Tuberculous Meningitis

 Affects 1/3 of world’s population

 Leading cause mortality and morbidity
 5 years / >, kills > AIDS, malaria,
diarrhea, leprosy and all of the tropical
dis combined.
 Treating TB most efficient and cost
effective of all health interventions.
 Emergence of the AIDS pandemic,
Tuberculous Meningitis
 TB in those regions of the world where it
had declined earlier to a negligible level.
 Other factors : poverty, unhygenic living
conditions, malnutrition, drug abuse &
immigration.
 WHO : incidence 1990 was about 7.5
million,12 million by 2005.1
 New cases will be in Southeast Asia due to
AIDS.
 TB CNS constitutes about 5% of
extrapulmonary cases.
Tuberculous Meningitis
 AIDS + TB, 50% or > develop extra-pulmonary
involvement, the CNS being a common site.
 Lower TB prevalence TBM occurs mostly in adults
 Higher TB prevalence the peak incidence is 0-4
years.
 Certain ethnic groups are more susceptible to M.
tuberculosis, such as blacks.
 Polymorphisms human NRAMPI gene may affect
susceptibility to pulmonary TB in West Africans but
the relevance of these factors is not known in MTB
Etiopathogenesis

 All CNS TB is due to human M.

tuberculosis
 Nonmotile, rod-shaped, nonspore forming
bacterium, 0.5 µm by 3 µm.
 Gram’s (-) staining; once stained the
bacillus can-not be decolorized by
acid/alcohol (=acid fast bacillus(AFB)).
 Grows slowly. Generation time is 15-20
hours, <1 hour for pyogenic bacteria.
 It takes weeks for visible mycobacterial
colonies.
Etiopathogenesis
 Mycobacterial cell wall : complex proteins,
peptides, lipids & glycolipids with specific
immunologic properties.
 Other antigens are present in the cytoplasm.
 These molecules determine the characteristic
immune response to tubercular infection and
resultant pathology.
 Immunocompetent individual : infection develops
overt TB in only 10%,indicating a good immune
response.
 CNS infection begins with inhalation of droplet
infectious particles reach the alveoli & multiply
within the alveolar spaces, alveolar macrophages
& macrophages derived from circulation.
Etiopathogenesis

 For 2-4 weeks following infection, no

immune response. hematogenous
dissemination occurs throughout the
body.
 Lungs, liver, spleen & bone marrow filter
many organisms from the blood,
whereas the organs not belonging to the
RES system, such as the brain &
meninges, trap relatively few organisms.
Etiopathogenesis

 2-4 weeks following the infection, cell-

mediated immunity to mycobacteria
develops. T lymphocytes are stimulated
by bacterial antigens to produce
lymphokines which in turn attract &
activate mononuclear phagocytes from
the blood stream.
 The immune response in tuberculosis is
not poor, but is disregulated.
Etiopathogenesis
 The protective immune response in
tuberculosis is mediated by Th1 cells,
whereas Th2 / mixed Th1-Th2 response
renders cells sensitive to killing.
 Organisms may be killed within
activated macrophages but many
macrophages are also killed by the
organism/by their toxic antigenic
products.
Etiopathogenesis
 A tubercle : consists of macrophages,
lymphocytes and other cells surrounding
a necrotic caseous center.
 The fate of tubercles & subsequent
course of the infection depends on
immunogenic capacity of the host &
other genetic factors.
Etiopathogenesis
 In good immune status, the minute
caseous foci are completely eliminated
& there is a positive tuberculin test.
 Less effective but still efficient host
immune response results in large
caseous foci with a fibrous
encapsulation harboring mycobacteria
(may later cause reactivation of TB if
host immune vigilance decreases(old
age & immunocompromised state))
Etiopathogenesis
 In impaired host immunity, the primary
tubercular infection continues to
proliferate & the tubercle ultimately
ruptures & discharging the organisms into
the surrounding tissue.
 Most often rupture of a ‘rich’ foci which are
subependyma/ subpial foci, or an
intracerebral tubercle which is
 formed during initial silent hematogenous
dissemination of M. tuberculosis, result in
tuberculous meningitis.
Etiopathogenesis
 Rarely the source of TBM is adjacent
extraneural infection (vertebrae, ear,
mastoid sinuses, etc.)
 In a relatively immunoincompetent
host(infants/< 5 years old) the ‘richs’
focus may rupture during primary
infection resulting in concomittent
meningeal & pulmonary / meningeal &
miliary infection.
Clinical Features
 The clinical picture of TBM can be influenced by
1/> of the following pathophysiologies:
 1. Meningitis & meningeal exudates resulting
in meningeal signs, cranial nerve palsies &
hydrocephalus.
 2. Extension of inflammation to brain
parenchyma resulting in alteration of
sensorium, seizure, hypothalamic & brainstem
signs.
 3. Vasculitis is responsible for focal
neurological deficits.
 4. Allergic & hypersensitivity responses result
in massive brain edema and raised intracranial
pressure in the absence of hydrocephalus.
The clinical feature of TBM has been
divided in to :

