CNS Tuberculosis

Prof R Shukla(DM,Neurology)
KGMU

Case history
20 yrs old female patient presented with c/o
Fever mild to moderate grade since 1 months
Headache with vomiting since 1 months
Decreased vision both eyes since 1 month

Examination
General examination including vitals Normal
CNS examination
GCS- 15/15

Neck rigidity/ Kernigs sign Absent.

Optic nerves-

Visual acuity- PL/PR absent both eyes.

Fundus- Bilateral primary optic atrophy.
Bilateral 3rd 4th 6th cranial nerves palsy present.

Right LMN facial nerve palsy present.

Rest of the neurological examination - normal

Oculomotor examination

Looking down

Looking to right

Looking up

Looking to left

Investigations
Routine hematological & biochemical investigations Normal
CSF examination
TLC 440 cells
Lymphocytes 95%
Polymorphs 5%
Proteins 111 mg%
Sugar 21 mg%
Corresponding blood sugar 171 mg%.
AFB, Grams stain & India ink staining normal
TB PCR report awaited.

MRI brain with Gd contrast

Axial

Sagittal

Introduction
Tuberculosis is a major cause of death worldwide.
India has the highest TB burden, accounting for 1/5 of the
global incidence and 2/3 of cases in SE Asia.

Nearly 40% of population in India is affected.

CNS tuberculosis occurs in up to 10% and has protean
clinical manifestations.

The burden of CNS tuberculosis is directly proportional to the

prevalence of tuberculous infection.

Tuberculous meningitis is the most devastating form of extrapulmonary tuberculosis with 30% mortality and disabling
neurological sequelae in > 25% survivors.

Classification of neurotuberculosis

Tuberculous meningitis
Basal and spinal
Tuberculoma
Intracranial (parenchymal & extraparenchymal)
Spinal (parenchymal & extraparenchymal)
Tuberculous abscess
Tuberculous encephalopathy
With or without meningitis
Spinal cord involvement secondary to skeletal
tuberculosis

Contd

Classification of neurotuberculosis Contd

Intracranial
-

Tuberculous meningitis
Tuberculoma
Tuberculous abscess
Tuberculous encephalopathy
Tuberculous vasculopathy

Spinal
-

Potts spine and Potts paraplegia

Tuberculous arachnoiditis
Spinal tuberculoma
Spinal meningitis

Causative organism

CNS tuberculosis is caused by the human strain of

Myobacterium tuberculosis.

However in immunocompromised patients, atypical

mycobacteria are an important cause of infection.

They are now called non-tuberculous mycobacteria

which include:
Mycobacterium avium
Mycobacterium intracellulare

Pathophysiology
CNS tuberculosis is secondary to disease elsewhere in the
body.

Mycobacteria reach the brain by hematogenous route.

Initial small tuberculous lesions (Rich foci) develop in meninges,
subpial or subependymal surface of the brain or the spinal cord,
and may remain dormant for years.

Reactivation may be due to endogenous factors:

Innate immunological and non immunological defenses
Level of function of cell mediated immunity.

Tumour necrosis factor may have a role.

Pathology
Release of M tuberculosis results in a
T lymphocyte dependent necrotising
granulomatous inflammatory
response.

Thick gelatinous exudate around the

sylvian fissures, basal cisterns,
brainstem and cerebellum.

Three processes cause most of the

neurological deficits:
Hydrocephalous
Adhesive arachnoiditis
Obliterative vasculitis

Tuberculous brain abscess

Distinct from CNS tuberculoma.

4 to 7.5% of patients with CNS
tuberculosis.
Usually solitary, uniloculated or
multiloculated of variable size
Progresses much more rapidly
than tuberculomas.
Clinical features include partial
seizures, focal neurological
deficit and raised intracranial
tension.
CT and MRI show a large size
lesion with marked surrounding
oedema.

Tuberculous encephalopathy

Seen in infants and children.

Characterized by convulsions, stupor and coma with

signs of meningeal irritation or focal neurological deficit.

CSF is largely normal.

Responsive to corticosteroids.

Tuberculoma

Firm avascular spherical

granulomatous mass.
Usually 2-8cm in diameter.
Symptoms related to their
size and location.
Low grade fever, headache,
vomiting, seizures, focal
neurological deficit, and
papilloedema are the
characteristic.
Target sign is characteristic.

