This presentation briefly summarizes pathophysiology, clinical features, diagnosis and treatment of different types of tuberculosis of brain and spinal cord.

1. Tuberculosis of the Central
Nervous System
Dr Pramod Krishnan
Consultant Neurologist and Epileptologist
HOD Neurology,
Manipal Hospital, Bengaluru

2. Introduction
• CNS TB is an infrequent but most devastating form of TB infection.
• CNS TB can be broadly grouped into: subacute or chronic meningitis,
intracranial tuberculoma, and spinal tuberculous arachnoiditis.
• All 3 forms occur with equal frequencies in endemic regions like India.
• CNS TB occurs in 1 to 2% of all patients with active TB.
• It accounts for about 8% of all extrapulmonary TB reported to occur in
immunocompetent individuals.
• Case fatality rate of CNS TB is 15- 40% despite effective therapy.
Leonard JM. 2017. Central nervous system tuberculosis. Microbiol Spectrum 5(2):TNMI7-0044-2017.

3. Intracranial tuberculosis: Spinal tuberculosis:
Tubercular meningitis Tubercular spondylitis (Potts spine)
Pachymeningitis Spinal tuberculomas
Granulomatous basal meningitis Tubercular arachnoiditis with myeloradiculopathy
Parenchymal tuberculosis Tubercular myelitis
• Tuberculomas Others:
• Tubercular abscess Orbital tuberculosis
• Miliary tuberculosis Tubercular otitis media and temporal bone tuberculosis
• Focal tubercular cerebritis Tuberculosis of calvarium and skull base
• Tubercular encephalopathy
Tubercular hypophysitis
Tuberculoma en plaque
Classification of CNS TB

4. Pathophysiology of CNS
tuberculosis

5. Pathophysiology
• Baccillemia due to hematogenous
spread from lung (primary infection,
reactivation) or other organ results in
seeding of brain and meninges.
• These granulomatous foci in the
meninges (tubercles) may caseate
(Rich focus) into the subarachnoid
space causing meningitis.
• These foci may remain dormant for
several years depending on the host
immunity and other local brain factors.

6. Pathogenesis of tuberculous meningitis (TBM).
Cresswell FV, Davis AG, Sharma K et al. Recent Developments in Tuberculous Meningitis Pathogenesis and
Diagnostics [version 2]. Wellcome Open Res 2020, 4:164 (doi:10.12688/wellcomeopenres.15506.2)

7. Clinical features

8. Symptoms/ signs Frequency reported
Fever 20-70 %
Headache 25-70 %
Meningeal irritation 35-90 %
Lethargy/ drowsiness 25-30 %
Vomiting 30-70 %
Confusion/ delirium 30-65 %
Focal neurologic signs 25-40 %
Cranial nerve palsy 20-35 %
Hemiparesis 5-30 %
Presenting symptoms and signs of TBM

9. Tubercular meningitis
• Tuberculous meningitis (TBM) is the most severe form of TB.
• Over half of treated TBM patients die or suffer severe neurological
sequelae, largely due to late diagnosis.
• If untreated, death occurs within 5 to 8 weeks of the onset of illness.
Phase Features
Prodromal phase Malaise, lassitude, low-grade fever, intermittent headache, vague
discomfort in the neck or back, and subtle personality change.
Meningitic phase Occurs in 2-3 weeks with protracted headache, meningismus, vomiting,
mild confusion, and various degrees of CN palsy and long-tract signs.
At this stage the pace of illness may accelerate rapidly.
Paralytic phase Delirium followed by stupor and coma, seizures, multiple CN deficits,
hemiparesis, and hemiplegia.

10. MRI brain axial T1W gadolinium study of patient A
(above) showing prominent meningeal enhancement
and basal exudates, and Patient B (right) showing
similar basal exudates and tuberculoma in the basal
region.

