Approach to a patient of neurological tuberculosis

APPROACH TO A PATIENT OF
NEUROLOGICAL TUBERCULOSIS
Presenter-Dr Rahul Arya

INTRODUCTION
 Tuberculosis is a major cause of death worldwide.
 India has the highest TB burden, accounting for 1/5th of
global incidence and 2/3rd of cases in SE Asia.
 CNS tuberculosis occurs in up to 1% and has different
manifestations.
 The burden of CNS TB is directly proportional to the
prevalence of TB infection.
 Tubercular Meningitis is the most devastating form of
extra-pulmonary TB with 30% mortality and disabling
neurological sequelae in >25% survivors.

CLASSIFICATION OF NEUROTUBERCULOSIS
 Intracranial
 Tuberculous Meningitis (TBM).
 Tuberculous Encephalopathy.
 Tuberculous vasculopathy.
 CNS Tuberculoma.
 Tuberculous brain abscess.
 Spinal
 Pott’s spine and Pott’s paraplegia.
 Non-osseous spinal tuberculoma.
 Spinal meningitis.

PATHOPHYSIOLOGY
 CNS tuberculosis is secondary to disease
elsewhere in the body.
 Mycobacteria reach the brain by hematogenous
route.
 The disease begins with the development of small
tuberculous foci (Rich foci) in the brain, spinal cord
or meninges.
 The location of these foci and capacity to control
them ultimately determine which form of CNS TB
occur.

 TNF alpha play a important role in pathogenesis
and leads to altered BBB permeability and CSF
leukocytosis.

TUBERCULOMA
 Firm, avascular,
spherical
granulomatous mass.
 These arise when
tubercles in brain
parenchyma enlarge
without rupturing into
subarachnoid space.
 Target sign is
characteristic.

 Clinical Features:-
 usually 2-8 cm in diameter.
 Symptoms are related to their size and location.
 Low grade fever, headache, vomiting, seizures,
focal neurological deficit and papilloedema.

TUBERCULOUS BRAIN ABSCESS
 It is characterized by an
encapsulated collection of
pus containing viable bacilli
without evidence of classic
tubercular granuloma.
 Usually solitary, uniloculated
or multiloculated of various
size.

 Clinical Feature:-
 Partial seizures, focal neurological deficit and
raised ICT.
 CT and MRI shows a large size lesion with marked
surrounding edema.

TUBERCULOUS ENCEPHALOPATHY
 Rare; more common in younger population.
 Characterized by convulsions, stupor and coma with
signs of meningeal irritation or focal neurological deficit.
 CSF is largely normal.
 It is responsive to corticosteroids.

SPINAL TUBERCULOSIS
 Seen in <1% of patients.
 Infection starts in
cancellous bone usually
adjacent to an iv disc or
anteriorly under
periosteum.
 Thoracic (65%), lumbar
(20%), cervical(10%),
atlanto axial(<1%).
 Para spinal abscess 55-
90%.

 Clinical Features:
 Local pain, tenderness over
the affected spine or a gibbus
associated with paravertebral
muscle spasm or a palpable
paravertebral abscess.
 Patient usually have acute or
sub acute, progressive spastic
type of sensorimotor
paraparesis.

NON OSSEOUS SPINAL CORD TB
 Can occur in form of tuberculoma.
 Extradural tuberculoma are most common.
 Intramedullary tuberculoma are rare.
 Features are indistinguishable from those of any
extramedullary or intramedullary tumors.
 These tuberculoma may increase in size while
patient is on ATT.

TUBERCULOUS ARACHNOIDITIS
 Features of spinal cord or nerve involvement may
predominate but most often there is a mixed
picture.
 Subacute paraparesis, radicular pain and bladder
dysfunction.
 The hallmark of diagnosis is the characteristic
myelographic picture showing poor flow of contrast
material multiple irregular filling defects, cyst
formation and sometimes spinal block.

SPINAL FORM OF TUBERCULAR MENINGITIS
 May result from rupture of rich foci in spinal
arachnoid space.
 The acute form present with fever, headache and
root pains accompanied by myelopathy.
 The chronic form presents with spinal cord
compression.
 It may be associated with syrinx formation.

TUBERCULAR MENINGITIS
 Commonest form of neurotuberculosis (70-80%).
 Clinical features includes H/O vague ill health for 2-8
weeks prior to development of meningeal irritation.
 Non specific symptoms includes malaise, anorexia,
fatigue, low grade fever, myalgia and headache.
 Prodormal symptoms in children include irritability,
drowsiness, poor feeding and abdominal pain.

TUBERCULAR MENINGITIS- PATHOLOGY
 The tubercle bacilli form
dense gelatinous exudate
into subarachnoid space.
 This exudate envelops
arteries and cranial nerves,
creating a bottle neck in flow
of CSF which leads to
hydrocephalus.
 Most of neurological deficit is
caused by hydrocephalus,
adhesive arachnoiditis,
obliterative vasculitis.

