Neuro-TB

1. CNS Tuberculosis
Prof R Shukla(DM,Neurology)
KGMU

2. 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

3. 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

4. Looking down Looking up
Looking to right Looking to left
Oculomotor examination

5. 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.

6. Axial Sagittal
MRI brain with Gd contrast

7. 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.

8. 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…

9. 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

10. 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

11. 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.

12. 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

13. 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.

14. 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.

15. 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.

16. 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.
Potts spine
Myelitis

17. Non-osseous spinal cord tuberculosis
• Can occur in the form of tuberculomas.
• Extradural tuberculomas are the most common.
• Intramedullary tuberculomas are rare.

18. 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.

19. 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.

20. 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…

21. 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.

22. Clinical presentation of TBM
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
Clinical Features Children (%) Adults (%)
Zuger A. Tuberculosis. In: Scheld WN, Whitley RJ, Marra CM, editors. Infections of
Central Nervous System. Philadelphia: Lippincott, 2004. pp. 441-9.

23. 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.

24. 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.

25. Diagnostic rule for TBM
4
0
≥ 90
< 90
CSF neutrophil %
3
0
≥ 750
< 750
CSF WBC count (103 / ml)
-5
0
> 6
≤ 6
History of illness (days)
4
0
>15000
≤15000
Blood WBC count (103/ ml)
0
<36
2
>36
Age (years)
Score
Variable
Score : < 4 –TBM; > 4 - Non TBM

26. 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

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

28. 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%.

29. 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.

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

31. Sensitivity and specificity of adjunctive
tests for the diagnosis of TBM
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
Tests Sensitivity (%) Specificity (%) Time Required (h)
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.

32. Sensitivity & specificity of various
diagnostic tests for TBM
Menzies et al, Ann Int Med. 2007; 146: 340-354.
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%

33. Diagnostic criteria for TBM
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.
Possible
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.
Probable
Acid-fast bacilli seen in the cerebrospinal fluid.
Definite
Definition
Class
Thwaites GE et al. Diagnosis of adult tuberculosis meningitis by use of clinical and laboratory features.
Lancet 2002; 360: 1287-92.

34. 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.

35. Imaging abnormalities in TBM

36. 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.

37. 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.

38. List of antitubercular drugs
INH Cycloserine
Rifampicin Ethionamide
Rifapentine Levofloxacin*
Rifabutin* Moxifloxacin*
Ethambutol Gatifloxacin*
Pyrazinamide p-aminosalicylic acid**
Streptomycin**
Amikacin/Kanamycin*
Capreomycin
First-Line Drugs Second-Line Drugs
* Not approved by U.S. FDA
** Included in second-line drugs due to toxicity, limited efficacy or difficulty in
administration.

39. 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.

40. 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.

41. 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.

42. 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.

43. 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.

44. 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).

45. 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.

46. 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.

47. 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.

48. 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)

49. 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.

50. 1. Spinal tuberculosis is classically thought to begin in which
portion of the vertebral body:
– Antero inferior
– Antero superior
– Postero superior
– Postero inferior

51. 1. Spinal tuberculosis is classically thought to begin in which
portion of the vertebral body:
– Antero inferior
– Antero superior
– Postero superior
– Postero inferior

52. 2. A decreased CSF glucose concentration is not seen in
– Tuberculous meningitis
– Fungal meningitis
– Viral meningitis
– Neuro-Sarcoidosis

53. 2. A decreased CSF glucose concentration is not seen in
– Tuberculous meningitis
– Fungal meningitis
– Viral meningitis
– Neuro-Sarcoidosis

54. 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

55. 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

56. 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

57. 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

58. 5. Maximum CSF concentration occurs with:
– INH
– Rifampicin
– Pyrazinamide
– Ethambutol

59. 5. Maximum CSF concentration occurs with:
– INH
– Rifampicin
– Pyrazinamide
– Ethambutol

60. 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

61. 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

62. 7. Which of the following quinolone antibiotics has highest CSF
penetration
– Levofloxacin
– Moxyfloxacillin
– Gatifloxacin
– Ofloxacin

63. 7. Which of the following quinolone antibiotics has highest CSF
penetration
– Levofloxacin
– Moxyfloxacillin
– Gatifloxacin
– Ofloxacin

64. 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

65. 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