11. Atypical presentation of TBM
• In children, headache is less common, while irritability, restlessness,
anorexia, and protracted vomiting are prominent symptoms.
• Seizures are more common in children and occur in the early stages.
• Rarely, TBM presents as a slowly progressive dementia.
• Others present with acute meningitis syndrome.
• Focal neurologic deficits (CN palsies, hemiparesis, and seizures) or
hydrocephalus may precede the signs of meningitis.
• An “encephalitic” syndrome may occur in children, and occasionally
adults, without meningitis signs or CSF abnormalities.

12. MRI brain axial and sagittal T1W gadolinium study of
patient A (above) showing multiple small ring
enhancing lesions in the supra and infra tentorial
regions. MRI brain axial T1W gadolinium study (right)
shows shows similar military TB with communicating
hydrocephalus.

13. Optochiasmatic arachnoiditis
• Rupture of tubercles into the subarachnoid space initiates an intense,
cytokine-mediated inflammatory reaction that is most marked at the
base of the brain.
• Within days to weeks a proliferative, basal arachnoiditis produces a
thick, gelatinous exudate extending from the pons to the optic chiasm.
• As it matures, the arachnoiditis becomes a fibrous mass encasing
nearby cranial nerves (CNs), most commonly CNs VI, III, and IV.
• The optic chiasm can be involved resulted in progressive visual loss.
• Intrathecal hyaluronidase, oral thalidomide may be required.
• Microsurgical decompression may be needed.

14. MRI brain T1W post gadolinium coronal
sections showing optochiasmatic arachnoiditis
(a) and multiple tuberculoma in the left sylvian
region (b) with ventricular dilatation.
MRI brain T1W post gadolinium axial (a, b, c), coronal (d) and sagittal (e) sections showing thick exudates
in the basal cisterns and optochiasmatic arachnoiditis.

15. Infarcts due to tubercular meningitis
• Arteries and veins are caught up in the inflammatory process, resulting
in a vasculitis that extends within the substance of the brain.
• Initially, direct invasion of the vessel wall by mycobacteria, or secondary
extension of adjacent inflammation, leads to an intense PMN reaction
followed by infiltration of lymphocytes, plasma cells, and macrophages.
• This is followed by fibrinoid degeneration within small arteries and
veins leading to aneurysms, thrombi, and focal hemorrhages.
• Most involved are middle cerebral artery branches and perforating
vessels to the basal ganglia, pons, thalamus, and internal capsule.

16. MRI brain showing an acute infarct in the left basal ganglia on T2 (a), T2 FLAIR (b), and DWI
sequences (c). An old left border-zone infarct, leading to gliosis, is seen. Intracranial MR
angiography (d) is suggestive of non-visualization of the left middle cerebral artery (red arrows).

17. Hydrocephalus due to tubercular meningitis
• Extension of the inflammatory process to the basal cisterns may
impede CSF circulation and absorption, leading to communicating
hydrocephalus.
• This is seen in the majority of cases in which symptoms have been
present for 3 weeks or more.
• Obstructive hydrocephalus, arising from edema of the midbrain or a
localized brain stem granuloma that occludes the aqueduct, is less
common.

18. MRI brain T2W (a) and T2F (b) axial sections
showing dilatation of third ventricle and both
lateral ventricles with periventricular
hyperintensities.
CT brain plain axial sections shows
dilatation of third ventricle and both
lateral ventricles in a patient with
tubercular meningitis.

19. Tuberculoma/ Tubercular abscess
• Tuberculomas are conglomerate caseous foci in the brain that develop
from deep-seated tubercles acquired during a recent or remote
disseminated bacillemia.
• Centrally located, active lesions may reach considerable size without
producing meningitis.
• When the host response to infection is poor, this process may result in
focal cerebritis and frank abscess formation.
• More commonly, the lesions coalesce to form caseous granulomas with
fibrous encapsulation (tuberculomas).

