TUBERCULOUS

MENINGITIS
Dr . NANDAKUMAR P R
EPIDEMIOLOGY
CLINICAL PRESENTATION
COMPLICATIONS
DIAGNOSIS
MANAGEMENT
SUMMARY
EPIDEMIOLOGY
Year 2019
TB incidence (world)- About 1 crore.
TB incidence(India)- About 26.9 lakhs.

India, China, Indonesia, Philippines, Pakistan, Nigeria, and South Africa-

account for 64% of World TB cases.

EPTB - Accounts for about 20% (40-50% among HIV infected) of all TB
cases.

CNS TB in India 17,000 cases (1% of all TB cases) – WHO 2015

CNS TB-
MENINGITIS (MOST COMMON)
TUBERCULOMA
ABSCESS(LESS THAN 10%)
ARACHNOIDITIS
RADICULOMYELITIS
Risk factors for developing CNS TB
Past h/o pulmonary TB
HIV - 5 times more likely to develop CNS involvement during TB
- progression from latent infection to active disease
recent measles, and measles in childhood
concomitant malignancy, use of immunosuppressive medications
malnutrition, alcoholism
Pathophysiology
Extension of infection into the subarachnoid space from a caseating
focus in the adjacent cortex -the Rich focus
Hematogenous dissemination could result in a meningeal or
cortical focus.
Inflammatory exudates cause occlusion of basilar cisterns by fibrin
deposits resulting in raised intracranial pressure.
Intracranial vasculopathy is common- stroke can occur as a
complication of vasospasm, thrombosis, vasculitis, or hemorrhagic
infarction. The most commonly affected arteries are the MCA and
their branches
Working case definitions
Presumptive case: A patient with symptoms and signs of EPTB who
needs to be investigated.

Bacteriologically confirmed case: Positive microscopy, culture or PCR-

based test.

Clinically diagnosed case: Strong clinical suspicion and compatible

CSF Cells and biochemistry, imaging findings, histological findings or
response to anti- TB treatment. Negative microscopy, culture and PCR
based tests,
Working case definitions

Successfully treated: A TB patient who has clinical and radiological

evidence of resolution of active TB at the end of ATT.
Completed treatment: A TB patient who completed treatment without
clinical evidence of failure or no record(bacteriological or
radiological) to show complete resolution of persisting infection by
the last month of treatment.
Presumptive treatment failure:
A patient who has no satisfactory clinical or imaging response to
treatment after completing 3 months ATT.
Presumptive relapse:
Declared successfully treated at the end of ATT and now presents again
with symptoms and signs of any form of TB.

Non-EPTB case: investigated for EPTB and has been diagnosed with a
different condition
Clinical features
The most common manifestation of CNS TB is tuberculous
meningitis.
Most frequent in young children.
Complication of pulmonary TB(most often within 3 months of
primary infection.)
TBM classically presents as subacute or chronic meningitis with
symptoms developing over days or weeks.
Evidence suggests that patients presenting with less than 5 days of
symptoms are more likely to have bacterial or viral meningitis than
TBM (Thwaites, 2009).
 The most typical symptoms of CNS-TB
-Irregular fever, headache, nausea and vomiting,
-Lassitude, night sweat, anorexia, depression, irritability,
-Consciousness change.
-Cranial nerve dysfunction is frequent(2,6,7 most common)
-Neck stifness,Kernig's sign, Brudzinski's sign
-Signs of intracranial hypertension.
Hyponatremia is present in nearly 45% of patients with tuberculous
meningitis and is most often due to cerebral salt wasting.
The British Medical Research Council (MRC)
staging for severity of TBM-

Stage I Mild cases, those without altered consciousness or focal

neurological signs,Meningismus can be present
Stage II Moderate cases, those with altered consciousness and those
with moderate neurological signs, e.g. single cranial nerve palsies,
paraparesis, and hemiparesis
Stage III Severe cases, comatose patients and those with multiple
cranial nerve palsies, hemiplegia or paraplegia, or both
Mortality due to TB meningitis in india-1.5/lac
Diagnostic workup
Delay in diagnosis can be fatal because of life threatening sequale
Lumbar puncture for CSF sampling and testing
Done in every patient (unless there are contraindications)
At least 6 mL of CSF should be collected for adults, 2–3 mL for
children.
More important that a CSF test be highly sensitive so the diagnosis of
CNS infection is not missed
Cells-50 cells/mm3 to 500 cells/mm3.
Protein - frequently elevated during tuberculous meningitis.
If CSF is allowed to stand at room temperature for 6 to 12 hours-
forms Cobweb (fibrin clot)
The ratio of CSF/blood glucose is less than 0.5 in 95% of TBM
patients.The chloride content is also decreased in CSF.
Normalization of CSF glucose occurred much faster, with 58%
returned to normal after 1 month and 88% normal after 2 months.
Delayed normalization of protein level and cell count (8 months)
Acid-fast Bacilli staining

only one CSF examination is performed, the sensitivity of smear and

culture are 37%
the yield increases to 87% with three sample examination.

