Central Nervous System Tuberculosis, Mycobacteriology Module, Residency year 1 King Fahd Hospital of The University

1. CNS Tuberculosis
Abdullatif S. Al Rashed
Clinical Microbiology Resident.
King Fahd Hospital of the University.
Teaching Assistant, Department of Microbiology, Imam Abdulrahman Bin Faisal
University, Dammam, Saudi Arabia.

2. INTRODUCTION
Outlines:
• Basics Review.
• CNS Tuberculosis:
• Introduction.
• Epidemiology.
• Tuberculous Meningitis:
• Introduction.
• Clinical Manifestations.
• Diagnosis.
• Treatment.

4. • M. tuberculosis is:
1. Free-living organisms that lack a cell wall.
2. Gram-negative intracellular organisms
3. Strictly aerobic, non-sporing, non-motile, weakly Gram-positive bacilli.
4. Aerobic, oxidase positive Gram Negative bacilli.

5. INTRODUCTION
• M. tuberculosis belongs to the genus Mycobacterium.
• They are strictly aerobes, nonmotile slender rods, and
don’t form spores.

6. Which of the following stains used to identify M. tuberculosis:
1. Giemsa stain
2. India ink stain
3. Ziehl neelsen stain
4. Silver stain
5. Periodic acid–Schiff stain

7. INTRODUCTION
• M. tuberculosis cell wall is a Lipid-rich that enables it to
resist de-staining with acid-alcohol after staining with
aniline dyes hence acid-fast bacilli (AFB).
• The Ziehl-Neelsen stain (ZN stain), is a type of
differential bacteriological stain used to identify acid-fast
organisms.

8. • Which of the following organisms is NOT acid fast:
1. Nocardia spp
2. Rhodococcus spp
3. Mycobactrium spp
4. Tsukamurella spp
5. Gordonia spp
6. Non of the above

9. CNS Tuberculosis

10. THIS IS A SLIDE TITLE
▰ Central Nervous System (CNS) Tuberculosis (TB) occurs
in approximately 1% of all patients with active TB.
▰ The CNS Involvement includes:
Meningitis Tuberculoma Abscess
Spinal
tuberculous
arachnoiditis

11. INTRODUCTION
Epidemiology

12. INTRODUCTION

13. 251
218
95
55
Most common KSA regions of Extrapulmonary TB Cases 2017 (Total Cases in KSA=744)
Riyadh Jeddah Eastern Jazan & Najranhttps://www.moh.gov.sa/en/Ministry/Statistics/Book/Pages/default.aspx

14. Tuberculous Meningitis

15. TB meningitis accounts for 5% of all
extrapulmonary TB and is one of the most
devastating manifestations of TB infection.
It may have an insidious onset, physicians
should have a high clinical suspicion in patients
with altered level of consciousness in TB-
endemic areas especially young children.

16. Fever Headach
e
Altered
level of
conscious
ness
Vomiting
Clinical Manifestations (Adults)
Anorexia/
Weight Loss
Neck
stiffness Confusio
n
Hemiparesis

17. Seizures
Nausea
Vomiting
Clinical Manifestations (Pediatrics)
Headache is
Less
Frequent
Rock RB, Olin M, Baker CA, Molitor TW, Peterson PK. Central nervous system tuberculosis: pathogenesis and clinical aspects. Clin Microbiol Rev 2008; 21:243–61.

18. 01
Especially of the 6th (abducens)
& 7th (facial) cranial nerves.
Cranial nerve dysfunction
02
Other Clinical Manifestations
high protein levels causes
obstruction of cerebrospinal
fluid (CSF) flow
Hydrocephalus

19. 03
stroke can occur as a complication of
vasospasm, thrombosis, vasculitis, or
hemorrhagic infarction
Intracranial vasculopathy
Other Clinical Manifestations

20. • Image A: basilar meningeal
enhancement (arrows).
• Image B: meningeal
enhancement (arrows).
Other Clinical Manifestations (Radiography)

21. • (A) hydrocephalus
• (B) moderate hydrocephalus (asterisks) with trans-ependymal edema (arrows),
Other Clinical Manifestations (Radiography)

22. •Early recognition of tuberculous meningitis is of extreme
importance because the clinical outcome depends greatly
upon the stage at which therapy is initiated.

23. 1 Patients are lucid with no focal neurologic signs or
evidence of hydrocephalus.
2
3
Patients exhibit lethargy, confusion; they may have
mild focal signs, such as cranial nerve palsy or hemi
paresis.
Advanced illness with delirium, stupor, coma, seizur
es, multiple cranial nerve palsies, and/or dense hemi
plegia.
Stageofillness
Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2013. US Department of Health and Human Services, Atlanta, GA 2014.
Farer LS, Lowell AM, Meador MP. Extrapulmonary tuberculosis in the United States. American journal of epidemiology. 1979 Feb 1;109(2):205-17.