Spinal tuberculosis

< 1% of patients.
Infection starts in cancellous bone
usually adjacent to an inter-vertebral
disc or anteriorly under the
periosteum.
Thoracic (65%) lumbar (20%),
cervical (10%), thoraco-lumbar (5%),
and atlanto-axial region (< 1%).
Two (<90%), Three (50%) vertebrae
Paraspinal abscess 55-90%.
Local pain, tenderness over the
affected spine or a gibbus associated
with paravertebral muscle spasm or a
palpable paravertebral abscess.
Neurological deficit results from
multiple causes.

Myelitis

Potts spine

Non-osseous spinal cord tuberculosis

Can occur in the form of tuberculomas.
Extradural tuberculomas are the most common.
Intramedullary tuberculomas are rare.

Tuberculous arachnoiditis

Features of spinal cord or nerve involvement may

predominate, but most often there is a mixed picture.

Subacute paraparesis, radicular pain and bladder

dysfunction.

The hallmark of diagnosis is the characteristic

myelographic picture, showing poor flow of contrast
material with multiple irregular filling defects, cyst
formation and sometimes spinal block.

Spinal form of tuberculous meningitis

May result from rupture of Rich foci in the spinal arachnoid space.
The acute form presents with fever, headache, and root pains accompanied by myelopathy.
The chronic form presents with spinal cord compression.
Spinal forms of tuberculous meningitis may be associated with syrinx formation.

Tuberculous meningitis (TBM)

Commonest form of neurotuberculosis (70 to 80%) .

TBM is also the commonest form of chronic meningitis.

Clinical features include h/o vague ill health for 2-8

weeks prior to development of meningeal irritation.

Non specific symptoms include malaise, anorexia,

fatigue, low grade fever, myalgia and headache.

Prodromal symptoms in infants and children include

irritability, drowsiness, poor feeling, and abdominal pain..
Contd

Tuberculous meningitis (TBM) Contd

Meningeal irritation - neck stiffness, Kernigs sign,

Bickelles sign and Brudzinskis sign.

Cranial nerve palsies (20-30%), fundus - papilloedema

or rarely choroid tubercles, seizures, focal neurological
deficits secondary to infarction.

Visual loss may be due to optic nerve involvement,

optochiasmatic arachnoiditis, third ventricular
compression of optic chiasma, ethambutol toxicity and
occipital lobe infarction.

Increasing lethargy, confusion, stupor, deep coma,

decerebrate or decorticate rigidity.

Clinical presentation of TBM

Clinical Features

Children (%)

Adults (%)

History
Tuberculosis 55
8-12
Symptoms
Headache
20-50 50-60
Nausea/vomiting
50-75 8-40
Apathy/behavioural changes 30-70 30-70
Seizures
10-20 0-15
Signs
Fever 50-100 60-100
Meningismus 70-100 60-70
Cranial nerve palsy 15-30 15-40
Coma 30-45 20-30
Zuger A. Tuberculosis. In: Scheld WN, Whitley RJ, Marra CM, editors. Infections of
Central Nervous System. Philadelphia: Lippincott, 2004. pp. 441-9.

Staging of TBM
TBM is classified into 3 stages according to the British Medical
Research Council (MRC) criteria
Stage I:
Prodromal phase with no definite neurologic
symptoms.
Stage II:

Signs of meningeal irritation with slight or no

clouding of sensorium and minor (cranial nerve
palsy) or no neurological deficit.

Stage III: Severe clouding of sensorium, convulsions, focal

neurological deficit and involuntary movements.

Modified MRC criteria

Grade I: Alert and oriented (GCS 15) without focal
neurological deficit.
Grade II: GCS 14-10 with or without focal neurological
deficit or GCS 15 with focal neurological deficit.
Grade III: GCS less than 10 with or without focal
neurological deficit.

Diagnostic rule for TBM

Variable
Age (years)

Score
>36

<36

Blood WBC count (103/ ml)

>15000
15000

4
0

History of illness (days)

>6
6

-5
0

CSF WBC count (103 / ml)

750
< 750

3
0

CSF neutrophil %

90
< 90

4
0

Score : < 4 TBM; > 4 - Non TBM

Differential diagnosis of TBM

Fungal meningitis (cryptococcosis, histoplasmosis,

blastomycosis, coccidioidal mycosis)
Viral meningoencephalitis (herpes simplex, mumps)
Partially treated bacterial meningitis
Neurosyphills
Focal parameningeal infection
CNS toxoplasmosis
Neoplastic meningitis (lymphoma, carcinoma)
Neurosarcoidosis

Investigations
CSF examination
CSF Smear examination: Zeihl Nelsons, Grams
and India Ink stain.
Egg or agar based
CSF culture on solid media:
BACTEC systems.
CSF tuberculostearic acid,
Adjunctive tests
adenosine deaminase,
radiolabelled bromide
partition test.
Nucleic acid
Molecular diagnosis :
amplification,
DNA finger printing, PCR.

