Central nervous system tuberculosis (CNS TB) is a severe form of TB infection that can affect the brain and spinal cord. It is most common in children under 5 years old. Left untreated, CNS TB has an almost 100% fatality rate and can cause permanent neurological damage even with treatment. Diagnosis involves examination of cerebrospinal fluid which shows increased white blood cells and protein with low glucose. Brain imaging also helps with diagnosis. Treatment requires a multi-drug regimen administered over 9-12 months. Adjunctive steroids are also often used to reduce inflammation and complications. Even with treatment, CNS TB has poor outcomes with only one third of patients fully recovering neurologically.

1. 7We Care
CNS TUBERCULOSIS
MAJ MANOJ

2. 7We Care
Incidence
• 10% cases of TB have CNS involvement
• 60-80 % between age of 06 mnths to 05 yrs.
• Male pedominence
• Case fatality 100% in untreated cases.

3. 7We Care
• While pulmonary disease is the most common
manifestation of TB
• the involvement of the CNS and tuberculous
meningitis represents its most severe form
• The case fatality rate of untreated TBM is
almost 100% and a delay in treatment may
lead to permanent neurological damage

4. 7We Care
• The causative agents of TBM is M. tuberculosis
and less commonly NTM.
• The incidence of CNS infection due to the
latter has increased since the onset of the HIV
epidemic mainly mycobacterium avium
complex (MAC)

5. 7We Care
CLASSIFICATION
Intracranial
Tuberculosis
Spinal tuberculosis
Tuberculous meningitis
TBM with miliary spread
Tuberculous encephalopathy
Tuberculous vasculopathy
CNS tuberculoma
brain abscess
Pott’s spine and paraplegia

6. 7We Care
Pathogenesis
1) Entrance of the bacilli into the host with
subsequent lung invasion and regional lymph
node dissemination leading to the primary
complex formation.
2) In case of CNS involvement the
characteristic lesions known as Rich’s foci
tuberculous subpial or subependymal foci
about 1 mm in diameter are formed

7. 7We Care
Pathogenesis
CNS TB is a three step process
1)Hematogenous seeding of meninges during
bacteremia of primary TB
• In case of miliary TB dissemination to the
CNS is more probable and particularly
involved in the pathogenesis of TBM in
childhood
• spread from a site of tuberculous otitis or
calvarial osteitis also exists

8. 7We Care
2) Quiescent phase: may last from few weeks
to many years.
3)mycobacteria in Richs foci multiply and with
immune or traumatic stimulus rupture or
grow and clinical manifestations occur.

9. 7We Care
• In adults and older children there may not be
any immune response and cause latent
disease or
• immune recognition or reactivation causes
formation of the CNS lesions
• the rupture of a Rich’s focus and release of
bacilli into subarachnoid space giving rise to a
T cell granulomatous response leading to TBM

10. 7We Care
• Triad of a) macrophages b) T helper
lymphocytes and c) host plays a central role
• interferon interleukin1 TNF
• granuloma formation

11. 7We Care

12. 7We Care
PATHOGENESIS OF
COMPLICATIONS
Inflammatory reaction can lead to
• Adhesion formation due to the cell and fibrin
rich basal meningeal exudates
• Obliterative vasculitis: mainly affecting the
internal carotid artery, proximal middle
cerebral artery and perforating vessels of the
basal ganglia
• Encephalitis: due to extention into the
parenchyma

13. 7We Care
• Cranial n palsies: adhesions in the
interpendicular fossa cranial nerves II IV and
VI are affected.
• Hydrocephalus: obstruction of the basal
cisterns the outflow of the forth ventricle or
the cerebral aqueduct and have poor
prognosis .
• Spinal meningitis: direct extension from
vertebrea or intracranial spread.

14. 7We Care
Clinical staging
Stage I ( alert no focal neurological signs)
Irritability
Excessive cry
Apathy
Low grade fever

15. 7We Care
• Stage II(non comatose)
• Signs of meningeal irritation
• Signs of increased ICT
• Altered sensorium
• Convulsions
• Focal neurodeficits

16. 7We Care
Stage III(comatose)
• Deep coma
• Multiple cranial N palsies
• Decerebrate or decorticate rigidity

17. 7We Care
Clinical features
• Prodromal:
A)Infants: 1.poor feeding 2. irritability 3.
drowsiness 4. bulging fontanelles
B)Elder : headache and mental state changes
• Cranial N : 20-30% .
A) II III IV VI VII blindness squint diplopia VI MC
B) IX X XI XI less commonly.