24. Diagnosis
The diagnosis of Tuberculous Meningitis can be
very difficult; maintaining a high degree of
suspicion is vital in order to initiate therapy
promptly.

25. CSF Examination
Cell Counts and
Chemistries
AFB stain and
culture
Others (NAAT,
ADA..)
Radiography
CT Scan
MRI

26. PPD Skin Test & IGRAs?

27. • The performance of the
tuberculin skin test for the
diagnosis of tuberculosis
varies according to:
• Age,
• Vaccination with BCG,
• Nutritional status,
• HIV infection, and
• Technique of administration.
•Some studies shows:
• Only 10-20% of patients
with CNS tuberculosis have
a positive test. (Girgis N et al, 1998)
•Others report around 50%
are positive. (Mahadevan B et al, 2005)
•Rates for children vary
between 30 and 65% (van den Bos
F et al, 2004)

28. The tuberculin skin test may provide
indication of previous tuberculosis infection
and is probably most useful in young children
British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children

29. • Free IFN-γ levels have not been as extensively studied.
IDSA

30. BIS

31. CSF EXAMINATION
Cell counts and chemistries

32. CSF Examination
• (IDSA Recommendation) Although no studies reported the
sensitivity and specificity of cell counts and chemistries in the
identification of extrapulmonary TB, committee recommend that
cell counts and chemistries be performed on amenable fluid
specimens collected from sites of suspected extrapulmonary
TB.
• (British Infection Society) Examination of the cerebrospinal fluid
(CSF) is essential and can help distinguish TBM from other causes of
meningitis.

33. CSF Examination
When TB meningitis is suspected in adults at
least 6 ml of CSF should be taken exclusively
for mycobacterial studies

34. Test Results
WBC Count
100–399 cells/lL;
lymphocyte predominance (85%)
Appearance Clear
Protein
>40 mg/dL (77%)
CSF glucose : blood glucose 0.6 (67%)
Opening pressure 200-250 mm H2O (54%)
Lactate 5.0-10.0 mmol/L

35. Torok ME, Nghia HD, Chau TT, et al. Validation of a diagnostic algorithm for adult tuberculous meningitis. Am J Trop Med Hyg 2007; 77:555–9.

36. Acid Fast Bacilli Stain

37. • Accuracy studies indicate that CSF AFB smear
microscopy has a sensitivity of 10%–30% .
• Liquid culture media is more sensitive than CSF
microscopy for AFB, but is too slow (>2 weeks to
positive result) to help treatment decisions. It
recovers more bacteria from CSF than solid
media

38. • In contrast, the specificity of AFB smear
microscopy tends to be quite high as
described for pulmonary TB (≥90%).

39. Factors that
increases the
diagnostic
yield of AFB
Staining:
1. Repeated lumbar punctures
• Some authorities recommend a
minimum of three serial lumbar
punctures be performed at daily
intervals
• Although empiric therapy need
not be delayed during this time.
2. Large volume of CSF:
• CSF volume and production rate
increase with age and weight.

41. Despite the low sensitivity, The search for AFB in
CSF remains the best rapid diagnostic test for TB
Meningitis
Negative AFB stain doesn’t role out TB Meningitis!

42. Nucleic Acid Amplification
Test (NAAT)

43. WHO. Xpert MTB/RIF assay for the diagnosis of
pulmonary and extrapulmonary TB in adults and
children. Policy update. 2013.

44. • 16 studies have been published for the use of Xpert
MTB/RIF in meningeal tuberculosis.
• Studies used compared against culture as a
reference as the reference standard.
• The sensitivity is 79.5% (95% CI, 62.0–90.2%), and
the Specificity is 98.6% (95% CI, 95.8–99.6%).
WHO. Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in
adults and children. Policy update. 2013.

45. • NAAT cannot replace mycobacterial culture for
diagnosis because it is not sensitive enough and it
does not produce an isolate, which is needed for
DST.
• However, NAAT is appropriate as an adjunct to
mycobacterial culture because NAAT can be
performed within hours, thereby offering the
opportunity for early diagnosis and treatment.Cautions and Limitations
At this time there are no FDA-approved NAATs for
use with extrapulmonary specimens.

46. CSF Mycobacterial Culture

47. • The Accuracy studies indicate that mycobacterial
culture has a sensitivity of 45%–70%.
• In the other hand, The specificity of mycobacterial
culture tends to be comparatively higher than the
sensitivity (>97%).

48. •Positive result can be used as
evidence of extrapulmonary TB
and guide decision making
because false-positive results are
unlikely.
•However, a negative result may not
be used to exclude TB because
false-negative results are
exceedingly common.
According
to the
previous
findings:

49. Most importantly, positive mycobacterial
cultures are the only way to obtain isolates
for Drug Susceptibility Testing (DST).