20. MRI brain axial sections showing:
(a) well-defined hypointense lesion on T1W
(b) hyperintense on T2W
(c) T2FLAIR
(d) diffusion-weighted images
(e) ring enhancement after gadolinium
administration
(f) MRS showing the lipid peak
MRI brain T1W axial sections showing thick walled ring
enhancing lesion involving left posterior frontal region
(right) and left basal ganglia along with small left mesial
occipital lesion (left).

21. Tuberculoma/ Tubercular abscess
• Usual presentation is a children or young adult with headache, seizure,
progressive hemiplegia, and/or signs of raised intracranial pressure.
• Most have no features of systemic infection or meningitis.
• There are occasional reports of clinically significant, transient
tuberculomas appearing during the early course of anti-TB therapy.
• Medical management with ATT and steroids is effective for most cases.
• Surgery is reserved for cases where lesions have produced obstructive
hydrocephalus or brain stem compression.

22. MRI brain T1W axial (a), sagittal (b) and coronal (c) sections showing large left frontal tubercular abscess
along with multiple tuberculomas which are coalescent and discrete. These lesions appear hyperintense on
T2 with perilesional edema (d, f) and hypointense on T1 (e).

23. MRI brain T1W post gadolinium sagittal (a) and coronal (b) sections
showing thick enhancing en plaque tuberculoma involving the right
fronto-parietal hemispheric convexity with underlying mass effect.
MRI brain T1W post gadolinium coronal sections showing thick
enhancing en plaque tuberculoma involving the left lateral temporal
lobe convexity.

24. Tuberculosis of spine
• Arachnoiditis or tuberculoma can form at any spinal cord level due to
breakdown of a Rich focus within the cord or meninges, or by
extension from an area of spondylitis.
• The inflammatory reaction progresses over weeks to months, with
encasement of the cord by a gelatinous or fibrous mass.
• They present as an ascending or transverse radiculomyelopathy of
variable pace at single or multiple levels.
• Symptoms include pain, hyperesthesia, or paresthesia in the
distribution of the nerve root, lower motor neuron paralysis, and
bladder or rectal sphincter incontinence.

25. Tubercular Spondylodiscitis Advanced tuberculosis of spine
MRI Spine sagittal T1W (A) and T2W (B) sequences
showing altered marrow signals in L2 and L3
vertebral bodies and intervening L2 to L3 disc.
MRI Spine sagittal T1W (A) and T2W (B) showing
destruction of end plates, reduced intervertebral disc
height, vertebral collapse and cord compression.

26. Tuberculosis of spine
• Localized vasculitis may result in thrombosis of the anterior spinal
artery and infarction of the cord.
• Arachnoiditis results in subarachnoid block with unusually high CSF
protein levels, with or without cellular pleocytosis.
• Spinal TB arachnoiditis should be considered for a patient with
subacute onset of spinal or nerve root pain, rapidly ascending
transverse myelopathy or multilevel myelopathy, increased CSF protein
and cell count, and evidence of TB elsewhere in the body.
• Tissue biopsy for stains and culture is required for diagnosis.

27. Intramedullary TB: MRI Spine T2W sagittal (A)
section shows lower cervical cord edema with disc
enhancing lesion in post contrast T1W sagittal
sequence (B)
TB Arachnoiditis: MRI spine sagittal (a, b), axial
(c) showing clumping of cauda equina nerve roots
and brain axial T1W sequences (d) showing
leptomeningeal enhancement with hydrocephalus.

28. HIV and CNS tuberculosis
• CNS TB occurs more frequently in HIV patients with active TB.
• TB and HIV coinfection does not alter the clinical manifestations, CSF
findings, or response to therapy of TB.
• For HIV co-infected patients TBM mortality is around 60%.
• Patients with CNS TB may experience immune reconstitution
inflammatory syndrome (IRIS) on starting Anti Retroviral Therapy.

