Tuberculous Meningitis
Zheng Lan, MD/PhD
Neurocritical Care Fellow
Montefiore Medical Center
TB Meningitis
Mycobacterium tuberculosis
Leptomeningeal infection
Thick, fibrinous exudate at the basal
cistern
Epidemiology:
Most common in countries with a significant TB burden
High:
sub-Saharan Africa
India, islands of Southeast Asia, Micronesia
Intermediate:
China, Central and South America, Eastern
Europe and Northern Africa
Low:
US, Western Europe, Canada, Japan and Australia
Epidemiology: ( Cont’d)
Global Prevalence of TB Meningitis
Navarro-Flores et al: Journal of Neurology March 2022
Epidemiology: ( Cont’d)
https://www.cdc.gov/tb/statistics/surv/surv2022/
images/Slide36.PNG
Pathogenesis
Pathogenesis of TBM and postulation of the formation of Rich foci. (a) Aerosol
transmission of MTB, ( images/alveoli-268.htm) (b) Phagocytosis of MTB by
alveolar macrophages inside alveoli. (c) Granuloma formation in the lung,
which subsequently occurs due to cellular and cytokine network responses;
90% of hosts with granulomas maintain them stably over the course of their
lives. (d) MTB escapes from the granuloma, which occurs in 10% of latent TB
patients. (e) MTB can cause TBM by escalating from the lung or by
secondary reactivation from a “leaked granuloma”, which is then filtered into
a regional lymph node. ( images/alveoli-268.htm) (f) After spreading through
the blood circulation, MTB can enter the CNS through the BBB, likely by a
Trojan horse mechanism. (g) Bacilli seed to the meninges or the brain
parenchyma, forming subpial or sub-ependymal primary complexes,
Clinical Manifestation
Typical Presentation
1. HA, fever, vomiting and AMS
Features that help distinguish TB meningitis from bacterial
meningitis
Subacute Onset (160 TB Meningitis patients): time between
onset of symptoms and clinical presentation
• < 1 week: 7%
• 1-3 weeks: 53%
• >3 weeks: 36%
• Bacterial Meningitis: <1 week
Pehlivanoglu et al: The Scientific World Journal Vol
2012
Clinical Manifestation (Cont’d)
2. Neurological changes: AMS, personality
changes and coma
3. Cranial nerve palsies (VI, III) – uncommon
with bacterial meningitis
Pehlivanoglu et al: The Scientific World Journal Vol 2012
Clinical Manifestation (Cont’d)
Sharma P et al: European Journal of Internal Medicine 2011
Complication:
1. Stroke : dense hemiplegia
Wasay et al: Stroke 2018
Complication: (Cont’d)
2. Seizures:
* primarily focal
* mechanism: meningeal irritation, infarction, and
hyponatremia
3. Hydrocephalus
N=80 with TB
Incidence:
65%
38.5% - mild HCP
61.5%- moderate or severe HCP
Raut et al: J Infect 2013
Complication: (Cont’d)
4. Hyponatremia
Mistra et al: Journal of the Neurological Sciences 2016
Complication: (Cont’d)
5. Vision loss
N= 101
¼ has vision impairment
Etiology: optochiasmatic
arachnoiditis/tuberculom
a
Predict death or severe
disability
Sinha et al: J Neurol Sci. 2010
Diagnosis:
Bedside evaluation with careful neurologic exam
Mental status, cranial nerves, sensory and motor exam, cerebellar function and reflex
Diagnostic tools
1. LP – Opening pressure is usually moderately elevated 18-30 cm H20
2. CSF Examination (acid-fast bacilli smear and culture, PCR)
3. Radiographic imaging
Diagnosis: (Cont’d)
Acid-fast bacilli smear and culture
Sensitivity: 30-60%
Sensitivity increased with volume of CSF (10-15 cc) and number of CSF specimens (up to 4)
Could be positive even days after initiation of treatment
Diagnosis: (Cont’d)
PCR
High sensitivity and specificity
Can be used in combination with AFB
smear and culture , but not substitute
Not approved by FDA
Negative PCR should not exclude TBM
given variability
Mycobacterial DNA may remain
detectable in CSF up to 1 month after
Rx initiation
Pormohammad A et al: Journal of Clinical Microbiology 2019
Diagnosis: (Cont’d)
Radiographic imaging
Copyrights apply
Treatment
Antituberculous therapy
Drug susceptible disease
• Intensive phase – four drug regimen x2 months
• Continuation phase- isoniazid and rifampin x7-10 months
Major Adverse Effect of TB
medications
Isoniazid:
Peripheral neuropathy
Add Vit B6 supplement (10-50 mg qD)
Rifampin:
Orange-red Urine
Potent inducer of P450 enzyme, therefore
major drug-drug interaction (warfarin,
oral contraceptives, cyclosporine,
glucocorticoids, ketoconazole, digitoxin,
verapamil, HIV-related proteinase
inhibitor, nifedipine, midazolam)
Ethambutol:
Treatment (Cont’d)
Antiretroviral treatment (HIV patient)
• Already on ART before TBM
• ART naiive: CDC/ATS/IDSA recommend inititation
of ART should be delayed for the first 8 weeks of
antituberculous therapy, regardless of CD4
count due to IRIS.
