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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.
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• 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
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• 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)
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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
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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
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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.
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• 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
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• Triad of a) macrophages b) T helper
lymphocytes and c) host plays a central role
• interferon interleukin1 TNF
• granuloma formation
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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
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• 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.
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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.
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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
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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
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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
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• 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
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• 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.
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• 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.
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• Adenosine deaminase levels and TBM
• enzyme involved in the purine catabolism
related to the activated T lymphocytes and
macrophages in response to TB antigens
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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
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• 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
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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.
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CT finding of complicated cases
• communicating hydrocephalus
• ventriculitis
• parenchymal spread (infarction, cerebritis and
abscess)
• Empyema (epidural, subdural)
• tuberculomas in the brain.
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• MRI is the most sensitive test
• superior to CT in detecting parenchymal
abnormalities, such as tuberculomas,
abscesses, and infarctions.
• MRI also readily depicts hydrocephalus
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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
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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
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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)
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• 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.
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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
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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
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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
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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
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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
