Tubercular-Meningitis - in Children

TUBERCULER
MENINGITIS
IAP UG Teaching slides 2015-16 1

INTRODUCTION
• Tuberculosis
‐ major global health problem
• 2nd most common cause of

death due to infectious
disease after HIV

• Central nervous system (CNS) disease caused by
Mycobacterium tuberculosis is an uncommon yet
highly devastating manifestation of tuberculosis
• Infection of the CNS is one of the most devastating

clinical manifestations of tuberculosis.

EPIDEMIOLOGY
•Approximately 95% of tuberculosis cases occur in the
developing world.
•Worldwide ‐‐ 8.7 million incident cases,

(2013) ‐‐ 12 million prevalent cases,
‐‐ 1.4 million deaths from
tuberculosis
•The WHO estimates that in 2013 ‐ 550,000 childhood cases
and 80,000 tuberculosis‐associate deaths among non–HIV‐
infected children.
• India accounts for 1/5 of the global TB burden.
•The global burden is influenced by ‐ the HIV pandemic;

‐the development of MDR tuberculosis.
‐ the disproportionate access of populations in low‐resource settings
BURDEN OF TB ‐ INDIA
2014
TB burden Number
Incidence 2.2 million
Mortality 0.27 million

MYCOBACTERIA
• Discovered by Robert Koch at Berlin on 24th March 1882.
• 24th March is World Tuberculosis day.
• M. tuberculosis is pathogenic for humans.
• Slender, non‐spore‐forming, non motile, pleomorphic,

weakly Gram‐positive curved rods 1‐5 μm long .
• Habitats ‐ water or soil or intracellular pathogens of animals

and humans.
• Aerobes grows in tissues with a high oxygen content ‐ lungs.

MYCOBACTERIA –
CONTD..
•They are obligate aerobes that grow in synthetic

media containing glycerol and ammoniums alts (LJ
Media).
• Grow slowly, with a generation time of 12‐24 hr.
• Mycobacteria grow best at 37‐41°C (98.6‐105.8°F).
•A lipid‐rich cell wall accounts for resistance to the
bactericidal actions of antibody and complement
•Acid fastness—the capacity to form stable mycolate
complexes with arylmethane dyes (crystal violet,
carbolfuchsin, auramine, and rhodamine) and resist
discoloration with ethanol andhydrochloric or other acids.
TERMINOLOGY
• Exposure : a child has had significant contact (“shared

the air”) with an adult or adolescent with infectious
tuberculosis but lacks proof of infection. Tuberculin skin
test (TST) or interferon‐γ release assay (IGRA) result is
negative.
• Infection : the individual inhales droplet nuclei containing

M. tuberculosis, which survive intracellularly within the lung
and associated lymphoid tissue. The hallmark of
tuberculosis infection is a positive TST or IGRA result.
• Disease :signs or symptoms or radiographic

manifestations caused by M. tuberculosis become
apparent IAP UG Teaching slides 2015-16 8
TRANSMISSION OF M.
TUBERCULOSIS
• Spread by droplet nuclei
• Transmission is by inhalation of airborne mucus

droplet nuclei, particles 1‐5 μm in diameter that
contain bacilli.
• Close contacts at highest risk of becoming infected
• Transmission occurs from person with

infectious TB disease (not latent TB infection)
• Young children with tuberculosis rarely infect other

children or adults.

PATHOGENESIS
• By inhalation of infected droplets

containing Mycobacterium
• Deposited in distal bronchiole or alveoli
• Alveolar macrophages phagocytose but not able to

kill the bacilli
2‐4 weeks later

PATHOGENESIS
• Cell mediated response develops
• CD4 helper T Cells appear and activate the macrophages
• Low level bacteremia leads to seeding of distant foci by the

hematogenous spread to the areas of rich vascular supply
like brain
• Activated macrophages phagocytose and kill the

Tubercle bacilli

LYMPHO HEMATOGENOUS
SPREAD
• CNS involvement in 2‐ 6 months
• Endobronchial TB in 3‐9 months
• Bone and joint lesion after several

years
• Renal

EVOLUTION OF
TBM
• Usually as hematogenous spread.
• May also result from direct rupture or extension of a

subependymal or subpial focus (Rich focus) and may be
located in the meninges, brain or direct extension from
cerebrospinal fluid (CSF) infection
• Location of these foci and the capacity to control

them ultimately decide the form of CNS
Tuberculosis.

