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 ½ months

• Headache with vomiting since 1 ½ 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 up

Looking to right 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, Gram’s 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

extra-pulmonary 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
- Pott’s spine and Pott’s 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 ά 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 Myelitis
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.

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, Kernig’s sign,
Bickelle’s sign and Brudzinski’s 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 Score
Age (years) >36 2
<36 0
Blood WBC count (103/ ml) >15000 4
≤15000 0

History of illness (days) >6 -5

≤6 0

CSF WBC count (103 / ml) ≥ 750 3

< 750 0
CSF neutrophil % ≥ 90 4
< 90 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:
• CSF culture on solid media:
• Adjunctive tests
• Molecular diagnosis :
Zeihl Nelson’s, Gram’s
and India Ink stain.
Egg or agar based
BACTEC systems.
CSF tuberculostearic acid,
adenosine deaminase,
radiolabelled bromide
partition test.
Nucleic acid 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:
• CSF culture on solid media:
• Adjunctive tests :
• Molecular diagnosis :
Zeihl Nelson’s, Gram’s
and India Ink stain.
Egg or agar based
BACTEC systems.
CSF tuberculostearic acid,
adenosine deaminase,
radiolabelled bromide
partition test.
Nucleic acid 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 90-94 88-96 48
CSF adenosine deaminase level 73-100 71-99 <24
CSF tuberculostearic acid level 95 99 <24

Immunologic test (ELISA)

Antigen ELISA 38-94 95-100 <24
Antibody ELISA 52-93 38-94

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. 145-
66.
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 evidence of extrapulmonary tuberculosis.
Possible Patients with at least four of the following:
i. History of tuberculosis.
ii. Predominance of lymphoytes in the cerebrospinal fluid.
iii. A duration of illness of more than six days.
iv. A ratio of CSF glucose to plasma glucose of less than 0.5.
v. Altered consciousness
vi. Turbid cerebrospinal fluid.
vii. 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 (15-30%), 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 Second-Line Drugs

INH Cycloserine
Rifampicin Ethionamide
Rifapentine Levofloxacin*
Rifabutin* Moxifloxacin*
Ethambutol Gatifloxacin*
Pyrazinamide 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 (500-
1000mg/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
– 10×10
– 10×102
– 10×103
– 10×104
3. For a positive smear on Zeihl-Neelsen staining, the bacterial
load (in AFB/ml) required is
– 10×10
– 10×102
– 10×103
– 10×104
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