The diagnosis and management of tuberculous meningitis

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
• What’s 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
• Pott’s 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
0-1.9
2
2.0-3.9
3
4-5.9
4
6-7.9
Volume of CSF examined (mls)
5
>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
3
7
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.
What’s 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
8
4
0
0
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-γ 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 O’Garra
Seb Gagneux