PATHOGENESIS
• TB Bacillemia (primary or late
reactivation)
RICH
subependymal
FOCUS
tubercles
rupture into the subarachnoid space
meningitis.
• Dense gelatinous exudate develops at the base of the
brain surround arteries and CN at the base of the brain
hydrocephalus, vasculitis
infarction, hemiplegia,
quadriplegia
Tuberculous Meningitis. Donald and Shoerman,
NEJM. 351:17. 10/21/2004
neuropathology.neoucom.edu IAP UG Teaching slides 2015-16 16 16

TB – HOW TO
APPROACH
• Step : Detailed
1 history
: Thorough clinical
• Step examination
2 :
Investigation
• Step :
3 Treatment
• Step
4

CLINICAL FEATURES
Always secondary to primary tuberculosis.
•Tuberculous meningitis complicates approximately

0.3% of untreated tuberculosis infections in
children.
•Neuro TB occurs in all ages
•Most common between 6 mo‐4 years of age

1ST STAGE ‐ PRODROME STAGE /
STAGE OF INVASION
• lasts 1‐2 wk and is characterized by nonspecific

symptoms
‐ such as fever, headache, irritability, drowsiness,
and malaise.
‐ Anorexia & vomiting may be present.
‐ Child may present with head banging and resents
exposure to sunlight.
Focal neurologic signs are absent, but infants can

experience a stagnation or loss of developmental
milestones.
2ND STAGE – STAGE OF MENINGITIS
‐ Begins more abruptly.

‐ The most common features are lethargy, nuchal
rigidity, seizures, positive Kernig and Brudzinski signs,
hypertonia, vomiting, cranial nerve palsies, and other
focal neurologic signs.
‐ The accelerating clinical illness usually correlates with
the development of hydrocephalus, increased
intracranial pressure, and vasculitis.
‐ Some children have no evidence of meningeal irritation
but can have signs of encephalitis, such as disorientation,
movement disorders, or speech impairment.

3RD STAGE – STAGE OF
COMA
- Loss of consciousness , rise of temp and altered
respiratory pattern
- Pupils are dilated, often unequal with nystagmus and
squint.
- Ptosis and ophthalmoplegia .
- Progression of disease ‐‐ coma deepens , episodic
decerebration , Chyne Stokes breathing , bradycardia
and eventually death

DIAGNOSIS
• Mainly by indirect evidences due to
– Paucibacillary nature of the infection in

children
– Requirement of sophisticated instruments
– More false positive results
– Cost factor

INVESTIGATIONS
Direct evidence Indirect evidence

• Biochemical markers
• Detection ‐ M. Tb
• Demonstrate AFB in • Immunological
sputum / body techniques
fluids / nodes
• Supportive investigations
• Grow AFB in culture – Tuberculin test
– solid / liquid
• Detect AFB • Blood examination
using nucleic
acid • Radiology
amplification
• Family screening

CSF EXAMINATION
Tuberculou Acute Partially treated Viral meningitis or
s bacterial bacterial meningoencephalitis
meningitis meningitis meningitis
PRESSURE (mm H Usually Usually Normal or Normal or

2 elevated 10‐ elevated (100‐ elevated slightly elevated
O) Normal 50‐80 (80‐150)
500 300)
LEUKOCYTES (mm ; PMNs early, 100‐10,000 or 5‐10,000; PMNs usual but Rarely > 1,000
3) but more; usually mononuclear cells may cells.
< 5, ≥ 75% lymphocytes predominate if pretreated
300‐2,000; PMNs
Lymphocytes predominate for extended period of time
predominate
PROTEIN (mg/dL) 100‐3,000 may Usually 100‐500 Usually 100‐500 Usually 50‐200
20‐45 be higher in
presence
of Block.
GLUCOSE (mg/dL) < 50 in most cases; Decreased, usually < Normal or decreased Generally normal; may
> 50 (or 75% decreases with 40 be decreased to < 40
Serum Glucose time if
(or < 50% in some viral
treatment is
not Provided. serum glucose) diseases,

CONTRAINDICATION FOR
LP
• Increase intracranial
pressure.
• Unstable patient.
• Skin infection at site of LP.
• Thrombocytopenia.
• Papilledema.
AFB
• ZN tech ‐ AFB + if > 10,000 bacilli /ml.
• Rapid detection (< 1 hr.)
• Low cost
• High operator dependence
• Labor intensive
• Do not differentiate live/ dead AFB/

NTM

CARTRIDGE BASED NUCLEIC ACID AMPLIFICATION TEST BNAAT
(C )
– CBNAAT (Genexpert TB) ‐ endorsed by WHO

