Neuro-Tuberculosis

1
CNS Tuberculosis
Prof R Shukla(DM,Neurology) KGMU
2
Case history

• 20 yrs old female patient presented with c/o
• Fever mild to moderate grade since 1 ½ months
• Headache with vomiting since 1 ½ months
• Decreased vision both eyes since 1 month

3
Examination

• General examination including vitals Normal
• CNS examination
• GCS- 15/15
• Neck rigidity/ Kernigs sign Absent.
• Optic nerves-
• Visual acuity- PL/PR absent both
  eyes.
• Fundus- Bilateral primary optic
  atrophy.
• Bilateral 3rd 4th 6th cranial nerves palsy
  present.
• Right LMN facial nerve palsy present.
• Rest of the neurological examination - normal

4
Oculomotor examination
Looking down
Looking up
Looking to right
Looking to left
5
Investigations

• Routine hematological biochemical
  investigations - Normal
• CSF examination
• TLC 440 cells
• Lymphocytes 95
• Polymorphs 5
• Proteins 111 mg
• Sugar 21 mg
• Corresponding blood sugar 171 mg.
• AFB, Grams stain India ink staining normal
• TB PCR report awaited.

6
MRI brain with Gd contrast
Axial
Sagittal
7
Introduction

• Tuberculosis is a major cause of death worldwide.
• India has the highest TB burden, accounting for
  1/5 of the global incidence and 2/3 of cases in
  SE Asia.
• Nearly 40 of population in India is affected.
• CNS tuberculosis occurs in up to 10 and has
  protean clinical manifestations.
• The burden of CNS tuberculosis is directly
  proportional to the prevalence of tuberculous
  infection.
• Tuberculous meningitis is the most devastating
  form of extra-pulmonary tuberculosis with 30
  mortality and disabling neurological sequelae in
  gt 25 survivors.

8
Classification of neurotuberculosis

• Tuberculous meningitis
• - Basal and spinal
• Tuberculoma
• - Intracranial (parenchymal extraparenchymal)
• - Spinal (parenchymal extraparenchymal)
• Tuberculous abscess
• Tuberculous encephalopathy
• - With or without meningitis
• Spinal cord involvement secondary to skeletal
  tuberculosis

Contd
9
Classification of neurotuberculosis Contd

• Intracranial
• - Tuberculous meningitis
• - Tuberculoma
• - Tuberculous abscess
• - Tuberculous encephalopathy
• - Tuberculous vasculopathy
• Spinal
• - Potts spine and Potts paraplegia
• - Tuberculous arachnoiditis
• - Spinal tuberculoma
• - Spinal meningitis

10
Causative organism

• CNS tuberculosis is caused by the human strain of
  Myobacterium tuberculosis.
• However in immunocompromised patients, atypical
  mycobacteria are an important cause of infection.
  
• They are now called non-tuberculous mycobacteria
  which include
• Mycobacterium avium
• Mycobacterium intracellulare

11
Pathophysiology

• CNS tuberculosis is secondary to disease
  elsewhere in the body.
• Mycobacteria reach the brain by hematogenous
  route.
• Initial small tuberculous lesions (Rich foci)
  develop in meninges, subpial or subependymal
  surface of the brain or the spinal cord, and may
  remain dormant for years.
• Reactivation may be due to endogenous factors
• Innate immunological and non immunological
  defenses
• Level of function of cell mediated immunity.
• Tumour necrosis factor ? may have a role.

12
Pathology

• Release of M tuberculosis results in a T
  lymphocyte dependent necrotising granulomatous
  inflammatory response.
• Thick gelatinous exudate around the sylvian
  fissures, basal cisterns, brainstem and
  cerebellum.
• Three processes cause most of the neurological
  deficits
• Hydrocephalous
• Adhesive arachnoiditis
• Obliterative vasculitis

13
Tuberculous brain abscess

• Distinct from CNS tuberculoma.
• 4 to 7.5 of patients with CNS tuberculosis.
• Usually solitary, uniloculated or multiloculated
  of variable size
• Progresses much more rapidly than tuberculomas.
• Clinical features include partial seizures, focal
  neurological deficit and raised intracranial
  tension.
• CT and MRI show a large size lesion with marked
  surrounding oedema.