 Prodrome

 Stage of meningeal irritation

 Stage of focal or diffuse cerebral

involvement
Prodrome

 Lasts for 2-3 weeks, and occasionally 2-

3 months. In children, it manifests with
vaguely ill health, apathy, lack of
appetite, vomiting and pain in abdomen.
 Unless there is history of contact with
tuberculosis, the prodromal symptoms
seldom arouse suspicion of TBM.
Prodrome
 Unusual manifestations of
neurotuberculosis in children
 Atypical febrile fits.
 Unexplained fever, positive PPD following
measles, head injury or pertussis.
 Chronic ear discharge not responding to
treatment
 Headache, vomiting, ptosis, squint, facial palsy.
 Child in contact, presenting with fever,
headache, vomiting and bulging fontanelle.
 Hypothalamic pituitary syndrome.
Stage of meningeal irritation
 With the onset of meningeal symptoms,
headache, vomiting & fever become more
prominent.
 Fever is generally 101-102° F (39° C).
Apathy, irritability, photophobia and varying
degrees of neck stiffness set in and may
progress to opisthotonus in young children,
although it is not as prominent as in pyogenic
meningitis.
 In infants, a tense fontanelle & vomiting are
more frequent than headaches & neck
stiffness.
Stage of meningeal irritation
 Focal neurological signs (seizures, cranial
nerve palsy, hemiparesis) may precede,
accompany or follow the meningeal signs
and symptoms.
 Symptoms and signs of raised intracranial
tension may precede or follow the classical
signs of meningeal irritation. Sometimes
TBM is diagnosed in a patient being
investigated for hydrocephalus or brain
tumor.
 Clinical presentation of
tuberculous meningitis
Parameters Children Adults
Symptoms:

Headache 20-50% 50-60%

Nausea/Vomiting 50-75% 8-40%

Apathy/behavioral change 30-70% 30-70%

Seizures 10-20% 0-13%

Prior history of tuberculosis 55% 8-12%

Signs:

Fever 50-100% 60-100%

Meningismus 70-100% 60-70%

Cranial nerve palsy 15-30% 15-40%

Coma 30-45% 20-30%

Stage of focal or diffuse cerebral
involvement
 As disease progresses, increasing evidence
of cerebral dysfunction become apparent.
Stupor and coma replace apathy & irritability.
 Signs and symptoms of raised intracranial
tension become obvious; enlarging head,
tense fontanelle in young children and
sutural diastesis in older children.
 Papilloedema in adults is seen frequently.
 In children optic disc pallor may progress to
optic atrophy and blindness due to
involvement of the optic nerve or chiasma by
basal exudates.
Stage of focal or diffuse cerebral
involvement
 In older patients, papilloedema may progress to
secondary optic atrophy. Fundus changes were
reported in 61% of patients with TBM. These
changes were present in 73% of patients above
10 years and only in 37% below < 1 years old.
 Facial, oculomotor and abducence nerves are
commonly affected.
 The pupils are dilated due to an obscure toxic
factor.
 Seizures are common in all the stages of TBM
and may be partial/generalized. The clinical
course may be punctuated by sudden onset of
focal neurological deficits.
Stage of focal or diffuse cerebral
involvement
 Monoplegia, hemiplegia and aphasia may
develop at any time during the illness following
seizure or ischemic stroke.
 Rapid improvement in focal deficit occurs
following relief of intracranial pressure.
 In some of these patients, dilating ventricles
stretch the already narrowed vessels, producing
ischemia.
 Progressive focal neurological signs in TBM
may be due to tuberculoma, tuberculoma
enplaque & progressive strangulation of the
cranial nerves, brainstem and cerebral vessels
due to the organization of basal exudate.
Stage of focal or diffuse cerebral
involvement
 Rarely abnormal movement disorders
(chorea, hemiballismus, tremor) may
dominate the clinical picture.
 During the course of illness, spread of
inflammation and exudate to spinal
meninges results in radiculomyelopathy.
 There may be progressive paraparesis or
less commonly tetraparesis due to
development of spinal block. In some
cases, rapidly developing or even sudden
onset of paraparesis may occur due to
tubercular vasculitis or tubercular myelitis.
Stage of focal or diffuse cerebral
involvement
 The clinical picture of TBM is rarely dominated
by spinal involvement from the very beginning.
 The terminal illness in TBM is characterized by
deep coma, decerebration or decortication,
extensor rigidity and convulsions.
 Pupils are dilated and fixed. Respiration
becomes irregular Cheyne-Stoke’s or Biot’s
type.
 The features of brain herniation and infarctions
may contribute to the clinical picture. Direct
infiltration of the diencephalon may be
responsible for irreversible coma.
The severity of TBM has been
classified into three stages.