TBM- EXAMINATION
 Signs of meningeal irritation :-
 neck stiffness, positive Kernig’s and Brudzinski’s
sign.
 Cranial nerve palsies- 20-30%
 Focal neurological deficit secondary to infarction.
 Visual loss d/t optic nerve involvement,
optochiasmatic arachnoiditis, 3rd ventricular
compression of optic chiasma, occipital lobe
infarction.

 Increasing lethargy, confusion, stupor, deep coma,
decerebrate or decorticate rigidity.

CLINICAL PRESENTATION OF TBM
Clinical Feature Percentage
History
Tuberculosis 8-12
Symptoms
Headache 50-60
Nausea- vomiting 8-40
Apathy/ behavioral changes 30-70
Seizures 0-15
Signs
Fever 60-100
Meningismus 60-70
Cranial nerve palsy 15-40
Coma 20-30

TBM CLASSIFICATION- MODIFIED MRC CRITERIA
 GRADE 1 :- alert and oriented (GCS 15) without
focal neurological deficit.
 GRADE 2 :- GCS 14-10 with or without focal
neurological deficit.
 GRADE 3 :- GCS less than 10 with or without focal
neurological deficit.

DIAGNOSTIC FEATURES OF TBM
 Clinical
 Fever and headache
 Vomiting
 Altered sensorium or focal neurological deficit.
 CSF
 Pleocytosis (>20 cells, >60% lymphocytes).
 Increased protein (> 100 mg/dl).
 Low sugar (< 60% of corresponding blood sugar).
 India ink studies and microscopy for malignant cells
should be negative.

 Imaging
 Exudates in basal cistern
 Hydrocephalus
 Infarcts
 Gyral enhancement
 Tuberculoma formation.

INVESTIGATIONS
 Cerebrospinal fluid examination:-
 Definitive diagnosis is by detection of tubercle
bacilli in the CSF either by smear examination or by
culture.
 Predominantly lymphocytic pleocytosis with
increased proteins and low CSF/blood glucose
ratio.
 TLC count may be normal in presence of
depressed cell mediated immunity (elderly and HIV
+ve individual).

 Repeat CSF frequently shows a falling glucose
levels, a rising protein concentration and a shift to
mononuclear predominance.
 Once anti-tubercular medication is commenced, the
sensitivity of smear and culture falls rapidly.

MOLECULAR AND BIOCHEMICAL ANALYSIS
 PCR based methods.
 Antibody detection.
 Antigen detection.
 Adenosine deaminase.
 Tuberculostearic acid measurement.

Test Sensitivity Specificity
Biochemical
CSF ADA level 73-100 71-99
CSF Tuberculostearic
acid level
95 99
Immunological test
Antigen ELISA 38-94 95-100
Antibody ELISA 52-93 38-94
Molecular
PCR 56 98

ADENOSINE DEAMINASE (ADA)
 ADA is an important enzyme in purine metabolism;
irreversibly deaminates adenosine to inosine.
 It is associated with lymphocytic proliferation and
differentiation and is a marker of cell mediated
immunity.
 Two isoforms ADA1 and ADA2; ADA2 is the major
contributor to the total ADA seen in TBM.
 Sensitivities and specificities range from 73-100%
and 71-99% respectively.

 While some studies showed statistically significant
differentiation from aseptic meningitis and bacterial
meningitis several other studies could not
demonstrate a distinction between TBM and
bacterial meningitis by ADA alone.
 In one study ADA was not valuable in distinguishing
TBM in patient with HIV infection.

 High CSF ADA activity has been reported in patient
with lymphoma, malaria, brucellosis, pyogenic
meningitis and cerebral lymphoma.

TUBERCULOSTEARIC ACID
 It is a fatty acid component of M. tuberculosis cell
wall.
 Has good sensitivity and specificity
 Requires expensive equipments hence has limited
clinical use.

 Antibody detection :-
 Has poor sensitivity and specificity
 Cannot differentiate acute infection from previous
infection.
 Cross-reactivity.
 Antigen detection :-
 Theoretical advantage over antibody detection is
that they would be released only as a result of
host’s immune response or treatment.

MOLECULAR METHODS
 The challenges of applying NAA technique for rapid
diagnosis of M.tb in CSF is b/s of low number of
bacilli typically present in TBM and presence of
amplification inhibitors in CSF.
 It has sensitivity of 56% and specificity of 98%; not
ideal for ruling out TBM.
 They are useful as a supplement to conventional
approaches.

RADIOLOGICAL EVALUATION
 Every patient with TBM should preferably be
evaluated with contrast enhanced CT/MRI before
the start or within 1st 48 hr of treatment.
 Abnormalities depends on the stage of the disease.
 Hydrocephalus (70-85%), basal meningeal
enhancement (40%), infarction (15-30%),
tuberculoma (5-10%).

 Meningeal enhancement, tuberculoma or both have
a sensitivity of 89% and specificity of 100%.
 Precontrast hyperdensity in basal cisterns is the
most specific radiological sign.
 Radiological findings also helps in prognostication.