50. CSF adenosine deaminase
(ADA) level

51. Two meta-analyses estimated the sensitivity
and specificity of an elevated ADA level in
the cerebrospinal fluid
• The 1st meta-analysis included 10
studies estimated the sensitivity
and specificity of ADA for diagnosis
of TB meningitis to be 79 and 91
Percent, respectively.
• They used a threshold of 9-10 U/L
to define an elevated ADA.
• The 2nd meta-analysis included 13
studies noted the sensitivity and
specificity of ADA for diagnosing TB
meningitis depends on the level of
ADA.
• If 4 U/L used, sensitivity (>93%) &
Specificity (<80%).
• If 8 U/L used, sensitivity (<59%) &
Specificity (>96%)Lack of specificity has been the major problem: high CSF
ADA activity has been reported from patients with
lymphomas, malaria, brucellosis and pyogenic meningitides.
(BIS)

52. Thwaites et al and
To ̈ro ̈k et al have
developed and
validated diagnostic
algorithms for TB
meningitis that use
basic clinical and
laboratory data
Torok ME, Nghia HD, Chau TT, et al. Validation of a diagnostic
algorithm for adult tuberculous meningitis. Am J Trop Med Hyg 2007;
77:555–9.

55. Treatment

56. Important To Know
•Anti-tuberculous therapy
should be initiated on the
basis of strong clinical
suspicion and
should not be delayed until
bacteriologic proof has
been obtained.
•Definitions:
•MDR TB (resistant to
isoniazid [INH] and
rifampicin)
•Extensively drug-resistant
TB (resistant to INH,
rifampin, fluoroquinolones,
capreomycin, kanamycin,
and amikacin)

57. Isoniazid
Rifampicin
Pyrazinamide
Ethambutol or
streptomycin
First-line Drugs:
4 drugs for
2 months, then
isoniazid plus
rifampicin for
>=10 months

58. Fluoroquinolone (eg,
moxifloxacin or levofloxacin)
Ethionamide or
prothionamide
Pyrazinamide
Injectable agent: (eg,
amikacin or capreomycin)
MDR TB:
Initial therapy with at least
these 4 drugs subsequent
treatment should be directed
by patient resistance profile,
national guidelines, and CSF
penetration of candidate
drugs; 18-24 months total
treatment duration

59. Recommended for all patients with TB meningitis,
regardless of severity.
Adjunctive corticosteroids:
Drug <=14 years >14 years
Dexamethasone 0.6 mg/kg (IV or PO)
for
4 weeks, then reduce
course over next 4
weeks.
Stage I: 0.3 mg/kg in week 1; 0.2 mg/kg
in week 2; and then 4 weeks of oral
therapy.
Stage II/III: 0.4 mg/kg initially, then
reduce course over 6–8 weeks.
Prednisolone 4 mg/kg (PO or IV) for 4 weeks, then reduce course over next
4 weeks

60. INTRODUCTION
References:
• Nelson CA, Zunt JR. Tuberculosis of the central nervous system in immunocompromised patients: HIV infection and solid organ
transplant recipients. Clinical infectious diseases. 2011 Nov 1;53(9):915-26.
• Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, Keane J, Lewinsohn DA, Loeffler AM, Mazurek GH,
O’Brien RJ. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and
Prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children. Clinical Infectious Diseases. 2017 Jan
15;64(2):e1-33.
• Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J. British Infection Society guidelines for the diagnosis and
treatment of tuberculosis of the central nervous system in adults and children. Journal of Infection. 2009 Sep 1;59(3):167-87.
• Daikos GL, Cleary T, Rodriguez A, Fischl MA. Multidrug-resistant tuberculous meningitis in patients with AIDS. Int J Tuberc Lung
Dis 2003; 7:394–8.
• Thwaites GE, Chau TT, Stepniewska K, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory
features. Lancet 2002; 360:1287–92.
• Torok ME, Nghia HD, Chau TT, et al. Validation of a diagnostic algorithm for adult tuberculous meningitis. Am J Trop Med Hyg
2007; 77:555–9.
• Girgis NI, Sultan Y, Farid Z, Mansour MM, Erian MW, Hanna LS, et al. Tuberculosis meningitis, Abbassia Fever Hospital-Naval
Medical Research Unit No. 3-Cairo, Egypt, from 1976 to 1996. Am J Trop Med Hyg 1998;58(1):28e34.
• Mahadevan B, Mahadevan S, Serane VT, Narasimhan R. Tuberculin reactivity in tuberculous meningitis. Indian J
Pediatr 2005;72(3):213e5.
• van den Bos F, Terken M, Ypma L, Kimpen JL, Nel ED, Schaaf HS, et al. Tuberculous meningitis and miliary
tuberculosis in young children. Trop Med Int Health 2004;9(2):309e13.

61. ‫دام‬ ‫ما‬ َ‫ا‬‫عالم‬ ‫المرء‬ ‫يزال‬ ‫ال‬
‫ظن‬ ‫فإذا‬ ، ‫العلم‬ ‫طلب‬ ‫في‬
‫جهله‬ ‫بدأ‬ ‫فقد‬ ‫علم‬ ‫قد‬ ‫أنه‬.
“

62. Thank you