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

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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

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n

t

a

g

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C

S

F

c

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t

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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

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a

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S

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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

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100

120

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68

DAYS

C

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M

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A

T

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%

P

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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?