14
Tuberculous encephalopathy

• Seen in infants and children.
• Characterized by convulsions, stupor and coma
  with signs of meningeal irritation or focal
  neurological deficit.
• CSF is largely normal.
• Responsive to corticosteroids.

15
Tuberculoma

• Firm avascular spherical granulomatous mass.
• Usually 2-8cm in diameter.
• Symptoms related to their size and location.
• Low grade fever, headache, vomiting, seizures,
  focal neurological deficit, and papilloedema are
  the characteristic.
• Target sign is characteristic.

16
Spinal tuberculosis

• lt 1 of patients.
• Infection starts in cancellous bone usually
  adjacent to an inter-vertebral disc or anteriorly
  under the periosteum.
• Thoracic (65) lumbar (20), cervical (10),
  thoraco-lumbar (5), and atlanto-axial region (lt
  1).
• Two (lt90), Three (50) vertebrae
• Paraspinal abscess 55-90.
• Local pain, tenderness over the affected spine or
  a gibbus associated with paravertebral muscle
  spasm or a palpable paravertebral abscess.
• Neurological deficit results from multiple
  causes.

Myelitis
Potts spine
17
Non-osseous spinal cord tuberculosis

• Can occur in the form of tuberculomas.
• Extradural tuberculomas are the most common.
• Intramedullary tuberculomas are rare.

18
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 with multiple irregular filling
  defects, cyst formation and sometimes spinal
  block.

19
Spinal form of tuberculous meningitis

• May result from rupture of Rich foci in the
  spinal arachnoid space.
• The acute form presents with fever, headache, and
  root pains accompanied by myelopathy.
• The chronic form presents with spinal cord
  compression.
• Spinal forms of tuberculous meningitis may be
  associated with syrinx formation.

20
Tuberculous meningitis (TBM)

• Commonest form of neurotuberculosis (70 to 80) .
• TBM is also the commonest form of chronic
  meningitis.
• Clinical features include h/o vague ill health
  for 2-8 weeks prior to development of meningeal
  irritation.
• Non specific symptoms include malaise, anorexia,
  fatigue, low grade fever, myalgia and headache.
• Prodromal symptoms in infants and children
  include irritability, drowsiness, poor feeling,
  and abdominal pain..

Contd
21
Tuberculous meningitis (TBM) Contd

• Meningeal irritation - neck stiffness, Kernigs
  sign, Bickelles sign and Brudzinskis sign.
• Cranial nerve palsies (20-30), fundus -
  papilloedema or rarely choroid tubercles,
  seizures, focal neurological deficits secondary
  to infarction.
• Visual loss may be due to optic nerve
  involvement, optochiasmatic arachnoiditis, third
  ventricular compression of optic chiasma,
  ethambutol toxicity and occipital lobe
  infarction.
• Increasing lethargy, confusion, stupor, deep
  coma, decerebrate or decorticate rigidity.

22
Clinical presentation of TBM
Clinical Features Children ()
Adults ()

• History
• Tuberculosis 55 8-12
• Symptoms
• Headache 20-50 50-60
• Nausea/vomiting 50-75 8-40
• Apathy/behavioural changes 30-70 30-70
• Seizures 10-20 0-15
• Signs
• Fever 50-100 60-100
• Meningismus 70-100 60-70
• Cranial nerve palsy 15-30 15-40
• Coma 30-45 20-30

Zuger A. Tuberculosis. In Scheld WN, Whitley RJ,
Marra CM, editors. Infections of Central Nervous
System. Philadelphia Lippincott, 2004. pp. 441-9.
23
Staging of TBM

• TBM is classified into 3 stages according to the
  British Medical Research Council (MRC) criteria
• Stage I Prodromal phase with no definite
  neurologic
• symptoms.
• Stage II Signs of meningeal irritation with
  slight or no
• clouding of sensorium and
  minor (cranial nerve
• palsy) or no neurological
  deficit.
• Stage III Severe clouding of sensorium,
  convulsions, focal
• neurological deficit and
  involuntary movements.

