Tuberculosis affecting Central Nervous System detailed discussion about manifestation, clinical findings, Imaging and investigations and treatment

1. CNS tuberculosis
DEPT OF PEDIATRICS

2. TB CAN CAUSE
- MENINGITIS
- CEREBRAL AND SPINAL TUBERCULOMA
- MYELITIS
- ARACHNOIDITIS

3. PREVALENCE
-Exact prevalence unknown
-Estimated 1% of all cases

4. Classification of Neurological Tuberculosis
- Intracranial TB
- Spinal TB

5. Intracranial TB
• Tubercular Meningitis
• Space occupying lesions (tuberculomas,
tubercular Abscess)
• Tubercular encephalopathy
• Tubercular vasculopathy

6. TB spine
• Pott’s spine and paraplegia
• Tubercular arachnoiditis
• Nonosseous spinal tuberculoma
• Spinal meningitis

7. Pathophysiology

11. Meningeal Exudate
-At the base of the brain.
-Involve structures at the base of the
brain

12. Obstruction of CSF Pathway
Hydrocephalus -obstruction of the CSF
1) Pathway of the basal cisterns
2) Interventricular foramina
3) Aqueduct of Sylvius
4) Foramina of Lushka and Magendie
5) Multiple levels.
Hydrocephalus is one of the most common
mechanisms of brain damage

13. Large Vessels
- Circle of Willis
- Middle cerebral artery in the sylvian fissure

14. Small Arteries
- Small arteries lenticulostriate vessels
- Focal lacunar infarcts with edema around them
- Localized encephalopathy
- CT scan as hypodense areas
- Better appreciated in MRI of the brain.

15. Nerves
- Engulfment and/or destruction
- Particularly II, III, IV, VI, VII
- Multiple cranial nerve palsies

16. Other Structures
- Extension of the basal meningeal exudate
- Involvement of nucleus subthalamicus and its
Pathways
- Ballismic movements
- Damage to hypothalamic nuclei

17. - Border-zone Encephalitis.
- Ventriculitis
- Choroid Plexitis
- Generalized Edema due to Microangiopathy
Generalized edema can produce severe damage to the
brain without any infarction, tuberculoma or other naked
eye lesions.

18. BCG-vaccinated Children
- Localized lesions
- Focal microangiopathy
- Clinical features - area involved.
- Detected in CT scan and MRI of the
brain.
- Edema is severe - necrosis

19. Venous Involvement
- Hemorrhagic infarction
- Thrombosis of superior longitudinal sinus

20. Atypical or Modified Clinical
Pictures in BCG-vaccinated Children
- Meningeal Tuberculoma Serous tuberculous meningitis—base of
the brain
- Localized meningitis on the Superiolateral surface of the brain
Localized meningitis in the posterior fossa
Snilateral or bilateral cerebellar hemispheric signs
Signs of involvement of vermis with disturbance of equilibrium
Isolated Spinal Tuberculous Meningitis
Localized Lesions

21. Medial
syndromes of
medulla
Paramedian
branches
Emerging fibres
of 9th nerves
Ipsilateral
hemiparesis
Inferior pons Paramedian branches
Anterior inferior
cerebellar
Pontine gaze centre
near orin the
nucleus of 6th nerve
Emerging fibres of
7th nerve
Paralysis of gaze to
side of the lesion
Ipsilateral facial
paralysis
Superior pons Paramedian branches Medial longitudinal
fasciculus
Internuclear
ophthalmoplegia

22. Classification and incidence of
various
syndromes at onset

23. Paralyses
- Hemiplegia 32%
- Quadriplegia 31%
- Monoplegia 4.2%
- Paraplegia (cerebral) 0.9%

24. Abnormal movements
- Hemiballismus 18%
- Tremors: Generalized 10%
- Parkinsonian 0.3%
- Myoclonic jerks 0.4%
- Posterior fossa meningitis 0.6%

25. - Therapeutic paradox 2%
- Spinal leptomengitis <1%

26. Classification of various syndromes
after the disease is well-established

27. - Cranial nerve palsies- optic nerve, motor nerves
- Decorticate rigidity
- Decerebrate rigidity
- Acute increase of intracranial pressure
- Cerebellar syndrome
- Involvement of brainstem
- Reappearance of neonatal reflexes

28. Classification of various
syndromes during the recovery

29. - Hypothalamic - pituitary syndromes
Cushing’s disease
Obesity*
Diabetes insipidus*
Excessive sleeping (somnolence)
Syndrome of SIADH
Clinical pictures like Barter's syndrome
- Syndrome of persistent pyrexia*
- Recurrent attacks of serous meningitis*
- Postmeningitic encephalopathy*
- Postlumbar puncture (postmeningitic)
spinal “epidermoid”

