Tuberculous Meningitis, diagnosis and treatment

Ahmad Rizal Department of Neurology 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%) 92.5% 82.5% 90%

Thwaites & Hien, TLID, 2005

E. Torok, ASNA Meeting, March 2007

TBM, clinical features

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

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 HIV-associated TBM

Thwaites et al, JID, 2005

Meningitis, HIV+ vs HIVDiagnosis HIV-positive (n=41) 27 (65.9%) 7 HIV-negative (n=111) 96 (86.5%) 59 Total population (n=152) 123 (80.9%) 66

Tuberculous meningitis Definite TBM

Probable TBM
Cryptococcal meningitis Probable bacterial meningitis Unknown cause

20
12 (29.3%) 2 (4.8%)

37
1 (0.9%) 10 (9%) 4 (3.6%)

57
13 (8.6%) 10 (6.6%) 6 (3.9%)

Factors Associated with 1-month death

Characteristics HIV positive** Altered consciousness (GCS < 14)** Dead (n=61) 28 / 61 (45.9) 33 / 55 (60) Alive (n=91) 13 / 91 (14.3) 27/89 (30.3)

Fever on presentation*
Focal neurological sign* CSF leukocyte count > 70/mm3 Peripheral leukocyte > 10,000/ mm3 Abnormal Chest X-ray

27/56 (48.2)
35 (57.4) 30 (49.2) 32/56 (57.1) 41/57 (71.9)

25/86 (29.1)
37 (40.7) 45 (49.4) 39/88 (44.3) 61/89 (68.5)

Plasma sodium < 136 mEq/L

** p<0.01; * p<0.05

30/49 (61.2)

64/87 (73.6)

Factors Associated with 1-month death

Characteristics Crude Odds Ratio (95% CI) 5.09 (2.35-11.03) 3.44 (1.70-6.96) 2.27 (1.13-4.58) 1.96 (1.02-3.79) .99 (.52-1.89) 1.68 (.85-3.29) 1.71 (.57-2.44) .57 (.27-1.20) 2.45 (1.13-5.29) .63 (.29-1.35) 1.52 (.71-3.25) Adjusted Odds Ratio Model without HIV Model with HIV

HIV positive Altered consciousness (GCS < 14) Fever on presentation Focal neurological sign CSF leukocyte count > 70/mm3 Peripheral leukocyte > 10,000/ mm3 Abnormal Chest X-ray Plasma sodium < 136 mEq/L

6.26 (2.50-15.72) 2.54 (1.10-5.84) .59 (.26-1.36) 1.74 (.76-3.96)

Survival curve, HIV+ vs. HIVSurvival of Data 1:Survival proportions

100

Percent survival

HI HI
HIV-negative

50

HIV-positive

0 0 100 200
daysdays

300

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