The diagnosis and management

of tuberculous meningitis

Guy Thwaites
Imperial College
London

Summary
Essential facts
Practical clinical issues: case illustrations
Common pitfalls in diagnosis and
treatment
Whats new?

Essential facts: the history

Non-specific prodromal period (loss of
appetite, malaise etc) 1-3 weeks
Gradual onset (days) of headache and
vomiting
Photophobia rarely reported
Previous TB treatment
Recent contact with TB (children)
Immune-suppression (HIV risks)

Essential facts: the examination

Essential facts: CSF

CSF
Pressure raised in 50%
WCC: 5-1000 cells/mm3
70:30 lymphocyte:
neutrophils
Protein 800-2000 mg/l
CSF:blood glucose <50% in
95%
ZN stain sensitivity 10-70%
PCR sensitivity 40-70%

Essential facts: radiology

CXR suggestive of TB
in 50%
Basal meningeal
enhancement (80%)
Hydrocephalus (70%),
Tuberculomas (20%)
Infarcts (10%)

Essential facts: spinal tuberculosis

Potts spine
Radiculo-myelitis
Tuberculoma

Essential facts: treatment

NICE guidelines 2006 recommend 2
months rifampicin, isoniazid, pyrazinamide
and ethambutol
Followed by 10 months rifampicin and
isoniazid (daily dosing)
Adjunctive dexamethasone for all patients
(regardless of severity) from the start of
treatment and for 6-8 weeks

Diagnostic pitfalls: the strange case

of Mr A
78 year old Indian man
Brought in to A&E by relatives
Not right for last 2 weeks: headaches, not eating,
vomiting last 2 days and confused
Hypertensive, NIIDM
Confused. GCS 13.
Temperature 37.50C
Palatal asymmetry and loss of gag reflex
Moving all 4 limbs. Reflexes brisk but symmetrical. ?
Right extensor plantar

Investigations and initial

management
WCC 12,000x106/L, Sodium
128 mmol/L
CRP 40 ESR 60
Total protein 110 g/l; albumin
28 g/l. Normal calcium.
ECG: atrial fibrillation
100/min. LVH.
CXR: poor film ? Shadowing
right base
Infection possibly
pneumonia
? CVA

Nil by mouth
IV fluids
IV cefuroxime and
erythromycin
CT head booked
Urine & serum protein
electrophoresis

Following few days

No improvement in condition
CT head (no contrast): Mild ventricular dilatation, but
marked cerebral atrophy. No CVA or bleed
Electrophoresis: distinct paraprotein band. No BJP in
urine. Haematology review: smouldering myeloma
Neurology: Bulbar palsy. Lumbar puncture and MRI.
LP: Pressure 28cm H20; WCC 5/mm3 (differential not
done); Protein 850 mg/L; CSF: blood glucose 0.45
MRI (after LP): 2 small round enhancing lesion in brain
stem. Cerebral atrophy ++.

Outcome
Continued diagnostic uncertainty: were brain lesions
plasmacytomas? Secondary metastatic deposits? Or
TB?
Patient getting worse. No agreement amongst senior
physicians
Empiric anti-tuberculosis therapy (4 drugs) started 12
days after admission
Respiratory arrest on ward 2 days later and the patient
died

Post-mortem examination

Lessons from this case

The diagnosis of tuberculous meningitis is
often difficult
Delayed treatment is strongly associated
with death
Empiric therapy is often required to
prevent death or severe sequelae

Critical clinical issues

Making a rapid and accurate diagnosis

Start treatment early

Can simple clinical features help?

Score <5 = TBM; >4 BM

Lancet. 2002;360(9342):1287-92.

Resubstitution

Test data
(75 adults)

Further
study*

Sensitivity

91%
(123/135)

86%
(36/42)

99% (93-100)
(76/77)

Specificity

97%
(104/107)

79%
(26/33)

82% (73-88)
(84/103)

Problems:
Not evaluated in HIV
infected
Performance will
vary dependant on
prevalence of TB
*Am J Trop Med Hyg Sept 2007

Is a ZN stain of the CSF useful?

10 mls CSF
Centrifuge 3000xg
for 20 minutes
Examine slide for
30 minutes
Yield: 50-70%

M.tb isolated from CSF (%)

100

80

75

78

62
57

50

40
25

0-1.9

2.0-3.9

4-5.9

6-7.9

Volume of CSF examined (mls)

>8

J Clin Microbiol. 2004 Jan;42(1):378-9.

Is PCR of CSF useful?

