The diagnosis and management of tuberculous meningitis
Guy ThwaitesImperial 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
Essential facts: radiology
CXR suggestive of TB in 50%
Basal meningealenhancement (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, pyrazinamideand 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?
79%(26/33)
86%(36/42)
Test data(75 adults)
82% (73-88)(84/103)
97%(104/107)
Specificity
99% (93-100)(76/77)
91%(123/135)
Sensitivity
Furtherstudy*
Resubstitution
Problems: Not evaluated in HIV
infected Performance will
vary dependant on prevalence of TB
Score 4 BM
Lancet. 2002;360(9342):1287-92. *Am J Trop Med Hyg Sept 2007
Is a ZN stain of the CSF useful?
1 2 3 4 5
Volume of CSF examined (mls)
0
25
50
75
100
M.tb
isol
ated
from
CSF
(%)
40
5762
80 78
0-1.9 2.0-3.9 4-5.9 6-7.9 >8
10 mls CSF Centrifuge 3000xg
for 20 minutes Examine slide for
30 minutes Yield: 50-70%
J Clin Microbiol. 2004 Jan;42(1):378-9.
Is PCR of CSF useful?
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
Days of treatment
41-8016-406-152-5Pre-treatmentS
e
n
s
i
t
i
v
i
t
y
(
%
)
100
90
80
70
60
50
40
30
20
10
0
ZN stain
MTD
Culture
ZN+ and/or MTD+
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?
0.77-0.990.83Haematocrit
1.25-8.223.20EPTB
0.86-0.930.90Age
7.7-76.924.4Male sex
95% CIOdds ratio
Similar clinical signs (neurological)
Extra-neural disease more common
Extremes of CSF WCC reported
More bacteria in CSF Worse outcomes
3002001000
P
r
o
p
o
r
t
i
o
n
a
l
i
v
e
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
.0
HIV negative
HIV positive
Log rank P
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?
1. Nothing2. Stop Streptomycin and
isoniazid and add fluoroquinolone and amikacin
3. Stop streptomycin4. Stop streptomycin and
add fluoroquinolone5. Something elseSource: Mitcheson, 2001
Early bactericidal activityof the anti-TB drugs
Days of treatment
270906030730
P
e
r
c
e
n
t
a
g
e
C
S
F
c
u
l
t
u
r
e
p
o
s
i
t
i
v
e
100
80
60
40
20
0
Drug sensitivity
Fully sensitive
INH+/-SM Resistant
MDR
P=0.706
P=0.096
P=0.017
P
Impact of drug resistance on survival from TBM (179 adults)
Time from start of treatment (days)
3002001000
C
u
m
u
l
a
t
i
v
e
S
u
r
v
i
v
a
l
1.0
.8
.6
.4
.2
0.0
SM resistant(24)
INH resistant(9)
Fully sensitive(108)
INH+SM resistant(28)
MDR(10)
RR death, 11.6 (5.2RR death, 11.6 (5.2--26.3), P
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
0
20
40
60
80
SMEAR MODS MGIT LJ
S
E
N
S
I
T
I
V
I
T
Y
52.664.9
70.2 70.2
METHODUnpublished data from Maxine Caws
Time to diagnosis
0
20
40
60
80
100
120
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68
DAYS
C
U
M
U
L
A
T
I
V
E
%
P
O
S
I
T
I
V
E
MODSMGIT LJ
6 days
15 days 34 days
Immunological approaches: T-spot?
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/ T-spot for use on CSF for diagnosis of TBM
J Immunol. 2006;176(3):2007-14 J Immunol. 2005;175(1):579-90.
AcknowledgmentsVIETNAM
TTH ChauPP MaiNT DungTT HienDX SinhNH PhuCam SimmonsMax CawsJeremy FarrarNick White
TT BangTH TuanNV HiepNN ThoaTN HoaDS HienHH Hai
UK(Imperial and NIMR)
Douglas YoungBrian RobertsonAnne OGarraSeb Gagneux
The diagnosis and management of tuberculous meningitisSummaryEssential facts: the historyEssential facts: the examinationEssential facts: CSFEssential facts: radiologyEssential facts: spinal tuberculosisEssential facts: treatmentDiagnostic pitfalls: the strange case of Mr AInvestigations and initial managementFollowing few daysOutcomePost-mortem examinationLessons from this caseCritical clinical issuesCan simple clinical features help?Is a ZN stain of the CSF useful?Is PCR of CSF useful?The case of Mr BMr BDoes HIV influence the clinical presentation of TBM?Does HIV influence treatment decisions?The case of Mr CMr CWhat do you do?Impact of drug resistance on survival from TBM (179 adults)Whats new in TBM?Microscopic observational drug susceptibility assay (MODS)MODS for the rapid diagnosis of TBM in VietnamTime to diagnosisImmunological approaches: T-spot?
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