Tubercular Bacilli in Z-N

Staining
(Bright pink slender beaded rods
against a blue background)
Limitations of smear microscopy

Low sensitivity

Limit of detection is 10,000 bacilli per ml of sputum.

Therefore unsuitable for paucibacillary specimens

Cannot distinguish live and dead bacilli

Requires skill to distingubetweenish between false Tubercular bacilli in fluorescence

positive and false negatives.51 staining

(Bright yellow slender beaded rods

against a black background)

CSF CULTURE
It can detect as few as 10 to 100 bacilli per ml of sputum.
The sensitivity of CSF culture 52% and 83%.(One CSF examination
and 3 CSF examination respectively).
CSF culture typically takes 2 to 4 weeks to become positive.
A negative result is given, if no growth appears after 12 weeks.
Rough, tough and buff
" colonies of MTB in
LJ media
Automated Liquid Culture System

BACTEC MGIT 960:Mycobacteria Growth Indicator Tube system

that detects the growth of mycobacteria.
Modified Middlebrook broth fluoresces following the oxygen
reduction induced by aerobically metabolizing bacteria within the
medium.
The culture results 42 days. DST results are available 14-26 days after
C/S.
What is Xpert MTB/RIF?
Diagnostic test for Mycobacterium tuberculosis complex
PCR based to test specimens for genetic material specific to Mtb and
simultaneously detects a gene, rpoB responsible for RIF resistance.
It is a fully automated test and cartridge based. Result in hours.
Xpert MTB/RIF test has a limit of detection of 131 colony forming
units/ml
Xpert MTB/RIF Ultra can detect as low as 16 cfu /ml
the size and quality of the specimens may affect the sensitivity of the
test.
Line Probe Assay (LPA)
Rapid molecular diagnostics that can detect M. tuberculosis and drug
resistance.
These are now available for RIF and INH resistance (MDR-TB) by
identifying mutations in the rpoB, katG, inhA genes and also for XDR-
TB (gyrA and gyrB for Fluoroquinolones, second line injectable and
low level kanamycin resistance.
CSF FOR TB PCR
Most PCR assays for M.Tuberculosis detection amplify the MPB64
gene or IS6110
10% to 15% clinical isolates of MTB in India lack IS6110 leading to
false negative results.
PCR targeting Protein b and MPB64 achieve higher sensitivity and
specificity in diagnosis of CNS-TB.
The WR-QNRT-PCR has sensitivity (95.8%) and specificity (100%)
of suspected TBM patients. But highly variable.
Depends on the amount of CSF sampled and antituberculous therapy.
BIOPSY
Biopsy can be useful for chronic meningitis with persistently negative
cultures.
Although the sensitivity of biopsy is unknown
Examination of infected tissue with Ziehl-Neelsen (acid-fast bacilli)
staining, culture, and PCR assays increase the diagnostic yield.
For Gene X pert analysis of the biopsy specimen sample has to be sent in
normal saline(0.9%)
When CNS TB was not suspected at the time of biopsy, consider sending
formalin-fixed or paraffin-embedded tissue for PCR assays
Chest radiograph showing
non homogenous opacity
with cavitation in the right
upper and midzone
ADA
Adenosine deaminase (ADA) is an enzyme in purine metabolism
associated with proliferation and differentiation of lymphocytes
Elevated levels reflecting nonspecific CNS damage and increased
permeability of the blood-brain barrier
Useful where CSF mycobacterial culture and PCR are not available.
Associated with poor prognosis of tuberculous meningitis in children.
Greater than 8 U/L improved the diagnosis of tuberculous meningitis
(sensitivity <59% and specificity >96%)
Bacterial infection should be ruled out before attributing theinfection
to M. tuberculosis
 Serological tests
In serological tests diagnosis of TB is done using blood sample, and
specifically by antibodies in the blood sample.
These tests are not recommended for diagnosis of TB.