30. Medical Research Council, Staging of
tuberculous meningitis (TBM)
Stage I The symptoms are nonspecific with few or
No clinical signs of meningitis. The patient
is fully conscious and alert
Stage II Signs of meningitis, drowsiness or lethargy,
cranial nerve palsies
Stage III Severe clouding of consciousness, stupor or
coma, convulsions, gross paresis or
paralysis

31. Patients who should be investigated for
TBM

32. Presumptive TBM
- Symptoms lasting for more than 5 days
Common symptoms Less frequent
symptoms
Uncommon
symptom
- Headache
- Fever
- Vomiting
- Neck stiffness
- Weight loss
- Confusion
- Cranial nerve palsy
- Hemiparesis
- Coma
- Photophobia
- Paraparesis
- Seizures

33. Diagnosis

34. Diagnosis of TBM
Demonstration of acid fast bacilli in the CSF or fulfillment of the
following criteria:
Essential
CSF showing:
• Predominant lymphocyte pleocytosis > 50/mm3
• Protein > 60 mg percent
• Sugar < 2/3 of blood sugar
Supportive
Along with the essential ones, two or more of the following
clinico-investigational criteria:
• History of fever of two weeks or more
• Positive family history of tuberculosis
• Generalized lymphadenopathy
• Mantoux test (5 TU) > 10 mm*
• Positive radiological evidence of tuberculosis elsewhere
• CT scan evidence of basal exudates or CNS tuberculosis
• Isolation of AFB from gastric lavage or other sites
• Histologically proven tubercular lymphadenitis

35. CSF Exam
- At least 6 mL for adults and 2–3 mL for children.
- Done in all presumptive cases unless absolutely
contraindicated

36. Hours to days
- Cell count and differentiation
- Protein
- CSF:serum glucose ratio (serum samples need to be taken
alongside the CSF)
- Gram stain for bacterial meningitis (e.g. N. meningitidis, S.
pneumonia)
- AFB stain for TB
- India ink and cryptococcal antigen testing for cryptococcal
meningitis
- Xpert MTB/RIF can be used as an adjunctive test in the
diagnosis of TBM, but a negative test does not rule out
a diagnosis of TBM. If it is safe to obtain, 1 mL of CSF is
optimal for this test (Nhu, 2014).
- Other PCR-based tests for Mtb are available, but diagnostic
accuracy is highly variable.
- PCR-based tests for viral pathogens, as appropriate

37. Days
- Bacterial culture and drug susceptibility testing
- Cytological examination for malignant cells

38. Days to weeks
- Fungal culture and drug susceptibility testing
- Mycobacterial culture and drug susceptibility
testing

39. Other investigations
- HIV testing
- Chest X ray
- CT brain with contrast
- MRI brain with contrast

40. Advantages of Godolinium enhanced MRI
vs CECT for diagnosis of TBM
• Detection of basal meningeal enhancement and
small tuberculomas
• Detect diffuse or focal meningeal granulomatous
change
• Delineate focal infarcts of basal ganglia and
diencephalons
• Can reveal hemorrhagic nature of infarcts

41. Treatment
Aims:
zz Microbiological cure
zz Prevention of complications, morbidity and
mortality
zz Management of treatment complications

42. Protocol Intensive
phase
Continuati
on phase
Total duration in
months
IAP 2HRZE 10 HRE 12
DOTS,
RNTCP
2H3R3Z3E3 7H3R3 Cat 1 of DOTS 9
months
ATT should be started as early as possible in all cases of TBM.

43. ISSC (Intermittent Short-Course
Chemotherapy)
- Supporting evidence children with pulmonary
tuberculosis (PTB) and other non-serious form
- Limited published data on its efficacy of ISSC
in serious extra pulmonary tuberculosis
(EPTB) particularly TBM

44. There are no randomized controlled trials
(RCTs) available to definitely conclude the
optimum duration of treatment to prevent
relapses and long term sequel.

45. Follow up
- Assessed for clinical response at the end of the treatment period
and at intervals for 2 years.
- Sustained resolution of clinical features including headache
and fever should guide stopping of ATT.
- Residual neurological defcits may be permanent and should not
be used to assess for active TB infection.