24
Modified MRC criteria

• Grade I Alert and oriented (GCS 15) without
  focal
• neurological deficit.
• Grade II GCS 14-10 with or without focal
  neurological
• deficit or GCS 15 with focal
  neurological deficit.
• Grade III GCS less than 10 with or without focal
  
• neurological deficit.

25
Diagnostic rule for TBM
Score
Variable
2
gt36
Age (years)
0
lt36
4 0
gt15000 15000
Blood WBC count (103/ ml)

• 5
• 0

gt 6 6
History of illness (days)
3 0
750 lt 750
CSF WBC count (103 / ml)
4 0
90 lt 90
CSF neutrophil
Score lt 4 TBM gt 4 - Non TBM
26
Differential diagnosis of TBM  

• Fungal meningitis (cryptococcosis,
  histoplasmosis, blastomycosis, coccidioidal
  mycosis)
• Viral meningoencephalitis (herpes simplex, mumps)
• Partially treated bacterial meningitis
• Neurosyphills
• Focal parameningeal infection
• CNS toxoplasmosis
• Neoplastic meningitis (lymphoma, carcinoma)
• Neurosarcoidosis

27
Investigations

• CSF examination
• CSF Smear examination Zeihl Nelsons, Grams
  and India Ink stain.
• CSF culture on solid media Egg or agar based
  BACTEC systems.
• Adjunctive tests CSF tuberculostearic acid,
  adenosine deaminase, radiolabelled
  bromide partition test.
• Molecular diagnosis Nucleic acid
  amplification,
• DNA finger printing, PCR.

28
Cerebrospinal fluid examination

• Predominantly lymphocytic pleocytosis, with
  increased proteins and low CSF/ blood glucose
  ratio.
• WBC count can be normal in presence of depressed
  CMI (elderly and HIV positive individuals).
• CSF protein (gt 150 mg/dl) should always raise the
  suspicion of tuberculosis or fungal infection,
  rarely seen in viral meningitis.
• Smear is ve in 10, can be increased by
  examining large volume of CSF.
• Culture is ve in 25-70.

29
Cerebrospinal fluid examination

• Repeat CSF frequently shows a falling glucose
  level, a rising protein concentration and a
  shift to mononuclear predominance.
• CSF cell counts decrease by 50 during the first
  month but may not become normal for a year.
• CSF glucose becomes normal in 1 to 2 months and
  protein becomes normal by 12 months or longer.
• CSF cultures should be sterile by the first
  month, but PCR results may remain positive for a
  month.

30
Investigations

• CSF examination
• CSF Smear examination Zeihl Nelsons, Grams
  and India Ink stain.
• CSF culture on solid media Egg or agar based
  BACTEC systems.
• Adjunctive tests CSF tuberculostearic acid,
  adenosine deaminase, radiolabelled
  bromide partition test.
• Molecular diagnosis Nucleic acid
  amplification,
• DNA finger printing, PCR.

31
Sensitivity and specificity of adjunctive tests
for the diagnosis of TBM
Tests Sensitivity ()
Specificity () Time Required (h)

• Biochemical
• Radiolabelled bromide partition ratio 90-94
  88-96 48
• CSF adenosine deaminase level 73-100
  71-99 lt24
• CSF tuberculostearic acid level 95 99
  lt24
• Immunologic test (ELISA)
• Antigen ELISA 38-94 95-100 lt24
• Antibody ELISA 52-93 38-94