HIV testing
To be done in all patients with tuberculosis.
Coronal postcontrast T1-weighted MRI shows diffuse enhancement of the
leptomeninges (more prominent on the right), including the basilar meninges, as
well as ventriculomegaly
B, Axial postcontrast T1-weightedMRI shows diffuse enhancement adjacent to the
ambient cistern
A, Tubercular meningitis.
Enhanced T1WI shows
dilated lateral ventricles
and meningeal
enhancement in basal
cisterns and middle
cerebral artery cisterns,
indicated by red
arrowheads.
Treatment
IP-2 months of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol,
followed by CP-10 months of Rifampin and Isoniazid.
(CDC,ATS,AAN-2018)
ATT for atleast 9 months, Use ethambutol in the continuation phase
because of the risk of isoniazid mono-resistance, (INDEX TB
GUIDLINE FOR EPTB 2016)
If vision is impaired or cannot be assessed, use streptomycin instead of
ethambutol in the intensive phase.
Use of streptomycin in pregnant women, and patients with kidney
impairment or hearing loss should be avoided
Empiric treatment should be started if CNS TB is suspected rather than
waiting for confirmation
Presumptive TBM
Any patient with fever, headache, neck rigidity and vomiting, with or
without altered sensorium and associated focal neurological deficits for a
period of 5 days or more.
If referral likely to take more than 24 h or patient is critically ill,
treatment with ATT may be started prior to transfer.
CSF sampling prior to initiation of treatment is preferred
Consider HIV status and presumed susceptibility of the TB organism
Treatment with Human Immunodeficiency Virus
Coinfection
Patients with profound immunosuppression (eg, CD4+ T-cell counts
less than 50 cells/mm3) should receive ART within the first 2 weeks
of initiating TB treatment.
Rifamycins can decrease serum concentrations of Pis and some
NNRTIs potentially making them ineffective.
HIV treatment should be started regardless of CD4+ T-cell count.
TB treatment should be initiated first, followed by ART as soon as
possible within the first 8 weeks of treatment.
Isoniazid: CSF/serum concentration ratio is 40% with normal
meninges, and 100 % when the meninges are inflamed.
Dosage is 10 mg/kg/d orally for adults (administer with 50 mg/d to 100
mg/d oral pyridoxine).
Rifampin: CSF/serum concentration ratio is poor with normal meninges
and 20% with inflamed meninges (less than minimal inhibitory
concentration for pan-sensitive M. tuberculosis).
Dosage is 15 mg/kg/d orally for adults.
Ethambutol: CSF/serum concentration ratio is poor without meningeal
inflammation but reaches adequate minimal inhibitory concentration
levels in the presence of meningeal inflammation.
Dosage is typically 15mg/kg/d orally; incidence of optic neuritis (2% at
25 mg/kg/d orally).
Pyrazinamide: CSF/ serum concentration ratio is similar to isoniazid
with dosage of 30mg/kg/d to 35 mg/kg/d orally.
Streptomycin: CSF/serum concentration ratio is nearly zero without
meningeal inflammation and poor even when meningeal inflammation
is present. Dosage is 1g/d IM in adults.
Sustained resolution of clinical features including headache and fever
should guide stopping of ATT
Patients should be assessed for clinical response at the end of the
treatment period and at intervals for 2 years.
Stage 1 at the time of diagnosis -All survived with few neurologic
disabilities
Stage 2 or stage 3 at the time of diagnosis - nearly 25% died or had
severe neurologic disabilities.
Steroids
Recommended for TB meningitis in HIV negative people (strong recommendation,
high quality evidence).
Dexamethasone
-12 mg/d to 16 mg/d for 3 weeks, then tapered off over 3
weeks.AAN.
-0.4 mg/kg/24 h in divided doses.Index TB 2016
For at least 6-8 weeks, with tapering as appropriate ATS,CDC,ID SOCIETY OF
AMERICA,WHO
For patients who experience worsening during or after tapering,
corticosteroids can be extended for a longer period
Steroids in TBM with HIV
May be used for TB meningitis in HIV positive people(conditional
recommendation, low quality evidence).
Oppurtunistic infecftions must be ruled out.
Important opportunistic infections to consider include cryptococcal
meningitis and cerebral toxoplasmosis.
Consultation with an infectious diseases specialist is
recommended.
Adverse effects
Decreasing penetration of antituberculous medications
Suppressing the immune system
- worsening of TB
- bacterial superinfection
Gastrointestinal bleeding.
High blood sugar and blood pressure.
Leukotriene A4 hydrolase (LTA4H) gene-encodes a protein
affecting the production of leukotriene B4
Polymorphism in this gene affects the risk for inflammation in
patients with tuberculous meningitis
Patients who possess the homozygous TT genotype have the
highest level of inflammation.
Multidrug-resistant and XDR TB
MDR TB- resistant to isoniazid and rifampin.
MDR TB can be transmitted, develops when a patient with fully
sensitive TB does not complete treatment, is not adherent to
recommended treatment, or receives inappropriate treatment.
Drug-resistant TBM should be suspected in patients with poor
response to standard ATT and history of exposure to MD
Extensively drug-resistant TB -resistant to H, R, a quinolone and at
least one of the second-line injectable treatments kanamycin,
capreomycin, or amikacin.
For patients with drug resistance, sensitive drugs should be
selected for treatment according to the treatment guidelines of drug
resistance
First-line anti-tuberculosis drugs are prone to cause changes in blood
cell count, and liver and kidney damage.
Monitor hematuria, liver and kidney function, and adverse drug
reactions.
Worsening of clinical and radiological features of EPTB in bothHIV-
positive and HIV-negative patients raisesseveral questions

Treatment failure due to drug-resistant TB?