TREATMENT
 CNS tuberculosis is categorized under category 1
by WHO.
 According to BTS and ATS duration of treatment is
9-12 months.
 Ethambutol should be replaced by Streptomycin.
 Intensive phase (2 months)—
Isoniazid, Rifampicin, Pyrazinamide and
Streptomycin.
 Continuation phase (7-9 months) –
Isoniazid and Rifampicin.

FIRST LINE ATT
Drug Daily Dose
Children Adults
Isoniazid 10-20 mg/kg 300 mg
Rifampicin 10-20 mg/kg 450mg (<50 kg)
600mg (>50 kg)
Pyrazinamide 30-35 mg/kg 1500 mg (<50 kg)
2000 mg (>50 kg)
Ethambutol 15-20 mg/kg 15 mg/kg
Streptomycin 20-40 mg/kg 15 mg/kg

 Isoniazid penetrates the CSF freely and has potent
early bactericidal activity.
 Resistance to Isoniazid develop quickly if used as a
monotherapy.
 Rifampicin penetrates the CSF less well, but high
mortality from Rifampicin resistant TBM has
confirmed its key role in t/t of CNS tuberculosis.

ADJUNCTIVE STEROID THERAPY
 The use of corticosteroids as adjunctive therapy in
t/t of CNS tuberculosis begin as early as 1950.
 Initially it was proposed that steroids causes
reduction of inflammation within subarachnoid
space.
 It causes modulation of the local production of
proinflammatory cytokines and chemokines by
microglial cells.
 But the exact mechanism is not clear.

 A meta-analysis by Prasad et al. found that steroid
use was associated with fewer death, but this effect
was noted only for children.
 A large placebo-controlled trial by Thwaites et al.
identified a significant reduction in mortality but not
in morbidity in adults.
 Further subgroup analyses revealed that the
mortality benefit of dexamethasone occurred
among all severity type of CNS tuberculosis but that
this benefit did not extend to patient coinfected with
HIV.

 The Infectious Disease Society of America ,CDC
and ATC recommends the use of steroid therapy as
an adjunctive therapy with standard anti
tuberculosis therapy in CNS Tuberculosis.
 Adults (>14 years) should start treatment with
dexamethasone 0.4 mg/kg/24 hr with a tapering
course over 6-8 weeks.

MANAGEMENT OF CNS TB IN HIV PATIENT
 Managed with same ATT drug regime as that
recommended for HIV uninfected individual.
 Adjunctive corticosteroids are recommended for
those with TBM and HIV.
 Decision for starting ATT in newly diagnosed HIV
patient depends on CD4 counts.

CD4 Count Recommended Action
>200 Defer HIV treatment as long as
possible, ideally until end of TB
treatment.
Start ART if CD4 count falls below
200 during TB treatment.
100-200 Start ART after approximately 2
months of ATT treatment.
<100 Start ART within first 2 weeks of ATT
treatment.
Not available Start between 2-8 weeks.

ATT IN PATIENT WHO ARE ALREADY ON ART

 ATT in patient who are already on ART:-
 When possible treat with Rifampicin and a non
nucleoside reverse transcriptase inhibitor (NNRTI),
preferably Efavirenz but the dose should be
increased to 800mg.
 Rifabutin should be used if treatment with a
protease inhibitor is required but at a reduced dose
(150 mg 3 times per week).

ROLE OF SURGERY IN CNS TUBERCULOSIS
 Indications-
- Hydrocephalus (non-communicating)
- Tuberculous Brain Abscess
- vertebral tuberculosis with cord compression.
 Early surgical drainage and chemotherapy are
considered the most appropriate treatment for TBA.
 The aim of surgical management of TBA is to
reduce the size of space occupying lesion and
thereby diminish intracranial pressure and to
eradicate the pathogen.

 In patient with communicating hydrocephalus with
GCS 15 could be tried on diuretics and
acetazolamide.
 Early surgical intervention is considered in all
patients with non-communicating hydrocephalus
and those who failed on medical management.
 If duration of illness is <4 weeks –
Ventriculoperitoneal shunt is procedure of choice.

 If duration of illness is > 4 weeks– Endoscopic 3rd
ventriculostomy can be offered.
 In case of extradural lesions causing paraparesis,
urgent surgical decompression is required.

PROGNOSIS
 The poor prognostic factors are:-
 Late stage of disease.
 Presence of miliary disease.
 Delay in initiation of treatment.
 Hydrocephalus.
 Focal neurological deficit.
 Extreme of age.
 Pre-existence of debilitating condition.
 Very abnormal CSF (very low glucose or elevated
protein).

 Comatose patients have a mortality of 50% and a
high incidence of residual disability.
 The incidence of residual neurological deficits after
recovery from TBM varies from 10-30%.
 Late sequelae include cranial nerve palsy, gait
disturbance, hemiplegia, blindness, deafness,
learning disability and dementia.

CONCLUSION
 Early recognition and timely treatment of CNS TB is
important in order to prevent the mortality and
morbidity associated with it.
 The single most important determinant of outcome
is the stage of the disease at which treatment has
been started.

Approach to a patient of neurological tuberculosis

Approach to a patient of neurological tuberculosis

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Approach to a patient of neurological tuberculosis