Kalita J, Misra UK. Tuberculosis Meningitis. In
Misra UK, Kalita J (Eds) Diagnosis and Management
of Neurological Disorders. Wolter Kluwers Health
New Delhi 2011 pp. 145-66.
32
Sensitivity specificity of various diagnostic
tests for TBM
Diagnostic test Sensitivity Specificity
ZN staining 10-20 100
LJ Culture 15 (25-80) 100
BACTEC Culture 55 100
ELISA 52.3 91.6
TB PCR 56 98
TST 73 56
QTF-GOLD 76 98
ELISPOT 87 92
Menzies et al, Ann Int Med. 2007 146 340-354.
33
Diagnostic criteria for TBM
Definition
Class
Acid-fast bacilli seen in the cerebrospinal
fluid.
Definite

• Patients with one or more of the following
• Suspected active pulmonary TB on chest
  radiography.
• AFB found in any specimen other than the CSF.
• Clinical evidence of extrapulmonary tuberculosis.

Probable

• Patients with at least four of the following
• History of tuberculosis.
• Predominance of lymphoytes in the cerebrospinal
  fluid.
• A duration of illness of more than six days.
• A ratio of CSF glucose to plasma glucose of less
  than 0.5.
• Altered consciousness
• Turbid cerebrospinal fluid.
• Focal neurologic signs.

Possible
Thwaites GE et al. Diagnosis of adult
tuberculosis meningitis by use of clinical and
laboratory features. Lancet 2002 360 1287-92.
34
Imaging in TBM

• CT/ MRI confirm the presence and extent of basal
  arachnoiditis, cerebral oedema, infarction,
  ventriculitis and hydrocephalus.
• Abnormalities depend upon stage of disease
• I (normal in 30), II (Normal in 10), III
  (Abnormal in all).
• 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 help in
  prognostication.

35
Imaging abnormalities in TBM
36
Search for extra CNS TB

• An extra-neural focus should be sought
  clinically and radiologically in all patients of
  CNS TB as it may indicate safer and more
  accessible sites for diagnostic sampling e.g.
  X-ray chest, FNAC of the enlarged lymphnodes,
  abdominal USG, CT scan .
• 77 of HIV ve TBM patients have extra-meningeal
  TB compared to only 9 with HIV ve patients.

Thwaites G, et al. J Neurol Neurosurg Psychiatry
200068289-99.
37
Principles of treatment of TBM

• Treatment should be started early in suspected
  TBM.
• Multiple antimicrobial drugs are required.
• Drugs must adequately cross the blood-CSF barrier
  to achieve therapeutic concentrations in CSF.
• Drugs should be taken on a regular basis for a
  sufficient period to eradicate the CNS infection.
• Intrathecal therapy is not required.
• No general consensus regarding the choice of
  drug, doses and duration of treatment.

38
List of antitubercular drugs
First-Line Drugs Second-Line Drugs

• INH Cycloserine
• Rifampicin Ethionamide
• Rifapentine Levofloxacin
• Rifabutin Moxifloxacin
• Ethambutol Gatifloxacin
• Pyrazinamide p-aminosalicylic acid
• Streptomycin
• Amikacin/Kanamycin
• Capreomycin

Not approved by U.S. FDA Included in
second-line drugs due to toxicity, limited
efficacy or difficulty in administration.
39
Treatment

• CNS tuberculosis is categorised under TB
  treatment category I by WHO.
• Initial phase therapy ( 2 mths) with isoniazid,
  rifampicin, pyrazinamide and streptomycin or
  ethambutol followed by continuation phase (7
  mths) with isoniazid and rifampicin.
• The BTS and IDSA/ATS recommend 9-12 months of
  ATT. Therapy should be extended to 18 months in
  patients who do not tolerate pyrazinamide.
• Short duration therapy (6 mths) might be
  sufficient if the likelihood of drug resistance
  is low.
• However as the emergence of neurological deficit
  has been seen in some of the studies so a minimum
  of 12 months treatment would be worthwhile.