Cerebrospinal fluid examination

Predominantly lymphocytic pleocytosis, with increased proteins
and low CSF/ blood glucose ratio.

WBC count can be normal in presence of depressed CMI

(elderly and HIV positive individuals).

CSF protein (> 150 mg/dl) should always raise the suspicion of
tuberculosis or fungal infection, rarely seen in viral meningitis.

Smear is +ve in 10%, can be increased by examining large

volume of CSF.

Culture is +ve in 25-70%.

Cerebrospinal fluid examination

Repeat CSF frequently shows a falling glucose level, a
rising protein concentration and a shift to mononuclear
predominance.

CSF cell counts decrease by 50% during the first month

but may not become normal for a year.

CSF glucose becomes normal in 1 to 2 months and

protein becomes normal by 12 months or longer.

CSF cultures should be sterile by the first month, but

PCR results may remain positive for a month.

Investigations
CSF examination:
CSF Smear examination: Zeihl Nelsons, Grams
and India Ink stain.
Egg or agar based
CSF culture on solid media:
BACTEC systems.
Adjunctive tests : CSF tuberculostearic acid,
adenosine deaminase,
radiolabelled bromide
partition test.
Nucleic acid
Molecular diagnosis :
amplification,
DNA finger printing, PCR.

Sensitivity and specificity of adjunctive

tests for the diagnosis of TBM
Tests

Sensitivity (%)

Specificity (%)

Time Required (h)

Biochemical
Radiolabelled bromide partition ratio
CSF adenosine deaminase level
CSF tuberculostearic acid level

90-94
73-100
95

88-96
71-99
99

48
<24
<24

38-94
52-93

95-100
38-94

<24

Immunologic test (ELISA)

Antigen ELISA
Antibody ELISA

Kalita J, Misra UK. Tuberculosis Meningitis. In Misra UK, Kalita J (Eds) Diagnosis and
Management of Neurological Disorders. Wolter Kluwers Health New Delhi 2011; pp. 14566.

Sensitivity & specificity of various

diagnostic tests for TBM
Diagnostic
test

Sensitivity

Specificity

ZN staining

10-20%

100%

LJ Culture

15% (25-80)

100%

BACTEC Culture 55%

100%

ELISA

52.3%

91.6%

TB PCR

56%

98%

TST

73%

56%

QTF-GOLD

76%

98%

ELISPOT

87%

92%

Menzies et al, Ann Int Med. 2007; 146: 340-354.

Diagnostic criteria for TBM

Class

Definition

Definite

Acid-fast bacilli seen in the cerebrospinal fluid.

Probable

Patients with one or more of the following:

i.
Suspected active pulmonary TB on chest
radiography.
ii.
AFB found in any specimen other than the CSF.
iii.
Clinical
of extrapulmonary
Patients
withevidence
at least four
of the following:tuberculosis.

Possible

i.
ii.
iii.
iv.
v.
vi.
vii.

History of tuberculosis.
Predominance of lymphoytes in the cerebrospinal
fluid.
A duration of illness of more than six days.
A ratio of CSF glucose to plasma glucose of less
than 0.5.
Altered consciousness
Turbid cerebrospinal fluid.
Focal neurologic signs.

Thwaites GE et al. Diagnosis of adult tuberculosis meningitis by use of clinical and laboratory features.
Lancet 2002; 360: 1287-92.

Imaging in TBM
CT/ MRI confirm the presence and extent of basal arachnoiditis, cerebral
oedema, infarction, ventriculitis and hydrocephalus.

Abnormalities depend upon stage of disease:

I (normal in 30%), II (Normal in 10%), III (Abnormal in all).

Hydrocephalus (70-85%), basal meningeal enhancement (40%), infarction (1530%), tuberculoma (5-10%).

Meningeal enhancement, tuberculoma or both have a sensitivity of 89% and

specificity of 100%.

Precontrast hyperdensity in basal cisterns is the most specific radiological sign.

Radiological findings also help in prognostication.

Imaging abnormalities in TBM

Search for extra CNS TB

An extra-neural focus should be sought clinically and
radiologically in all patients of CNS TB as it may indicate
safer and more accessible sites for diagnostic sampling
e.g. X-ray chest, FNAC of the enlarged lymphnodes,
abdominal USG, CT scan .

77% of HIV +ve TBM patients have extra-meningeal TB

compared to only 9% with HIV ve patients.

Thwaites G, et al. J Neurol Neurosurg Psychiatry 2000;68:289-99.

