.1)

39/88 (44.3)

Abnormal Chest X-ray

41/57 (71.9)

61/89 (68.5)

Plasma sodium < 136 mEq/L

30/49 (61.2)

64/87 (73.6)

Characteristics
HIV positive**

** p<0.01; * p<0.05

Factors Associated with 1month death

Characteristics

Crude
Odds Ratio
(95% CI)

Adjusted Odds Ratio

Model without
HIV

Model with HIV

HIV positive

5.09 (2.35-11.03)

Altered consciousness (GCS < 14)

3.44 (1.70-6.96)

2.45 (1.13-5.29)

2.54 (1.10-5.84)

Fever on presentation

2.27 (1.13-4.58)

.63 (.29-1.35)

.59 (.26-1.36)

Focal neurological sign

1.96 (1.02-3.79)

1.52 (.71-3.25)

1.74 (.76-3.96)

CSF leukocyte count > 70/mm 3

.99 (.52-1.89)

Peripheral leukocyte > 10,000/ mm 3

1.68 (.85-3.29)

Abnormal Chest X-ray

1.71 (.57-2.44)

Plasma sodium < 136 mEq/L

.57 (.27-1.20)

6.26 (2.50-15.72)

Survival curve, HIV+ vs. HIV-

HIV-negative

HIV-positive

days

Conclusion
Clinical meningitis with abnormal CSF
pattern, and supporting evidence of
extraneural TB significant for
diagnosis
Diagnostics: Lab! volume is
important for positive CSF result
Treatment ~ other EPTB: different PK
Give adjunctive corticosteroid

Conclusion
Influence of HIV in the development of
TBM anticipated burden to health
system
HIV dramatically decreases the survival
rate of TBM patients
High prevalence of HIV HIV
screening to any meningitis case
High mortality rate warrants further
studies