40
What is the best anti-tuberculous drug regimen?

• Isonaizid, rifampicin and pyrazinamide are
  considered mandatory at the beginning of TBM
  treatment.
• Isoniazid penetrates the CSF freely and has
  potent early bactericidal activity.
• Rifampicin penetrates the CSF less well (maximum
  concentrations around 30 of plasma), but the
  high mortality from rifampicin resistant TBM has
  confirmed its central role in the treatment of
  CNS disease.
• There is no conclusive evidence to demonstrate
  that pyrazinamide improves outcome of CNS
  tuberculosis, although it is well absorbed orally
  and achieves high concentration in the CSF.

Thwaites GE et al. J Neurol Neurosurg Psychiatry
2000 68 289-99
Lancet Neurol 2005 4 160-70.
41
Choice of the fourth drug

• No data from controlled trials.
• Most authorities recommend either streptomycin or
  ethambutol, although neither penetrates the CSF
  well in the absence of inflammation.
• Streptomycin should not be given to those who are
  pregnant or have renal impairment.
• Ethambutol should be avoided where optic
  neuropathy is a concern.
• The fluoroquinolones may represent an effective
  fourth agent, although data concerning their CSF
  pharamacokinetics and safety during prolonged
  therapy are limited.
• Others-Ethionamide, prothionamide.

42
Adjunctive steroid therapy

• The use of corticosteroids as adjunctive therapy
  in the treatment of CNS tuberculosis began as
  early as the 1950s.
• The rationale behind the use of steroids includes
  the reduction of inflammation within the
  subarachnoid space.
• The largest RCT in TBM recommends dexamethasone
  treatment in patient with TBM for 6-8 weeks.

Thwaites GE et al. N Engl J Med 2004 351
1741-51 Lancet
Neurol 2007 6 280-6.
43
Adjunctive steroid therapy

• A recent Cochrane review and meta-analysis of 7
  randomised controlled trials involving 1140
  participants (with 411 deaths) concluded that
  corticosteroids improved outcome in HIV-negative
  children and adults with TBM, but the benefit in
  HIV infected individuals remains uncertain.

Prasad K, Singh MB. Corticosteroids for managing
tuberculous meningitis. Cochrane Database Syst
Rev 2008(1)CD002244.
44
Role of surgery in CNS tuberculosis

• Hydrocephalus, tuberculous cerebral abscess and
  vertebral tuberculosis with paraparesis are all
  indications for neurosurgical referral (A,II).
• Early ventriculo-peritoneal shunting should be
  considered in those with non-communicating
  hydrocephalus (A,II) and in those with
  communicating hydrocephalus falling medical
  management (B,II).
• Communicating hydrocephalus may be treated
  initially with frusemide (40 mg/24 h adults, 1
  mg/kg children) and acetazolamide (10-20 mg/kg
  adults, 30-50 mg/kg children) (B,II) or repeated
  lumbar punctures (B,III).
• Urgent surgical decompression should be
  considered in all those with extra-dural lesions
  causing paraparesis (A,II).

45
TBM in HIV positive patients

• The optimal regimens have not been clearly
  established, should be same as in HIV ve
  individuals.
• Four drug regimen including pyrazinamide is
  recommended.
• Initiation of HAART depends upon CD 4 counts.
• Infection with NTM (M avium/M intracellulare).
• Current recommendations include using
  azithromycin (500-100mg/day) and clarithromycin
  (500- 1000mg/day) in combination with ethambutol
  (15mg/kg/day) or clofazimine (100 mg/day).
• Alternative regimens include the use of
  ciprofloxacin and rifampicin.
• Rifabutin is recommended in place of rifampicin
  for those taking protease inhibitors.

46
Treatment of multi-drug resistant TBM

• The treatment of multi drug resistant TBM should
  abide by the principles of treatment of multi
  drug resistant pulmonary tuberculosis.
• Never add a single drug to a failing regimen.
• Use at least three previously unused drugs, one
  of which should be a fluoroquinolone.
• Streptomycin resistance does not confer
  resistance to other aminoglycosides, therefore
  amikacin or kanamycin can be used.
• Treatment should be given for at least 18
  months.