18. 7We Care
• Vascular : MCA ACA involvement or vascular
endarteritis
N deficits monoparesis hemiparesis
• Cerebral edema: raised ICT hydrocephalus
tentorial herniation seizures
• Tuberculoma: seizures localizing sign raised
ICT

19. 7We Care
• Meningoencephalitis: altered sensorium to
terminal illness.

20. 7We Care
DIAGNOSIS
• CSF:increase in pressure with the appearance
clear to slightly turbid with a delicate web-like
clot formation, due to the high protein level
• Pleocytosis of 10–1000 leucocytes/ mm3 with
a lymphocytic predominance.
• CSF biochemistry reduced glucose levels
increased lactate levels while protein levels
increased

21. 7We Care
DIAGNOSIS
CONDITION WHITE BLOOD
CELLS(CELLS/MCL)
PROTEIN
(MG/DL)
G LUCOSE
(MG/DL)
NORMAL VALUE 0-5 UPTO 30 (NEWBORN) 15-45 40-85
TBM ELEVATED 10-1000
(<500)
INCREASED
(50-500)
DECREASED
(<40)
BACTERIAL M ELEVATED (>1000) INCREASED
(>250)
DECREASED
(<40)
VIRAL ELEVATED (<100) INCRESEAD
(<100)
NORMAL OR
DECREASED
(>40)
CRYPTOCOCAL M ELEVATED L>PMN INCREASED DECREASED

22. 7We Care
Microscopy :
• Rapid inexpensive, technically simple and
specific for AFB
• Lacks senstivity: unable to discriminate
between M. tuberculosis and other
mycobacteria and unable to discriminate
between viable and non viable bacilli

23. 7We Care
• Culture:Gold Standard method and for definite
diagnosis of the disease
• in clinical suspicion the isolation of the agent
from other specimens such as gastric aspirate
bronchial aspirate sputum or lymph node also
guides the diagnosis

24. 7We Care
• Egg-based Lovenstein-Jensen-LJ Petragnani
and Ogawa
• Agar-based Middlebrook 7H10 and 7H11
• Liquid media Middlebrook 7H9 Kirchner
BioFM and Dubos
• With liquid culture medium incubation time is
12-15 days and 40-60 days with solid media
• Meximum yeild with combination of liquid
and agar based.

25. 7We Care
• liquid cultures a mix of growth supplements
(OADC- Oleic acid, Albumin, Dextrose,
• Catalase) and antibiotics (PANTA- Polymyxin B,
Amphotericin B, Nalidixic acid Trimethoprim,
Azlocillin) are used, which collectively prevent
the growth of environmental bacteria.
• A positive result must be confirmed by
performing a ZN smear of the colonies with
AFB being demonstrated.

26. 7We Care
• Adenosine deaminase levels and TBM
• enzyme involved in the purine catabolism
related to the activated T lymphocytes and
macrophages in response to TB antigens

27. 7We Care
Molecular diagnosis
• Nucleic acid-based amplification (NAA) tests
allow the direct detection of mycobacterial
DNA or RNA
Post-amplification analysis includes
electrophoresis
hybridization
restriction or sequencing of the products
• hybridization being the most commonly used
one

28. 7We Care
• Newer techniques based on real-time PCR
amplify simultaneously different DNA targets
followed by fluorimetric detection
• The low sensitivity may be due to
paucibacillary nature of CSF
• minimum suggested volume of the fluid is 2ml

29. 7We Care
Neuroimaging
CT finding in case of non-complicated TBM
• can be entirely normal
• diffuse brain edema and lepto-meningeal
inflammation with increased uptake of
contrast material in CECT
• The meningeal enhancement is more
pronounced in the basal cisterns.

30. 7We Care
CT finding of complicated cases
• communicating hydrocephalus
• ventriculitis
• parenchymal spread (infarction, cerebritis and
abscess)
• Empyema (epidural, subdural)
• tuberculomas in the brain.