29. Diagnosis

30. Differential diagnosis of Tubercular Meningitis
Fungal meningitis (cryptococcosis, histoplasmosis, blastomycosis, coccidioidomycosis)
Neurobrucellosis
Neuroborreliosis
Partially treated bacterial meningitis
Focal parameningeal infections (sphenoid sinusitis, brain abscess)
Neurosyphilis
CNS toxoplasmosis
Neoplastic meningitis (lymphoma, carcinoma)

32. • Total score is the sum total of all the
parameters.
• If score is < 4: TBM
• If score is > 4: Bacterial Meningitis
Thwaites Diagnostic index score for admission diagnosis
of TBM vs Bacterial meningitis

33. CSF examination in tubercular meningitis
Opening pressure Elevated.
Appearance Ground glass, with a web like clot at the top.
Protein Elevated (100-500 mg/dl). Can be < 100 mg/dl in 25% patients
and > 500 mg/dl in 10% of patients. Protein level > 2g/dl
suggests subarachnoid block and carries a poor prognosis.
Glucose Reduced (<45 mg/dl in 80% of patients)
Cell count Elevated (100 to 500/mm3). It is <100 cells/mm3 in 15%, and
between 500 to 1,500 cells/mm3 in 20% of cases.
Cell type Lymphocyte predominant. Early in the disease course,
neutrophils may be prominent.
ZN stain Combined sensitivity of smear and culture was 82% with
repeated samplings and large CSF volumes.Culture
TB PCR Negative test does not exclude diagnosis.
Xpert MTB/RIF Pooled sensitivity was 80.5% and the specificity 97.8%

34. Phenotypic tests for detection of M. tuberculosis (MTB) in CSF and identifying drug resistance
1. Smear Microscopy
Ziehl-Neelsen stains
AFB auramine O or auramine-rhodamine stains fluorescence microscopy
2. Culture
Solid culture Löwenstein-Jensen medium
Liquid culture system like Mycobacteria Growth Indicator Tube (BACTEC™ MGIT 960™ TB
System). (The liquid culture systems are more rapid than conventional solid culture system)
3. IGRAs (IFN gamma release array): not recommended for diagnosis of tubercular meningitis
Commercial IGRAs: An ELISPOT evaluates the release of IFN-γ from T lymphocytes
following stimulation of the cells with MTB-specific antigens. QuantiFERON® TB Gold test
and the T-SPOT® TB IGRAs.

35. Genotypic tests for detection of M. tuberculosis (MTB) in CSF and identifying drug resistance
Polymerase Chain Reaction (PCR)
IS6110 PCR12: It is highly conserved part of M. tuberculosis complex genome and is specific
for MTB complex
Simple PCR, Real time PCR, Multiplex PCR
Multi-targeted (LAMP)
1. GeneXpert MTB/RIF assay: Cartridge-based technology that simultaneously detects MTB
complex and RIF resistance.
2. GeneXpert Ultra (Ultra): It is a new technology for faster detection of MTB complex and
RIF resistance.
3. Molecular line probe assays: These are strip-based technology meant for rapid detection of
MTB complex and RIF and INH resistance.
LAMP, loop-mediated isothermal amplification

36. Noraini PHILIP et al Malaysian J Pathol 2015; 37(1) : 1 – 9

37. Differences between GenoType MTBDR plus line probe assay and Xpert MTB/RIF assay
Line Probe assay Xpert MTB/RIF
Mycobacterium tuberculosis isolates or
AFB-positive samples.
Directly performed on clinical samples.
Initial test for tuberculous meningitis.
Diagnose MDR TB. Identifies M. tuberculosis and diagnoses
drug resistance.
Detects RIF and INH resistance. Detects RIF resistance only.
It takes 2-3 days for positive results. It takes 3-4 hours for positive results.
DNA strip technology. Cartridge based technology.
It is a multiplex PCR in combination with
reverse hybridization-based technique.
It is an RT-PCR-based assay.
Suitable for use at national/central reference
laboratories.
Suitable for public health settings.