Principles of treatment of TBM

Treatment should be started early in suspected TBM.
Multiple antimicrobial drugs are required.
Drugs must adequately cross the blood-CSF barrier to
achieve therapeutic concentrations in CSF.

Drugs should be taken on a regular basis for a sufficient

period to eradicate the CNS infection.

Intrathecal therapy is not required.

No general consensus regarding the choice of drug,
doses and duration of treatment.

List of antitubercular drugs

First-Line Drugs

INH
Rifampicin
Rifapentine
Rifabutin*
Ethambutol
Pyrazinamide

Second-Line Drugs

Cycloserine
Ethionamide
Levofloxacin*
Moxifloxacin*
Gatifloxacin*
p-aminosalicylic acid**
Streptomycin**
Amikacin/Kanamycin*
Capreomycin

* Not approved by U.S. FDA

** Included in second-line drugs due to toxicity, limited efficacy or difficulty in
administration.

Treatment
CNS tuberculosis is categorised under TB treatment
category I by WHO.

Initial phase therapy ( 2 mths) with isoniazid, rifampicin,

pyrazinamide and streptomycin or ethambutol followed by

continuation phase (7 mths) with isoniazid and rifampicin.

The BTS and IDSA/ATS recommend 9-12 months of ATT.

Therapy should be extended to 18 months in patients who

do not tolerate pyrazinamide.

Short duration therapy (6 mths) might be sufficient if the

likelihood of drug resistance is low.

However as the emergence of neurological deficit has

been seen in some of the studies so a minimum of 12
months treatment would be worthwhile.

What is the best anti-tuberculous drug regimen?

Isonaizid, rifampicin and pyrazinamide are considered mandatory at
the beginning of TBM treatment.

Isoniazid penetrates the CSF freely and has potent early

bactericidal activity.

Rifampicin penetrates the CSF less well (maximum concentrations

around 30% of plasma), but the high mortality from rifampicin

resistant TBM has confirmed its central role in the treatment of CNS
disease.

There is no conclusive evidence to demonstrate that pyrazinamide

improves outcome of CNS tuberculosis, although it is well absorbed

orally and achieves high concentration in the CSF.
Thwaites GE et al. J Neurol Neurosurg Psychiatry 2000; 68: 289-99;
Lancet Neurol 2005; 4: 160-70.

Choice of the fourth drug

No data from controlled trials.
Most authorities recommend either streptomycin or ethambutol, although
neither penetrates the CSF well in the absence of inflammation.

Streptomycin should not be given to those who are pregnant or have

renal impairment.

Ethambutol should be avoided where optic neuropathy is a concern.

The fluoroquinolones may represent an effective fourth agent, although
data concerning their CSF pharamacokinetics and safety during
prolonged therapy are limited.

Others-Ethionamide, prothionamide.

Adjunctive steroid therapy

The use of corticosteroids as adjunctive therapy in the
treatment of CNS tuberculosis began as early as the
1950s.

The rationale behind the use of steroids includes the

reduction of inflammation within the subarachnoid space.

The largest RCT in TBM recommends dexamethasone

treatment in patient with TBM for 6-8 weeks.
Thwaites GE et al. N Engl J Med 2004; 351: 1741-51;
Lancet Neurol 2007; 6: 280-6.

Adjunctive steroid therapy

A recent Cochrane review and meta-analysis of 7
randomised controlled trials involving 1140 participants
(with 411 deaths) concluded that corticosteroids improved
outcome in HIV-negative children and adults with TBM, but
the benefit in HIV infected individuals remains uncertain.

Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis.

Cochrane Database Syst Rev 2008;(1):CD002244.

Role of surgery in CNS tuberculosis

Hydrocephalus, tuberculous cerebral abscess and vertebral

tuberculosis with paraparesis are all indications for neurosurgical

referral (A,II).

Early ventriculo-peritoneal shunting should be considered in those

with non-communicating hydrocephalus (A,II) and in those with
communicating hydrocephalus falling medical management (B,II).

Communicating hydrocephalus may be treated initially with

frusemide (40 mg/24 h adults, 1 mg/kg children) and

acetazolamide (10-20 mg/kg adults, 30-50 mg/kg children) (B,II) or
repeated lumbar punctures (B,III).

Urgent surgical decompression should be considered in all those

with extra-dural lesions causing paraparesis (A,II).

TBM in HIV positive patients

The optimal regimens have not been clearly established,
should be same as in HIV ve individuals.

Four drug regimen including pyrazinamide is

recommended.

Initiation of HAART depends upon CD 4 counts.