47
Prognosis

• Virtually all patients with no focal deficits and
  only minor lethargy recover, most-without
  sequelae.
• 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 deficits,
  gait disturbance, hemiplegia, blindness,
  deafness, learning disability, dementia and
  various syndromes of hypothalamic or pituitary
  dysfunction.

48
Poor prognostic factors

• Stage of disease.
• Presence of miliary disease
• Severe disease on admission
• Delay in initiation of treatment
• Extremes of age, preexistence of a debilitating
  condition
• Very abnormal CSF (very low glucose or elevated
  protein)

49
Conclusion

• CNS tuberculosis is a common, eminently treatable
  disorder with protean manifestations.
• Early diagnosis requires a high index of
  suspicion.
• Careful bacteriology of CSF is as good as or
  better than molecular method before starting
  treatment.
• CT or MRI showing basal meningeal enhancement
  with any degree of hydrocephalus is strongly
  suggestive of TBM.
• Clinical outcome depends greatly on the stage of
  disease at which therapy is initiated.

50

• 1. Spinal tuberculosis is classically thought to
  begin in which portion of the vertebral body
• Antero inferior
• Antero superior
• Postero superior
• Postero inferior

51

• 1. Spinal tuberculosis is classically thought to
  begin in which portion of the vertebral body
• Antero inferior
• Antero superior
• Postero superior
• Postero inferior

52

• 2. A decreased CSF glucose concentration is not
  seen in
• Tuberculous meningitis
• Fungal meningitis
• Viral meningitis
• Neuro-Sarcoidosis

53

• 2. A decreased CSF glucose concentration is not
  seen in
• Tuberculous meningitis
• Fungal meningitis
• Viral meningitis
• Neuro-Sarcoidosis

54

• 3. For a positive smear on Zeihl-Neelsen
  staining, the bacterial load (in AFB/ml) required
  is
• 1010
• 10102
• 10103
• 10104

55

• 3. For a positive smear on Zeihl-Neelsen
  staining, the bacterial load (in AFB/ml) required
  is
• 1010
• 10102
• 10103
• 10104

56

• 4. Which of the following adjunctive tests has
  the highest sensitivity and specificity for the
  diagnosis of TBM
• Radiolabelled bromide partition test
• CSF adenosine deaminase level
• CSF tuberculostearic acid level
• CSF antigen ELISA

57

• 4. Which of the following adjunctive tests has
  the highest sensitivity and specificity for the
  diagnosis of TBM
• Radiolabelled bromide partition test
• CSF adenosine deaminase level
• CSF tuberculostearic acid level
• CSF antigen ELISA

58

• 5. Maximum CSF concentration occurs with
• INH
• Rifampicin
• Pyrazinamide
• Ethambutol

59

• 5. Maximum CSF concentration occurs with
• INH
• Rifampicin
• Pyrazinamide
• Ethambutol

60

• 6. In a patient with antitubercular therapy, if
  the primary elevation is in bilirubin and
  alkaline phosphatase, the most likely offending
  drug is,
• Isoniazid
• Rifampicin
• Ethambutol
• Pyrazinamide

61

• 6. In a patient with antitubercular therapy, if
  the primary elevation is in bilirubin and
  alkaline phosphatase, the most likely offending
  drug is,
• Isoniazid
• Rifampicin
• Ethambutol
• Pyrazinamide

62

• 7. Which of the following quinolone antibiotics
  has highest CSF penetration
• Levofloxacin
• Moxyfloxacillin
• Gatifloxacin
• Ofloxacin

63

• 7. Which of the following quinolone antibiotics
  has highest CSF penetration
• Levofloxacin
• Moxyfloxacillin
• Gatifloxacin
• Ofloxacin

64

• 8. Chemoprophylaxis for tuberculosis is indicated
  in persons with high risk medical conditions, if
  the tuberculin reaction size (in mm) is,
• lt5
• 5
• 10
• 15

65

• 8. Chemoprophylaxis for tuberculosis is indicated
  in persons with high risk medical conditions, if
  the tuberculin reaction size (in mm) is,
• lt5
• 5
• 10
• 15