• Heminested, cartridge based real time PCR
– Detects M Tb & Rifampin resistance ‐105

minutes
Method Direct
Culture CBNAAT
smea
r
Minimum no. of
bacilli needed / 10,000/ml 100/ml 131/ml
ml
Time to get result 1 hour 42 2
days hours
(MGIT
)
IMAGING AND
RADIOLOGY
• Brain imaging –
‐ basilar enhancement
‐ communicating hydrocephalus with signs of
‐ cerebral edema or early focal ischemia
‐ Tuberculoma.
• CT SCAN
Helpful with diagnosis of CNS tuberculosis and bone
• MRI
Contrast‐ enhanced MRI Considered to be superior to CT in detecting and

assessing CNS Tuberculosis.
Limitation is the limited availability and affordability

Axial contrast‐enhanced T1‐weighted
magnetic resonance (MR) image showing florid
meningeal
enhancement
Tuberculous meningitis.
© 2 007 by Radiological S ociety of North A meri c a

IAP UG Teaching slides 2015-16
B urrill J et al. R a d io g
3ra2p hics 2 007 ;27: 1255 -
127 3
P ar en c h y ma l tuberculosis.
© 2 0 0 7 b y Radiologi cal S oci e ty of Nor th A m e r i c a Bur r i l l J e t al . R a d i o g r a p h i c s 2 0 0 7 ; 2 7 : 1 2 5 5 - 1 2 7 3
Axial contrast‐enhanced T1‐weighted magnetic

resonance (MR) image shows florid
meningeal
enhancement
CT OF
TUBERCULOMA

• Axial contrast‐enhanced T1‐weighted MR
image shows multiple small high‐signal‐
intensity foci
within both cerebral hemispheres
Milia ry C N S tub e r c u l o s i s .
© 2 0 0 7 by Radiological Society of North A me ri ca Burrill J et al. R a d i o g r a p h i c s 2 0 0 7 ; 2 7 : 1 25 5 - 1 2 7 3

CHEST RADIOGRAPH….ADJUNCTIVE IN
DX
• Abnormalities often seen in
apical or posterior segments
of upper lobe or superior
segments of lower lobe
‐ sometimes Miliary pattern
• May have unusual appearance

in HIV‐positive persons
• Cannot confirm diagnosis of Arrow points to cavity in

TB patient's right upper
lobe.

Miliary Hilar and Mediastinal
TB Adenopathy

MANTOUX TEST
(TST)
•Type IV hypersensitivity reaction
•2 tuberculin unit [TU] PPD RT23 with Tween read 48‐72
80 after intradermal injections hrs
Positivity:
Induration 10 mm / more – immunocompetent Induration
5 mm / more – immunosuppressed
Erythema – don’t take it as positive test
•If child does not turn for results -positive results can be
read within 7 days

MANTOUX TEST
(TST)
• False negative ‐ infants, HIV positive / immuno‐

compromised children, malnutrition extensive
or miliary TB.
• False positive – retesting same site, non‐

tuberculous (environmental) mycobacteria, higher
strengths used

DIAGNOSIS ‐ CONTACT
TRACING
• Any person on anti tuberculosis treatment is considered

as a contact for a period of two years
a) Tuberculin test
b)Bacteriological evidence

BIOCHEMICAL
MARKERS
• Adenosine deaminase (ADA) –
– level co–relates with proliferation and differentation
of lymphocytes.
– Normal levels – 13 – 60 units / ml
• Bromide partition test –
• High performance liquid chromatography
• Tuberculostearic acid detection by gas chromatography

IMMUNODIAGNOSIS
• Antibody detection
– Antibodies to crude antigen/ specific antigen (35 KDa, P
64, P 32, 38 KDa etc)
• Antigen detection
– Protein antigens : using polyclonal
antibodies / monoclonal antibodies
– ELISA / RIA test used

CULTUR
E
• Solid Media –
– Lowenstein – Jensen Medium,
– Dorsets Medium,
– Petroff’s Medium
• Liquid Media – Middle – brooks
Medium
• Disadvantages
– Difficult to collect CSF & others,
– Takes 2 – 8 weeks for result,
– Only 5% results come true positive

RECENT CULTURE
TECHNIQUES.`
• Bactec:
– Radiometric culture system
– duration time 8 – 14 days
– Radiolabelled substrate is used
– Growth of AFB is detected radiometrically by
measuring the metabolite radiolabelled CO2 that is
released
• Septicheck : modified middlebrok broth used
• Rapid slide culture method
• Mycobacterium growth inhibitor tubes
• Remember
WHO has cautioned regarding the molecular and
genetic testing.