 Stage I : only meningitis.

 Stage II : meningeal signs with
cranial nerve palsy and clouding
of consciousness.
 Stage III : meningitis, neurological
signs and severe clouding of
consciousness.
Diagnostic Tests
 Laboratory tests are important
in the diagnosis of CNS
tuberculosis.
Cerebrospinal Fluid Analysis (CSF)
 high leukocyte count with lymphocytic
predominance, may be neutrophilic
predominance in the early stage.
 protein > 1 g/ml & cells 0.2 x 109/ml, mostly
lymphocytic.
 CSF is rarely normal. A wide variety of CSF
changes have been reported which include:
serous, pseudopyogenic, encephalitic or
block patterns.3
 CSF opening pressure is elevated in 49-75%
of patients.
Cerebrospinal Fluid Analysis
(CSF)
 CSF is typically clear, infrequently
opalescent and rarely xanthochromic.
 A cobweb coagulum forms on the
surface of the CSF if it is allowed to
stand for some time which is
suggestive but not pathognomonic of
TBM. Cobweb coagulum is attributed
to high fibrinogen content along with
the presence of inflammatory
exudate in the CSF.
Cerebrospinal Fluid Analysis
(CSF)
 Acid fast bacilli(AFB) in CSF are seen in
only 10-20% of patients. For smear
positivity, a bacterial load of 10x104
AFB/ml is required and conventional
cultures are positive at a concentration
of 10-100 AFB/ml.
 In most patients with CNS TB, the
bacterial load of such magnitude is
uncommon.
Cerebrospinal Fluid Analysis
(CSF)
 For a culture of AFB, CSF is inoculated in an
egg or agar based medium (Lowen Stein-
Jensen or Middle brook 7 H 10) and incubated
at 37° C under 5% CO2. It takes up to 8 weeks
for detectable colonies to appear.
 In modern laboratories, use of liquid media with
radiometric growth detection (BECTAC-460)
and the identification of isolates by nucleic acid
probes have replaced the traditional methods of
isolation on solid media and identification by
biochemical tests.
 These new methods have reduced the time
required for isolation and speciation to 2-3
weeks, however the decision to treat the patient
should not wait for culture results.
Tuberculin Test
 The tuberculin test involves a SC injection of 0.1
ml of 5 T4 of PPD-5 (Purified protein derivative)
or 1 unit of PPD-RT23 into the volar aspect of
the forearm. The response is read after 48-72
hours and the maximum diameter of induration
measured by palpation is interpreted as >15
mm or ulceration—strongly positive, >10 mm—
positive; 5-9 mm—intermediate, and <5 mm—
negative.
 This test is of limited value (low sensitivity and
specificity). False - reactions : False + results :
 In the absence of a history of BCG vaccination,
a positive skin test may provide additional
support for the diagnosis of tuberculosis.
Radiological Investigations

 CT scan

 Magnetic Resonance
Imaging (MRI)

 Cerebral Angiography
The newer adjunctive diagnostic
tests are broadly classified.
 1. biochemical assay measuring feature of
AFB or host response to it.
 2. immunologic test that detects mycobacterial
antigen or antibody in the CSF.
 3. DNA analysis of AFB.
 Radiolabelled ammonium bromide partition test
 Adenosine deaminase test
 Tuberculostearic acid
 Immunodiagnostic technique such as enzyme linked
immuno sorbent assay (ELISA)
 ( All these techniques are still considered
investigational and none is routinely.)
 Polymerase chain reaction (PCR)
 Neurophysiological
Investigations
 such as
electroencephalography (EEG),
 motor and somatosensory
evoked potentials
 Search for Extra CNS Tuberculosis
 a radiograph of the chest, FNAC of
the enlarged lymph node
abdominal ultrasound, etc.
Seventy-seven percent of TBM
patients with HIV had
extrameningeal TB compared to
only 9% without HIV.
Differential Diagnosis

