Thwaites - TBM

Guy Thwaites - TB Meningitis
Tuberculous meningitis
Summary
The basics Practical clinical issues: case illustrations Common pitfalls in diagnosis and treatment Whats new?
Guy Thwaites Imperial College, London Liverpool Neurological Infectious Diseases Course 2007
Please note the slides have been modified to exclude patient details/images and data/mages where permission for reproduction has not been granted
Liverpool Neurological Infectious Diseases Course 2007
The basics: 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)?
Guy Thwaites - TB Meningitis Liverpool Neurological Infectious Diseases Course 2007
The basics: investigations

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

Indian man in his 70s Brought in to A&E by relatives Not right for last 2 weeks: headaches, not eating, vomiting last 2 days and very confused this morning Hypertensive, NIIDM Lives in New Delhi in the UK visiting relatives for last 3 months (does not speak English)
On examination
Confused. Family say he is not making sense. ? dysarthric GCS 13. Temperature 37.5, BP 140/95, pulse 95. O2 sats: 95% on air ? Palatal asymmetry and loss of gag reflex (unsafe swallow) Moving all 4 limbs; reflexes brisk but symmetrical; ? Right extensor plantar
Preliminary investigations
WCC 12,000x106/L Sodium 128 mmol/L Glucose 13 mmol/L CRP 40 ESR 60 Total protein 110 g/l; albumin 28 g/l. Normal calcium. Urine: trace of blood and protein, glucose +, no ketones ECG: atrial fibrillation 100/min. LVH. CXR: poor film ? Shadowing right base
Differential diagnosis
Infection possibly pneumonia ? CVA Nil by mouth IV fluids IV cefuroxime and erythromycin CT head booked Serum protein electrophoresis
Following few days

No improvement in condition CT head (no contrast): ? Mild ventricular dilatation but marked cerebral atrophy. No evidence of CVA or bleed Electrophoresis: distinct paraprotein band. No BJP in urine. Haematology review: ? smouldering myeloma Neurology: Bulbar palsy. Lumbar puncture and MRI.
LP 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
Can simple clinical features help?

Resubstitution Sensitivity 91% (123/135) 97% (104/107) Test data (75 adults) 86% (36/42) 79% (26/33)
Making a rapid and accurate diagnosis Start treatment early
Specificity
Score <5 = TBM; >4 BM
Problems: Not evaluated in HIV infected Performance will vary dependant on Liverpool Neurological Infectious Diseases Course 2007 prevalence of TB
Is a ZN stain of the CSF useful?

10 mls CSF Centrifuge 3000xg for 20 minutes Examine slide for 30 minutes Yield: 50-70%
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
100 90 80 70
Sensitivity (%)
60 50 40 30 20 10 0 Pre-treatment 2-5 6-15 16-40 41-80 ZN stain MTD Culture ZN+ and/or MTD+
100
M.tb isolated from CSF (%)
75
80
78
62
50
57
Days of treatment
40
25
Guy 2.0-3.9 4-5.9 Meningitis 0-1.9 Thwaites - TB 6-7.9 >8

1 2 3 4 5
Volume of CSF examined (mls)
J Clin Microbiol. 2004 Jan;42(1):378-9.
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 2 of admission Died day 5
Does HIV influence the clinical presentation of TBM?

Odds ratio Male sex 24.4 0.90 3.20 0.83 95% CI 7.7-76.9 0.86-0.93 1.25-8.22 0.77-0.99
Does HIV influence treatment decisions?

Same TB drugs; same duration Corticosteroids? Yes probably ARVs immediate or deferred?
Similar clinical signs (neurological) Extra-neural disease more common Extremes of CSF WCC reported Worse outcomes
Age EPTB Haematocrit
1.0 .9 .8 .7 .6 .5 .4 HIV positive HIV negative
Proportion alive
.3 .2
.1 J Infect Dis. 2005 Dec 15;192(12):2134-41. Log rank Guy Thwaites - TB Meningitis Liverpool Neurological Infectious P<0.001 Diseases Course 2007 .0 0 100 200 300
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. 2.
Early Nothing 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
100 P=0.706 P<0.001
Impact of drug resistance on survival from TBM (179 adults)