DIFFERENTIAL
DIAGNOSIS
• Incompletely treated Bacterial meningitis
• Fungal Meningitis
– Crypto, Histo, Blasto, Cocci
• Viral meningoencephalitis – HSV, Mumps
• Parameningeal Infection
– Sphenoid sinusitis, brain abscess, spinal epidural
abscess
• Neurosyphilis
• Neoplastic Meningitis – Lymphoma
• Neurosarcoid

TREATMENT: ANTIMICROBIAL
THERAPY
• Same Guidelines as those for pulmonary TB
• Tuberculous meningitis, initial hospitalization

is recommended.
• Ethambutol is replaced by streptomycin in the

intensive phase and continuation phase of the
treatment is for 7 months.
• Steroids as adjunctive therapy may be useful in

pericardial and meningeal tuberculosis.

Intensive
Phase:
4 drug regimen of Isoniazid, Rifampicin, Pyrazinamide,
and Ethambutol or Streptomycin for 2 months .
(2HRZE)
Continuation Phase:
– Isoniazid and Rifampicin for another 7 – 10
months (10HR).
‐ Management of Complication

DRUG
&DOSAGES
Drugs Thrice a week Daily
INH 15 mg/kg 10 mg/kg
(max 300 mg)
Rifampicin 15 mg/kg 10 mg/kg
( max 600 mg)
Pyrazinamide 35 mg/kg 30‐35 mg/kg
( max 2000 mg )
Ethambutol 30 mg/kg 20‐25 mg/kg
(max 1500
mg )
Streptomycin 15 mg/kg 15 mg/kg
(max 1 g)
DIRECTLY OBSERVED TREATMENT SHORT
COURSE (DOTS)
• 6 ‐ 8 kg
Six weight • 9 ‐ 12 kg
bands and
• 13 ‐ 16
three patient
kg
wise boxes
• 17 ‐ 20
kg
• 21 ‐ 24
kg
• 25 ‐ 30
IAP UG Teaching slides 2015-16 kg
49
Weight INH RMP EMB PYZ
6‐8 100 100 200 250 (x 1)
9 -12 150 150 300 400 (x 1½)
13 ‐16 200 200 400 500 (x2)
17-20 250 250 500 650 (x2½)
21-24 300 300 600 750 (x3)
25-30 400 400 800 1000 (x4)

INH
• Introduced in the year 1952
• Inhibits the synthesis of mycotic acid in mycobacterial

cell wall‐ bactercidal drug
• Dose: 15mg/ kg Max: 300mg/day
• Hepatotoxicity, peripheral neuritis ‐ but rare in

pediatric age

RIFAMPICIN
• It inhibits RNA synthesis in mycobacteria
• Bactericidal drug
• Well absorbed in empty stomach
• Dose ‐ 10mg/kg Max: 450mg/day
• INH and Rifampicin always combined for beneficial

effect
• Hepato toxic drug

PYRIZINAMIDE
• Sterilizing drug
• Bactericidal drug more effective in caseous acidic

medium
• Resistance develops quickly
• Dose: 35mg/kg
• Side effects: elevation of uric acid

ETHAMBUTOL
• Bacteriostatic drug
• Dose: 30mg/kg Max: 800mg/day
• Side effects: Optic neuritis (usually reversible),

decreased red‐green color discrimination,
gastrointestinal tract disturbances, hypersensitivity.
• The side effects of all these 4 drugs are reversible

STREPTOMYCIN
• It is an aminoglycoside.
• Bactericidal drug.
• Dose : 15mg/kg ; max : 1g
• Side Effects : Auditory and vestibular toxic

effects, nephrotoxic effects, rash

TREATMENT
Adjunctive steroid therapy
All patients regardless of stage/severity of the

disease To decrease neurologic sequelae and
mortality
Lowering the intracranial pressure limits tissue damage and
favors circulation of anti‐tuberculosis drugs through the
brain and
meninges.
2mg/kg/24 hours of prednisolone for 6‐8 weeks at the start
of treatment starting 3 days after initiation of anti
tuberculosis
therapy.
II LINE OF
DRUGS
For MDRTB ,
• Six drugs—
kanamycin, levofloxacin, ethionamide, pyrazinamide,
ethambutol and cycloserine during 6–9 months of
the intensive phase and
• Four drugs—levofloxacin, ethionamide, ethambutol and
cycloserine during the 18 months of the continuation
phase.