Infection with NTM (M avium/M intracellulare).
Current recommendations include using azithromycin
(500-100mg/day) and clarithromycin
(5001000mg/day) in combination with ethambutol
(15mg/kg/day) or clofazimine (100 mg/day).
Alternative regimens include the use of ciprofloxacin
and rifampicin.
Rifabutin is recommended in place of rifampicin for
those taking protease inhibitors.

Treatment of multi-drug resistant TBM

The treatment of multi drug resistant TBM should abide by
the principles of treatment of multi drug resistant
pulmonary tuberculosis.

Never add a single drug to a failing regimen.

Use at least three previously unused drugs, one of which
should be a fluoroquinolone.

Streptomycin resistance does not confer resistance to

other aminoglycosides, therefore amikacin or kanamycin

can be used.

Treatment should be given for at least 18 months.

Prognosis
Virtually all patients with no focal deficits and only minor
lethargy recover, most-without sequelae.

Comatose patients have a mortality of 50% and a high

incidence of residual disability.

The incidence of residual neurological deficits after

recovery from TBM varies from 10-30%.

Late sequelae include cranial nerve deficits, gait

disturbance, hemiplegia, blindness, deafness, learning

disability, dementia and various syndromes of
hypothalamic or pituitary dysfunction.

Poor prognostic factors

Stage of disease.
Presence of miliary disease
Severe disease on admission
Delay in initiation of treatment
Extremes of age, preexistence of a debilitating condition
Very abnormal CSF (very low glucose or elevated protein)

Conclusion
CNS tuberculosis is a common, eminently treatable
disorder with protean manifestations.

Early diagnosis requires a high index of suspicion.

Careful bacteriology of CSF is as good as or better than
molecular method before starting treatment.

CT or MRI showing basal meningeal enhancement with

any degree of hydrocephalus is strongly suggestive of
TBM.

Clinical outcome depends greatly on the stage of disease

at which therapy is initiated.

1. Spinal tuberculosis is classically thought to begin in which

portion of the vertebral body:
Antero inferior
Antero superior
Postero superior
Postero inferior

1. Spinal tuberculosis is classically thought to begin in which

portion of the vertebral body:
Antero inferior
Antero superior
Postero superior
Postero inferior

2. A decreased CSF glucose concentration is not seen in

Tuberculous meningitis
Fungal meningitis
Viral meningitis
Neuro-Sarcoidosis

2. A decreased CSF glucose concentration is not seen in

Tuberculous meningitis
Fungal meningitis
Viral meningitis
Neuro-Sarcoidosis

3. For a positive smear on Zeihl-Neelsen staining, the bacterial

load (in AFB/ml) required is
1010
10102
10103
10104

3. For a positive smear on Zeihl-Neelsen staining, the bacterial

load (in AFB/ml) required is
1010
10102
10103
10104

4. Which of the following adjunctive tests has the highest

sensitivity and specificity for the diagnosis of TBM
Radiolabelled bromide partition test
CSF adenosine deaminase level
CSF tuberculostearic acid level
CSF antigen ELISA

4. Which of the following adjunctive tests has the highest

sensitivity and specificity for the diagnosis of TBM
Radiolabelled bromide partition test
CSF adenosine deaminase level
CSF tuberculostearic acid level
CSF antigen ELISA

5. Maximum CSF concentration occurs with:

INH
Rifampicin
Pyrazinamide
Ethambutol

5. Maximum CSF concentration occurs with:

INH
Rifampicin
Pyrazinamide
Ethambutol

6. In a patient with antitubercular therapy, if the primary

elevation is in bilirubin and alkaline phosphatase, the most
likely offending drug is,
Isoniazid
Rifampicin
Ethambutol
Pyrazinamide

6. In a patient with antitubercular therapy, if the primary

elevation is in bilirubin and alkaline phosphatase, the most
likely offending drug is,
Isoniazid
Rifampicin
Ethambutol
Pyrazinamide

7. Which of the following quinolone antibiotics has highest CSF

penetration
Levofloxacin
Moxyfloxacillin
Gatifloxacin
Ofloxacin

7. Which of the following quinolone antibiotics has highest CSF

penetration
Levofloxacin
Moxyfloxacillin
Gatifloxacin
Ofloxacin

8. Chemoprophylaxis for tuberculosis is indicated in persons

with high risk medical conditions, if the tuberculin reaction
size (in mm) is,
<5
5
10
15

8. Chemoprophylaxis for tuberculosis is indicated in persons

with high risk medical conditions, if the tuberculin reaction
size (in mm) is,
<5
5
10
15