 Chronic neutrophillic meningitis

associated with hypoglycorrhachia is
attributed to bacteria (nocardia,
actinomyces and brucella) and fungi.
 In exceptional cases, noninfectious
causes such as endogenous chemical
meningitis due to release of contents of
epidermoid tumor or craniopharyngioma,
exogenous chemical meningitis due to
intrathecally administered drugs or contrast
agents and systemic lupus
erythematosus should be considered.
Differential Diagnosis
 India ink preparation is positive in 50% of patients
only; therefore, reliance is placed on immunological
methods. About 90% of patients with cryptococcal
meningitis have cryptococcol polysaccharide antigen in
the CSF.
 Certain other conditions such as parameningeal
infection, brain abscess, cysticercosis,
toxoplasmosis and viral meningitis (mumps
meningoencephalitis, lymphocytic choriomeningitis and
persistent CNS echo virus infection in patients with
agammaglobulinemia) occasionally have a prolonged
course.
 Many noninfectious causes should also be considered,
e.g., carcinomatous meningitis, primary or
secondary neoplasms, meningeal sarcoidosis,
cerebral granulomatous arterities and multiple
sclerosis.
Management
 Management of TBM includes
chemotherapy and management
of complications such as
hydrocephalus, vasculitis, brain
edema and coma.
Chemotherapy

 First Line Drugs

 Isoniazid, Rifampicin, Pyrazinamide,
Ethambutol ,Streptomycin
 Second Line Antitubercular Drugs
 Para-amino-salicylic acid (PAS,
Ethionamide, Kanamycin and amikacin.
○ Among the quinolone antibiotics, ofloxacin has
the highest CSF penetration
 Treatment Regimens
 Drug Resistance
 Corticosteroids and Other
Adjuvents
 Surgical Therapy:
Hydrocephalus, Intracranial
Tuberculoma
Prognosis and Sequelae

 The steep decline in mortality in TBM

has been associated with a
corresponding rise in varying degrees of
neurologic sequelae in the survivors.
 Mortality in TBM is 20-30%.
CNS Tuberculosis and AIDS
 HIV patients are at a higher risk for primary or reactivation
tuberculosis or exogenous reinfection. The risk of death
was reported to be twice that in HIV patients without
tuberculosis, independent of CD4 cell count.
 The high mortality rate among HIV patients with
tuberculosis appears to be due to progressive HIV
infection rather than tuberculosis.
 All patients with tuberculosis, should be screened for HIV.
 The clinical presentation of TBM is similar in HIV and
immunocompetent patients, except intracranial mass
lesions are more common in HIV patients. The CSF may
occasionally be acellular and AFB positivity may be higher
in TBM patients with HIV infection.
 In patients with AIDS, co-infection with multiple pathogens
such as M. tuberculosis, toxoplasma and cryptococci have
been reported.
CNS Tuberculosis and AIDS
 The treatment protocol is similar to the patient
without HIV infection. However, the duration of
treatment is longer due to poorer bacteriological
clearance and drug resistance in HIV patients.
 Rifampicin induces the activity of cytochrome
P450 CYP3A, which lowers the concentration of
HIV protease inhibitors and non-nucleoside
reverse transcryptase inhibitors to
subtherapeutic levels.
 This results in incomplete viral suppression and
emergence of drug resistance; hence,
concomitant administration of rifampicin with
antiretroviral drugs is not recommended.
CNS Tuberculosis and AIDS
 Rifabutin, another antitubercular drug, is
less potent inducer of CYP3A and may be
preferred with indinavir or nelfinavir, but not
with saquinavir.
 Rifabutin in a dose of 150-300 mg is well-
tolerated and is as effective as rifampicin in a
standard antitubercular regimen.
 To avoid drug resistance, indinavir should be
increased to 1000 mg 98h and nelfinavir
1250 mg in patients receiving rifabutin.
CNS Tuberculosis and AIDS
 Rifabutin should not be administered with
ritonavir because it is a potent inhibitor of
rifabutin metabolism.
 In general protease inhibitors are
recommended in HIV patients with more than
5000 copies of HIV RNA/ml who are willing
to adhere to a demanding medical regimen.
 Patients who have benefited from protease
inhibitors before the development of
tuberculosis should generally continue to
receive them during antitubercular therapy.
CNS Tuberculosis and AIDS

 If the decision is made to initiate or

continue therapy with a protease
inhibitor, indinavir or nelfinavir should be
used and rifabutin should be substituted
for rifampicin in the antitubercular
regimen.
 It has been suggested that isoniazid,
ethambutol and pyrazinamide for 18-24
months may be preferable in HIV
patients with tuberculosis.
Prevention
 BCG should not be given in symptomatic AIDS
and immunosuppressed patients as it is a live
vaccine.
 In view of these limitations, search for an
alternative vaccine is for one which can be
given to the people already infected to prevent
post-primary tuberculosis.
 Approaches currently under investigation
include modified ways of administering BCG,
development of genetically modified live
vaccines and nonviable sub-unit vaccines
including naked DNA.
Prevention
 Supervised treatment programs have proved
successful in controlling outbursts of AIDS-
associated tuberculosis in the U.S.A.
 The principal cause of failed tuberculosis
control is oncompliance’ for which the patient
is usually blamed but generally the fault is of
health care provider.
 WHO has recommended directly observed
therapy (DOT) that will only work if the
attention is given to various social, cultural
and ethnic factors.