Malabsorption or inadequate adherence?
Complications of TBM ?
Another ongoing disease process?
Drug fever?
IMMUNE RECONSTITUTION INFLAMMATORY
SYNDROME
Unmasking IRIS occult (never symptomatic before )is recognized by
the host immune system that is recovering within the first months of
HAART treatment.
Paradoxical IRIS is the recurrence of inflammation against a - -
-previously treated infection,
-few or no viable organisms
-and cultures are typically negative
IRIS most frequently occurs in adults, with 17% to 32% of adults
developing IRIS after initiating HAART.
Respond favorably to steroids.
Unmasking IRIS requires treatment of the underlying infection as
well.
Approximately 18% of patients with TB who are HIV infected will
develop IRIS
-with median CD4+ count of less than 50 cells/mm3 and
-in 4 weeks after starting HAART.
-often manifests as fever , Clinical deterioration of preexisting
lymphadenopathy (in 70%) or respiratory disease (in 30%)
Other pathogens associated with IRIS-Cytomegalovirus, Cryptococcus
neoformans, Varicella-zoster virus, and Toxoplasma gondii.
Complications

Hydrocephalus
CSF protein greater than 500 mg/dl- obstruction of CSF flow can
occur and produce subarachnoid block, leading to hydrocephalus
Basilar cisterns occluded by fibrin deposits
Symptoms and signs of raised intracranial pressure (ICP) –worsening
headache, vomiting, ocular palsies, decreasing conscious level,
papilloedema.
Falsely low opening pressure with absence of the normal rise of
opening pressure during jugular compression
Urgent neuroimaging is needed if patient is deteriorating.
Ventriculo-peritoneal shunt insertion is indicated for
hydrocephalus or raised ICP not responding to ATT and steroids.
Mannitol -emergency management until shunt insertion can be
performed
External ventricular drainage is not usually recommended, unless
surgery is contraindicated or urgent CSF diversion is indicated to buy
time before a shunt
Stroke
Intracranial vasculopathy is common during tuberculous meningitis-
vasospasm, thrombosis, vasculitis, or hemorrhagic infarction.
The most commonly affected arteries are the middle cerebral arteries and
their branches.
Focal neurological deficit consistent with a stroke syndrome.
Continuation of steroids, usually intravenously.
Aspirin may prevent stroke in TBM.
C,D, Infarction. T2WI of left basal ganglia, intracranial
angiography shows nonvisualization of the left middle cerebral
artery.
Optico-chiasmatic arachnoiditis
Visual loss, which may arise during treatment with ATT, or on the
withdrawal of corticosteroids
Characteristic CT and MRI findings
Steroid therapy is the first-line treatment, intravenous
dexamethasone.
Pulsed methylprednisolone or oral thalidomide has been used in
some case series for patients not responding to steroids.
E, Arachnoiditis.
Spinal axial T2WI
shows enhancement
in arachnoid as
indicated by red
arrowheads
Seizures
Generalized seizures secondary to encephalopathy.
Acute management with anti-epileptic drugs as per local protocol for
seizure.
Prophylactic anti-epileptic drugs are not required in TBM.
.
Drug interactions and increased risk of liver dysfunction.
Continued treatment with anti-epileptic drugs may be necessary in
patients with recurrent seizure.
Decisions about duration and withdrawal should be individualized to the
patient by the treating specialist
Application of nanotechnology in diagnosis and
treatment of CNS-TB
conventional electroporation
method is used to
encapsulate anti-tuberculosis
drugs into nanoparticles.
This delivery system
carries drugs to specifically
cross brain-blood barrier into
the brain and maintain
effective concentration.
A nanoparticle of poly (DL-lactide-co-glycolide) (PLG) coupled
with anti-tuberculosis drugs has been approved by the FDA.
A single oral dose could sustain effective blood drug concentration
for 5 to 8 days and for 9 days in the brain tissue;
five oral doses of the formulation, every 10th day, cleared all MTB in
the mice meninges
References
Chen Wet al., Progress on diagnosis and treatment of central nervous system
tuberculosis, Radiology of Infectious Diseases, https://
doi.org/10.1016/j.jrid.2020.07.005
Index TB guidelines –guidelines on EPTB for india-WHO Collaborating
Centre (WHO-CC) for Training and Research in Tuberculosis Department of
Medicine, All India Institute of Medical Sciences, New Delhi Centre of
Excellence for Extra-Pulmonary Tuberculosis, Ministry of Health and Family
Welfare, Government of India
CONTINUUM (MINNEAP MINN) 2018;24(5, NEUROINFECTIOUS
DISEASE):1422–1438.