31. 7We Care

32. 7We Care

33. 7We Care
• MRI is the most sensitive test
• superior to CT in detecting parenchymal
abnormalities, such as tuberculomas,
abscesses, and infarctions.
• MRI also readily depicts hydrocephalus

34. 7We Care

35. 7We Care
Treatment
• Start as soon as there is suspicion for TB
meningitis
• Same Guidelines as those for pulmonary TB
– Intensive Phase: 4 drug regimen of
Isoniazid, Rifampin, Pyrazinamide, and
Ethambutol or Streptomycin for 2 months
– Continuation Phase: Isoniazid and Rifampin for
another 7 – 10 months

36. 7We Care
Role of steroids
• Glucocorticoids Indicated with:
– rapid progression from one stage to the next
– elevated OP on LP, CT evidence of cerebral edema
– worsening clinical signs after starting antiTb meds
– increased basilar enhancement, or moderate to advancing
hydrocephalus on head CT
• Glucocorticoid Dosing: Dexamethasone 12 mg/d x 3
weeks followed by a slow taper

37. 7We Care
TREATMENT
DRUG DAILY DOSE IN MG/KG THRICE WEEKLY
INH 10(10-15) 10 (8-12)
RIFAMPICIN 15(10-15) 10 (8-12)
PYRIZINAMIDE 35(30-40) 35 (30-40)
ETHAMBUTOL 20(15-25) 30 (20-35)

38. 7We Care
• Steroids are associated with lesser mortality in
Stage 3 TBM.
• Steroids are useful to decrease intracranial
tension and also for decreasing perilesional
edema
• Enhanced resolution of the basal exudate
may also occur.

39. 7We Care
neuropathology.neoucom.edu
Tuberculous Meningitis. Donald and Shoerman,
NEJM. 351:17. 10/21/2004

40. 7We Care
Differential Diagnosis
• Fungal Meningitis
– Crypto, Histo, Blasto, Cocci
• Viral meningoencephalitis – HSV, mumps
• Parameningeal Infection
– Sphenoid sinusitis, brain abscess, spinal epidural abscess
• Incompletely treated Bacterial meningitis
• Neurosynphilis
• Neoplastic Meningitis – Lymphoma
• Neurosarcoid
• Neurobrucellosis

41. 7We Care
Treatment: Antimicrobial
Therapy
• Start as soon as there is suspicion for TB
meningitis
• Same Guidelines as those for pulmonary TB
– Intensive Phase: 4 drug regimen of Isoniazid,
Rifampin, Pyrazinamide, and Ethambutol or
Streptomycin for 2 months
– Continuation Phase: Isoniazid and Rifampin for
another 7 – 10 months

42. 7We Care
Treatment: Adjunctive
Therapy
• Glucocorticoids Indicated with:
– rapid progression from one stage to the next
– elevated OP on LP, CT evidence of cerebral edema
– worsening clinical signs after starting antiTb meds
– increased basilar enhancement, or moderate to advancing
hydrocephalus on head CT
• Glucocorticoid Dosing: Dexamethasone 12 mg/d x 3
weeks followed by a slow taper
• Surgery: Ventriculostomy placement

43. 7We Care
TB Meningitis in HIV
population
• Study in S Africa compared 20 HIV + pts vs. 17 HIV - pts
• Similar findings in both groups:
– Presentation: HA, neck stiffness, fever
– CSF analysis: Similar amounts of
lymphocytes, neutrophils, protein, glucose, ADA levels
– Outcomes predicted by GCS score upon admission
• -Differences
– Both groups showed same incidence of abnormal Head CT, but HIV +
more likely to have ventricular dilatation and infarct
– HIV + patients were more likely to suffer no neurologic deficit on
discharge than HIV - pts

44. 7We Care
Outcomes
• Overall Poor
• Pts presenting in Stage I have 19% mortality
• Pts presenting in Stage III have 69% mortality
• Only 1/3 - 1/2 of patients demonstrate complete
neurologic recovery
• Up to 1/3 of patients have residual severe neurologic
deficits such as hemiparesis, blindness, seizure DO

45. 7We Care
References
• http://www.cdc.gov/TB/statistics/reports/surv2005/PDF/table27.pd
f
• Donald, PR and Schoerman, JF. Tuberculous Meningitis. NEJM,
351:17. 2004.
• Schutte, CM. Clincial, Cerebrospinal Fluid and Pathological Findings
and Outcomes in HIV-Positive and HIV-negative Patients with
Tuberculous Meningitis. Infection 2001: 29: 213-217.
• Jacob, H et al. Acute Forms of Tuberculosis in Adults. The American
Journal of Medicine (2009) 122, 12-17.
• Principles and Practice of Infectious Diseases. 4th Ed, c 1995.
• Central Nervous System Tuberculosis. www.uptodate.com