Treatment (Cont’d)
Glucocorticoids
WHO recommends 6-8 weeks of adjunctive
glucocorticoid therapy (decadron or prednisolone)
Decadron: 0.3-0.4 mg/kg/day IV x2 weeks with
taper
Prednisolone: 0.5 mg/kg/day PO x4 weeks with
taper
Prasad K et al: Cochrane Database of systematic Reviews 2016
Treatment (Cont’d)
Paradoxical worsening
- Unclear etiology, maybe due to
exaggerated immune response to
mycobacterial antigens
Singh et al: BMC Infectious Disease 2016
N= 141 TBM
31% developed paradoxical reaction
Outcome
Bedside prognostic score MASH-P- predict 6-month mortality
M: Modified Barthel Index
A: Age
S: Stage of TBM
H: Hydrocephalus
P: Papilledema
Outcome
Mortality of TB meningitis in hospitalized patients
Mortality of TB meningitis in meningitis patients
% %
study year sample cases ES (95% CI) Weight
study year sample cases ES (95% CI) Weight
Bergemann 1996 72 29 40.28 (28.88, 52.50) 13.73
Silber 1999 57 6 83.33 (35.88, 99.58) 9.93
Sung 1997 13 1 7.69 (0.19, 36.03) 8.49
Silber 1999 6 5 83.33 (35.88, 99.58) 5.64
Soumare 2005 470 11 45.45 (16.75, 76.62) 13.53
Soumare 2005 11 5 45.45 (16.75, 76.62) 7.85
Chapp-Jumbo 2006 1395 19 68.42 (43.45, 87.42) 16.79 Chapp-Jumbo 2006 19 13 68.42 (43.45, 87.42) 9.92
Yang 2007 19 5 26.32 (9.15, 51.20) 9.92
Yang 2007 1684 19 26.32 (9.15, 51.20) 16.79
Bhagwan 2011 4 3 75.00 (19.41, 99.37) 4.38
Xiao 2013 834 27 29.63 (13.75, 50.18) 18.67
Berhe 2012 78 42 53.85 (42.18, 65.21) 13.88
Watch 2017 8892 183 28.96 (22.51, 36.11) 24.30 Xiao 2013 27 8 29.63 (13.75, 50.18) 11.15
Watch 2017 183 53 28.96 (22.51, 36.11) 15.02
Overall (I^2 = 72.53%, p = 0.00) 42.12 (26.46, 58.53) 100.00
Overall (I^2 = 75.42%, p = 0.00) 41.06 (29.39, 53.20) 100.00
0 25 50
0 25 50 Percentage (%)
Percentage (%)
Cumulative Mortality
study (year) . (95% CI)
Bergemann (1996) 0.40 (0.28, 0.52)
Sung (1997) 0.25 (-0.07, 0.57)
Silber (1999) 0.41 (0.08, 0.75)
Soumare (2005) 0.42 (0.16, 0.68)
Chapp-Jumbo (2006) 0.47 (0.24, 0.71)
Yang (2007) 0.43 (0.24, 0.63)
Bhagwan (2011) 0.47 (0.28, 0.66)
Navarro-Flores et al: Journal of
Berhe (2012) 0.47 (0.32, 0.63)
Neurology March 2022
Xiao (2013) 0.45 (0.31, 0.59)
Watch (2017) 0.42 (0.31, 0.54)
-.5 0 .5
Cases x 1000 inhabitants