38. Hematoxylin and eosin stain showing necrotizing granulomatous inflammation in the spinal cord of a patient with
tuberculoma. Multinucleated giant cells (inset) and epitheliod macrophages adjacent to the necrosis (asterisk).

39. Non caseating
T1W Isointense
T2W Isointense
T1W disc enhancement
Ring enhancing tuberculoma
T1W Hypointense
T2W Hypointense
T1W ring enhancement
Tubercular Abscess
T2W Hyperintense
T1W Thick ring enhancement
DWI Diffusion restriction
Neuroimag Clin N Am 22 (2012) 677–705

40. Characteristic TUBERCULOMA NEUROCYSTICERCOSIS
Site Most common in posterior
fossa.
Present at gray-white matter
junction.
Size Usually larger than 2 cm. Smaller than 2 cm.
Coalescence is characteristic
Conglomeration is common.
Conglomeration not uncommon.
Associated meningitis Not uncommon. Rare.
Associated hydrocephalus Common if associated with
meningitis.
Absent (can be present in
intraventricular NCC).
MRI brain T2W Hypointense(caseating
granuloma with solid
center).
Hyperintense (Stage 1 & 2).
MRI brain T2F No or incomplete
suppression
More perilesional edema.
Complete suppression (Stage 1 & 2)
Smaller extent of perilesional edema.

41. TUBERCULOMA NEUROCYSTICERCOSIS
Scolex No scolex or mural nodule. Eccentric T2 hypointense scolex.
MRI brain T1W Hyperintense rim present (MT effect). No hyperintense rim.
MRI brain DWI No restriction (Only abscess shows
restricted diffusion).
Scolex & degenerating granuloma
may restrict.
MRS of brain Lipid peak. Amino acid peak.
Midline shift Can be present with neurological deficits. No midline shift.
Wall on T2WI Generally thick and bright. Commonly thin, complete and
hypointense.
SWI (Phase) Blooms only after healing (calcification). Wall (diamagnetic) & scolex
(paramagnetic) bloom.

42. Treatment

43. Anti TB therapy (ATT)
• Start ATT early: strong clinical suspicion is sufficient. Diagnosis can be
confirmed later.
• Initiating ATT before the onset of focal neurologic signs and coma is
the strongest predictor of survival in TBM.
• Regimen: HRZE 2 months, followed by HRE till treatment concludes.
• Duration of treatment: minimum of 9-12 months. Can be extended
based on clinical features and neuro-imaging.
• If PZA is omitted or not tolerated, the duration of treatment should be
extended to 18 months.

45. Adjunctive corticosteroids
• As adjunctive steroid therapy is beneficial in children and adults with
TBM, it is recommended in all patients with CNS TB.
• In children, it improved the resolution of basal exudates, tuberculomas
and improved survival and measures of intellectual development.
• Indications:
1. Progression from one clinical stage to the next at or before the start of ATT.
2. CT evidence of marked basal enhancement.
3. Moderate or advancing hydrocephalus
4. Spinal block or incipient block (CSF protein above 500 mg/dl).
5. Tuberculomas with marked perilesional edema.

46. • The duration is 3 weeks at the initial dose, followed by a gradual tapering
over the next 3 to 4 weeks.
• It does not improve mortality if started in the later stages of the disease.
Corticosteroid regimens associated with improvements in survival in controlled trials

47. NATIONAL TUBERCULOSIS MANAGEMENT GUIDELINES 2014

48. Conclusions
• Tubercular infection of the CNS can have varied manifestations.
• Clinical features, neuroimaging and CSF studies point to the diagnosis.
• Complications like hydrocephalus and infarcts are common.
• There are diagnostic and therapeutic challenges in managing CNS TB.
• CNS TB requires prolonged treatment with ATT along with supportive
care and management of complications.
• Use of steroids prevent complications like hydrocephalus and cranial
nerve palsies.
• CNS TB with HIV presents unique challenges.

49. THANK YOU