46. Drug Resistant TB
- Poor response to standard
- History of exposure to MDR-TB.

47. Steroids
For HIV negative patients
– TB meningitis
– duration 4 weeks
- f/b appropriate tappering

48. STEROIDS
For HIV positive patients
- TB meningitis
- life-threatening opportunistic infections are absent
- cryptococcal meningitis and cerebral toxoplasmosis
steroids are associated with increased adverse events
and disability in patients with HIV-associated
cryptococcal meningitis

49. - In hospital: intravenous dexamethasone 0.4
mg/kg/24h in 3–4 divided doses
- A slow switch to oral therapy and taper.
- Insuffcient evidence to recommend one
formulation/regimen of steroids over any other

50. SEIZURES
In acute phase
Seizures:
- electrolyte imbalance such as hyponatremia
- Raised intracranial pressure.
Treatment of underlying cause.

51. Initiation of antiepileptic drugs (AED).
- Later than the first week
- associated with tuberculoma and infarct
- May not necessitate the use of long term AED.

52. Starting long-term AED.
- In the absence of work up
- Seizures like focal seizures
- Generalized tonic clonic seizures
(GTCS)
- Tonic seizures
- Recurrent
- Those manifesting after first
Reasonable indications for starting long-term AED.

53. Phenobarbitone should not be used
- Cerebral depressant effect
- Induces hepatic microsomal enzymes
- Production of acetylating agents of INH
Increased hepatotoxicity

54. Medical Management of Cerebral
Edema
Mannitol:
- Emergency treatment of cerebral edema.
- The dose of mannitol (20 %) is 5 ml/kg stat
followed by 2 ml/kg 6 hourly for 8 doses.
- Used for the first 48-72 hours of therapy only
Repeated administration
- Fluid and electrolyte imbalance
- Secondary increase in intracranial pressure
(the rebound phenomenon).

55. Chronic raised intracranial pressure (ICP)
Glycerol
Acetazolamide

56. Paradoxical response
- At a pre-existing site, or the new tuberculomas
- Associated with extra pulmonary tuberculosis.
- First 2 weeks after OR even up to 1 year
- New granuloma(s) or abscess(es)
- Hydrocephalus
Immature faintly enhancing tuberculomas resolution with
antituberculous chemotherapy, glucocorticoids,
Well-formed and probably large sized (>3 cm) granulomas
- a risk of paradoxical enlargement.
Common in HIV positive patient.
30% in HIV positive patients
10% in immunocompetent patients.

57. Surgery
- Hydrocephalus with raised intracranial pressure
- CSF diversion byventriculo-peritoneal shunt
Insertion.
- neurosurgical services.

58. Prognosis
Mortality 18% for stage I TBM,
34% for stage II,
72% for stage III.
Neurological impairment
Afflicts approximately 20 to 30%.
cranial nerve palsies, ophthalmoplegia, seizures, psychiatric
disorders, and ataxia to hemiparesis, blindness, deafness, and
mental retardation.

59. Poor prognostic factors
- Advance stage of disease
- HIV coinfection
- The combination of isoniazid and rifampicin resistance
- CSF parameters
High CSF lactate
CSF leucopenia,
Low CSF glucose.
- Presence of brain stem lesion, as visualized
on MRI

60. Determinant of good prognosis
- Prompt diagnosis
- Timely initiation of antitubercular treatment and
corticosteroids

61. Complications

62. Hydrocephalus
Symptoms and signs
- Raised intracranial pressure (ICP)
- Worsening headache,
- Vomiting
- Ocular palsies
- Decreasing conscious level
- Papilloedema
- Urgent neuroimaging to assess cause of raised ICP
if patient is deteriorating

63. Management
- Ventriculo-peritoneal shunt insertion
At all stages of severity with hydrocephalus or raised
ICP not responding to ATT and steroids.
- Early shunt insertion may be benefcial.
- Mannitol limited to emergency management
- Decreasing ICP until shunt insertion can be
performed.
- External ventricular drainage is not usually
recommended, unless surgery iscontraindicated or
urgent CSF diversion is indicated
- To buy time before a shunt can be
inserted.

64. Stroke
- Focal neurological defcit consistent with a stroke
syndrome.
- Stroke in TBM may not be clinically apparent and
may be diagnosed on neuroimaging.
- Stroke is a signifcant contributor to disability
following TBM.