100
90
80
70

Sensitivity (%)

Meta-analysis Lancet ID
2003
49 studies
Results: Sensitivity
0.56 (0.46 to 0.66),
Specificity 0.98 (0.97 to
0.99)
Conclusion: Commercial
NAA tests useful for
confirming TBM, but not
good for ruling it out

60
50
40
30

ZN stain

20

MTD

10

Culture
ZN+ and/or MTD+

0
Pre-treatment

2-5

6-15

16-40

41-80

Days of treatment

J Clin Microbiol. 2004;42(3):996-1002

The case of Mr B

25 year old
IVDU
Unwell for 6 months
Progressive weakness
of both legs last 3
months
Noticed lump in neck 2
weeks ago
Now headache and
vomiting
Rapidly progressive
coma

Mr B
CSF: 8 WCC/mm3;
protein 2000mg/l;
CSF:blood glucose 0.30
Numerous AFB seen in
the CSF
HIV infected
CD4 count 35
TB treatment day of
admission
Died day 5

Does HIV influence the clinical

presentation of TBM?
Similar clinical signs
(neurological)
Extra-neural disease
more common
Extremes of CSF
WCC reported
More bacteria in CSF
Worse outcomes

Odds ratio

95% CI

Male sex

24.4

7.7-76.9

Age

0.90

0.86-0.93

EPTB

3.20

1.25-8.22

Haematocrit

0.83

0.77-0.99

1.0
HIV negative

.9
.8
.7
.6
.5

J Infect Dis. 2005 Dec 15;192(12):2134-41.

Proportion alive

.4

HIV positive

.3
.2
.1

Log rank P<0.001

.0
0

100

200

300

Does HIV influence treatment

decisions?
Same TB drugs;
same duration
Corticosteroids?
Yes probably
ARVs immediate
or deferred?

N Engl J Med. 2004;351(17):1741-51

The case of Mr C
55 year-old male
14/7 headache
and vomiting
Treated for
pulmonary TB 5
years previously
(took 2 courses)
HIV negative

Mr C
Immediate treatment with 5
drugs (streptomycin +
ethambutol)
Adjunctive dexamethasone
Improves, but still febrile
day 35
CSF culture result: Mtb
resistant to isoniazid and
streptomycin

What do you do?

3.
4.
5.

NothingEarly bactericidal activity

of the anti-TB drugs
Stop Streptomycin and
isoniazid and add
fluoroquinolone and
amikacin
Stop streptomycin
Stop streptomycin and
add fluoroquinolone
Something else

Source: Mitcheson, 2001

100

P=0.706

80

Percentage CSF culture positive

1.
2.

P<0.001

P=0.096

60

P=0.017

40

Drug sensitivity
Fully sensitive

20

INH+/-SM Resistant
0

MDR
0

Days of treatment

30

60

90

270

Impact of drug resistance on

survival from TBM (179 adults)
1.0

Cumulative Survival

Fully sensitive(108)

SM resistant(24)

.8

INH resistant(9)

.6

INH+SM resistant(28)

.4

RR death, 11.6 (5.2-26.3), P<0.001

.2

MDR(10)

0.0
0

100

200

300

Time from start of treatment (days)

J Infect Dis. 2005 Jul 1;192(1):79-88.

Whats new in TBM?

Microscopic observational drug

susceptibility assay (MODS)
Developed in Peru,
2000
Infect liquid media with
sample (+/- drug)
Observe growth by
microscopy
NEJM Oct 2006
12;355(15): as good as
conventional methods
for diagnosis of drug
resistant TB but much
faster (7 vs 68 days)

MODS for the rapid diagnosis of

TBM in Vietnam

SENSITIVITY

80
60

52.6

64.9

70.2

70.2

MGIT

LJ

40
20
0
SMEAR

MODS
METHOD

Unpublished data from Maxine Caws

Time to diagnosis
120

6 days
15 days

34 days

80

60

MODS
MGIT
LJ

40

20

DAYS

68

64

60

56

52

48

44

40

36

32

28

24

20

16

12

CUMULATIVE % POSITIVE

100

Immunological approaches: Tspot?

CSF lymphoctyes CD3+ CD4+
(76%)
Different surface expression
profile from peripheral blood
Ex-vivo stimulation with ESAT-6
(ELISPOT assay) failed to
demonstrate IFN- production
Activated phenoptype; rapid
cell-death ex-vivo
Implications for ELISPOT/ Tspot for use on CSF for
diagnosis of TBM
J Immunol. 2005;175(1):579-90.

J Immunol. 2006;176(3):2007-14

Acknowledgments
VIETNAM
TTH Chau
PP Mai
NT Dung
TT Hien
DX Sinh
NH Phu
Cam Simmons
Max Caws
Jeremy Farrar
Nick White

TT Bang
TH Tuan
NV Hiep
NN Thoa
TN Hoa
DS Hien
HH Hai

UK
(Imperial and NIMR)
Douglas Young
Brian Robertson
Anne OGarra
Seb Gagneux