COMPLICATIONS
• The most common complication is communicating

hydrocephalus, which can be seen at both MR imaging and CT
and is caused by blockage of the basal cisterns by inflammatory
exudates .
• Rarely non‐communicating hydrocephalus occurs due to the

mass effect of a tuberculoma causing the obstruction of CSF
flow.
• Ischemic infarcts are also a common complication, being seen

in 20%–40% of patients at CT , mostly within the basal ganglia
or internal capsule regions and resulting from vascular
compression and occlusion of small perforating vessels
TREATMENT OF
COMPLICATIONS:
Convulsions:
•Benzodiazepines and phenytoin
Cerebral edema:
•Initial therapy is with 20% Mannitol: 5ml/Kg IV over 15
minutes, f/b 3ml/kg 6th hrly till 48 hrs.
•I.V.Dexamethasone can then be used 0.15mg/kg/dose 6
hourly.
•Fluids –restricted to 2/3rd maintenance.
•Great care to be taken to maintain BP.
• Other drugs – Acetazolamide 20‐50mg/kg/day in 3‐4
doses oral glycerol 1ml/kg/dose
PROGNOSIS AND
OUTCOME
If left untreated, its course is characterized by confusion

and progressively deepening stupor and coma, coupled
with cranial nerve palsies, pupillary abnormalities, foci
neurologic deficits, raised ICP and decerebrate postures.
Fatal outcome then follows within 4 to 8 weeks at the

onset.

PROGNOSIS
• 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 hemi paresis, blindness, seizure DO
• Most patients in the 3rd stage who survive have permanent
disabilities, including blindness, deafness, paraplegia,
diabetes insipidus, or mental retardation.
• Prognosis for young infants is generally worse than for
older children

PREVENTIO
N
• BCG Vaccination provides protection against the

CNS Tuberculosis with an efficacy of 75—85%.
REMEMBER
• History of BCG vaccination does not eliminate the need to

investigate for CNS Tuberculosis in the right clinical
situations.

REFERENCES
• Nelson textbook
• Basic of pediatrics
• WHO
recommendations
• E‐medicine

THANK
YOU

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TUBERCULER

IAP UG Teaching slides 2015-16 1

• 2nd most common cause of

IAP UG Teaching slides 2015-16 2

• Infection of the CNS is one of the most devastating

IAP UG Teaching slides 2015-16 3

•Worldwide ‐‐ 8.7 million incident cases,

• India accounts for 1/5 of the global TB burden.

•The global burden is influenced by ‐ the HIV pandemic;

Incidence 2.2 million

Mortality 0.27 million

IAP UG Teaching slides 2015-16 5

• Discovered by Robert Koch at Berlin on 24th March 1882.

• 24th March is World Tuberculosis day.

• M. tuberculosis is pathogenic for humans.

• Slender, non‐spore‐forming, non motile, pleomorphic,

• Habitats ‐ water or soil or intracellular pathogens of animals

• Aerobes grows in tissues with a high oxygen content ‐ lungs.

•They are obligate aerobes that grow in synthetic

• Exposure : a child has had significant contact (“shared

• Infection : the individual inhales droplet nuclei containing

• Disease :signs or symptoms or radiographic

• Transmission is by inhalation of airborne mucus

• Close contacts at highest risk of becoming infected

• Transmission occurs from person with

• Young children with tuberculosis rarely infect other

IAP UG Teaching slides 2015-16 9

• By inhalation of infected droplets

• Deposited in distal bronchiole or alveoli

• Alveolar macrophages phagocytose but not able to

2‐4 weeks later

IAP UG Teaching slides 2015-16 10

• Cell mediated response develops

• CD4 helper T Cells appear and activate the macrophages

• Low level bacteremia leads to seeding of distant foci by the

• Activated macrophages phagocytose and kill the

IAP UG Teaching slides 2015-16 11

• CNS involvement in 2‐ 6 months

• Endobronchial TB in 3‐9 months

• Bone and joint lesion after several

IAP UG Teaching slides 2015-16 13

• Usually as hematogenous spread.

• May also result from direct rupture or extension of a

• Location of these foci and the capacity to control

IAP UG Teaching slides 2015-16 14

• Dense gelatinous exudate develops at the base of the

brain surround arteries and CN at the base of the brain

neuropathology.neoucom.edu IAP UG Teaching slides 2015-16 16 16

IAP UG Teaching slides 2015-16 17

Always secondary to primary tuberculosis.

•Tuberculous meningitis complicates approximately

•Neuro TB occurs in all ages

•Most common between 6 mo‐4 years of age

IAP UG Teaching slides 2015-16 18

• lasts 1‐2 wk and is characterized by nonspecific

Focal neurologic signs are absent, but infants can

‐ Begins more abruptly.

IAP UG Teaching slides 2015-16 20

IAP UG Teaching slides 2015-16 23