1.0 Fully sensitive(108) .8 SM resistant(24) INH resistant(9)
80
P=0.096
.6
INH+SM resistant(28)
Percentage CSF culture positive
60
40
P=0.017
Cumulative Survival
3. 4. 5.
.4
Drug sensitivity
20 Fully sensitive INH+/-SM Resistant 0 0 3 7 30 60 90 270 MDR
RR death, 11.6 (5.2-26.3), P<0.001 (5.2.2 MDR(10)
Source: Mitcheson, 2001
0.0 0 100 200 300
Days of treatment
Time from start of treatment (days)
J Infect Dis. 2005 Jul 1;192(1):79-88.
Microscopic observational drug susceptibility assay (MODS)
Whats new in TBM?
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

120
Time to diagnosis
100
80
SENSITIVITY
64.9 52.6
70.2
70.2
CUMULATIVE % POSITIVE
6 days 15 days 34 days
60 40 20 0
80
60
40
MODS MGIT LJ
20
SMEAR
MODS
METHOD
MGIT
LJ
0
32
36
12
40
16
44
20
24
28
48
52
56
60
64
Unpublished data from Maxine Caws
DAYS
68
Acknowledgments
HTD/ OUCRU TTH Chau PP Mai NT Dung TT Hien DX Sinh NH Phu Cam Simmons Max Caws Jeremy Farrar Nick White PNT TT Bang TH Tuan NV Hiep NN Thoa TN Hoa DS Hien HH Hai NT Phuong NT Lan HT Quy

Thwaites - TBM

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Guy Thwaites - TB Meningitis

Guy Thwaites - TB Meningitis

Liverpool Neurological Infectious Diseases Course 2007

The basics: history

The basics: investigations

Guy Thwaites - TB Meningitis

Liverpool Neurological Infectious Diseases Course 2007

The basics: treatment

Diagnostic pitfalls: the strange case of Mr A

Liverpool Neurological Infectious Diseases Course 2007

Guy Thwaites - TB Meningitis

Following few days

Guy Thwaites - TB Meningitis

Liverpool Neurological Infectious Diseases Course 2007

Liverpool Neurological Infectious Diseases Course 2007

Guy Thwaites - TB Meningitis

Lessons from this case

Guy Thwaites - TB Meningitis

Liverpool Neurological Infectious Diseases Course 2007

Guy Thwaites - TB Meningitis

Liverpool Neurological Infectious Diseases Course 2007

Critical clinical issues

Can simple clinical features help?

Making a rapid and accurate diagnosis Start treatment early

Guy Thwaites - TB Meningitis

Liverpool Neurological Infectious Diseases Course 2007

Guy Thwaites - TB Meningitis

Score <5 = TBM; >4 BM

Is a ZN stain of the CSF useful?

Is PCR of CSF useful?

M.tb isolated from CSF (%)

Guy 2.0-3.9 4-5.9 Meningitis 0-1.9 Thwaites - TB 6-7.9 >8

Liverpool Neurological Infectious Diseases Course 2007

Volume of CSF examined (mls)

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

Liverpool Neurological Infectious Diseases Course 2007

Liverpool Neurological Infectious Diseases Course 2007

Guy Thwaites - TB Meningitis

Does HIV influence the clinical presentation of TBM?

Does HIV influence treatment decisions?

Age EPTB Haematocrit

1.0 .9 .8 .7 .6 .5 .4 HIV positive HIV negative

Liverpool Neurological Infectious Diseases Course 2007

Guy Thwaites - TB Meningitis

What do you do?

Impact of drug resistance on survival from TBM (179 adults)

Percentage CSF culture positive

RR death, 11.6 (5.2-26.3), P<0.001 (5.2.2 MDR(10)

Source: Mitcheson, 2001

0.0 0 100 200 300

Time from start of treatment (days)

Guy Thwaites - TB Meningitis

Liverpool Neurological Infectious Diseases Course 2007

Guy Thwaites - TB Meningitis

Liverpool Neurological Infectious Diseases Course 2007

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

Microscopic observational drug susceptibility assay (MODS)

Whats new in TBM?

Guy Thwaites - TB Meningitis

Liverpool Neurological Infectious Diseases Course 2007

MODS for the rapid diagnosis of TBM in Vietnam

6 days 15 days 34 days