65. - Most effective treatment strategy uncertain and
evidence lacking.
- Acute stroke or evidence of on-going vasculopathy
may warrant continuation of steroids, usually
intravenously.
- There is some evidence that aspirin may prevent
stroke in TBM in adults. Further trials in adults and
children are on-going

66. Optico-chiasmatic arachnoiditis
Visual loss, which may arise
- during treatment with ATT,
- Or on the withdrawal of corticosteroids

67. - Most effective treatment strategy uncertain
- Steroid therapy is the frst-line treatment,
- Intravenous dexamethasone.
- Pulsed methylprednisolone or oral
- Thalidomide has been used in some case series for
patients not responding to steroids.
- Microsurgical intervention and intrathecal
hyaluronidase are controversial and not currently
recommended.

68. Seizures
- Generalized seizures secondary to encephalopathy
- Tuberculoma or infarction may cause secondary
generalized seizure

69. - Acute management with anti-epilepticdrugs as per local
protocol for seizure
- The use of anti-epileptic drugs alongside ATT must be
carefully managed due to the potential for drug
interactions and increased risk of liver dysfunction with
multiple hepatotoxic agents.
- Prophylactic anti-epileptic drugs are not required in TBM
patients who have not had seizures during their
clinical course.
- Continued treatment with anti-epileptic drugs may be
necessary in patients with recurrent seizure and
decisions about duration and withdrawal should be
individualized to the patient by the treating specialist.

70. TUBERCULOMA

71. Tuberculoma
- Tuberculosis which occurs in solid organs.
- Usually begins in an area of TB cerebritis
- Cluster of microgranulomas
- Coalesce into a mature noncaseating granuloma.

72. - A tuberculoma is a conglomerate mass of tissue
made up of small tubercles
- a central core of epithelioid cells and surrounded
by lymphocytes.
- Initial bacteremia which known to occur in chronic
tuberculous infections.
- Polymorphonuclear leukocytes infiltrate
- The center necrotic, caseous debris, periphery
encapsulate with fibrous tissue.
- “tuberculous abscess”

73. - <20 years are usually infratentorial
- supratentorial lesions predominate in adults.
- Most frequent site in children was considered to be
the cerebellum.
- However, with the advent of neuroimaging,
supratentorial lesions are increasingly being
recognized in children.
- In spite of hematogenous solitary tuberculomas are
more frequent

74. On gross examination
- Cerebral tuberculoma hard, nodular, comparatively
Avascular.
- Connection to the adjacent dura gross resemblance
to meningioma.
- Edema integral feature of tuberculoma.
- Indeed it is extensive
In addition
- atypical forms of tuberculoma
cysts and abscesses.

75. Clinical features
- size and site and concurrent meningitis.
- Seizures without associated meningeal signs or
evidence of tuberculosis elsewhere in the body.
- Raised intracranial tension.
- Cerebellar or brain stem syndromes
- Infratentorial tuberculoma raised ICT.

76. Diagnosis
- Clinical assessment, imaging findings and response
to therapy.
- Bacteriological cant be made and surgical biopsy
risky.
- A high clinical index of suspicion
- Evidence of extra cranial TB and a close
family contact with active TB
- When the signs and symptoms of concomitant TBM
are present
- The differential diagnoses neurocysticercosis
(NCC), brain abscess, fungal infection and
malignancy

77. MRI changes
Non- caseating granulomas
- Hypointense on T1 weighted images and
hypointense on T2 weighted
- Homogeneous nodular contrast enhancement and
a peripheral hypointensity.
Caseating granulomas with solid center
- Hypointense or isointense on T1 weighted images
with ring enhancement on contrast administration.
- Perilesional edema is present.
Caseating granulomas with liquid center
- Central hypointensity on T1 and hyperintensity on
T2 weighted images with a peripheral hypointense
ring which represents the capsule of tuberculoma

79. Treatment
The aims of treatment are:
- Resolution of neurological and constitutional
symptoms
- Resolution of the lesion on neuroimaging.
ATT should be given for 9 to 12 months initially, with
repeat neuroimaging at 3 months and 9–12 months to
monitor response to treatment.
Treatment should then be tailored to the clinical
and radiological response of the patient.

80. Paradoxical reaction
- Increase in the size and number of lesions can
occur, usually in the frst 3 months of treatment
- Requires treatment with steroids as
well as continued ATT

81. Treatment failure
- Increase in size or fail to reduce in size after 3 to 6
months ATT.
- Weigh the benefts and risks of biopsy
against those of commencing second-line treatment
empirically for suspected MDR-TB, or persisting
with frst-line treatment for suspected paradoxical
reaction.
If a biopsy is performed
a) histopathology with staining for AFB;
b) Mtb culture and drug susceptibility testing;
c) other microbiological tests as indicated
by the case history.