Professional Documents
Culture Documents
Definite (Microbiologically Confirmed) Tuberculous Meningitis: Predictors and Prognostic Impact
Definite (Microbiologically Confirmed) Tuberculous Meningitis: Predictors and Prognostic Impact
DOI 10.1007/s15010-015-0756-z
ORIGINAL PAPER
13
S. K. Jha et al.
acid-fast bacilli positivity on microscopy and 35 % posi- system of diagnostic scores. Definite cases were defined
tivity for culture [3]. In a prospective observational study by demonstration of tubercle bacilli in CSF either by
from Indonesia, only 11 % of CSF samples, taken from microscopy, culture, or tuberculosis PCR. Tuberculous
207 suspected cases of tuberculous meningitis, were tested meningitis was considered probable, if patients scored 10
positive by Ziehl–Neelsen staining. A low percentage of or more diagnostic points (when cerebral imaging is not
CSF samples yielded growth of Mycobacterium tuberculo- available) or 12 or more diagnostic points (when cerebral
sis by solid culture (36 %) and liquid culture (44 %). The imaging is available) along with exclusion of alternative
diagnostic yield of IS6110-PCR was much higher (68 %) differential diagnoses. Possible cases had a total diag-
[4]. A study from Vietnam reported CSF sensitivities for nostic score of 6–9 points (when cerebral imaging is not
Xpert MTB/RIF, Ziehl–Neelsen smear, and mycobacte- available) or 6–11 points (when cerebral imaging is avail-
rial growth indicator tube culture, of 59.3 % (108/182), able) along with exclusion of alternative differential diag-
78.6 % (143/182), and 66.5 % (121/182), respectively [5]. noses [6]. We divided the patients into two groups; defi-
Xpert MTB/RIF is a fully automated diagnostic molecu- nite tuberculous meningitis (bacteriologically confirmed)
lar test meant for rapid demonstration of Mycobacterium and non-definite tuberculous meningitis (probable and
tuberculosis in various biological materials. It also detects possible cases).
rifampicin drug resistance.
The matter of early microbiological diagnosis of tuber- Exclusion criteria
culous meningitis is crucial because early treatment
improves the prognosis. In many developing and poor Patients with cryptococcal meningitis or any other cause
countries, resources to confirm the diagnosis of tuberculous for meningitis were excluded from the study (Fig. 1).
meningitis microbiologically are limited and are often not
available in time. Clinicians, most of the time, have to rely Evaluation
on clinical parameters for the diagnosis. We sought to iden-
tify epidemiological, clinical, CSF, and imaging param- All included patients were subjected to a detailed clinical
eters that could indicate microbiological confirmation, evaluation. A battery of routine hematological and bio-
among patients with suspected tuberculous meningitis. chemical tests like complete blood count with peripheral
We also assessed the prognostic impact of microbiological smear examination, erythrocyte sedimentation rate, blood
confirmation. sugar, blood urea nitrogen and serum creatinine, liver func-
tion tests, serum electrolytes, chest X-ray, and antibodies
against human immunodeficiency virus by enzyme-linked
Materials and methods immunosorbent assay were performed. CSF routine exami-
nation was done for cells, glucose, protein, and Gram’s
This study was conducted in the Department of Neurology, staining including India ink preparation and corresponding
King George Medical University, Lucknow. Our institu- blood sugar level.
tion is a tertiary care medical facility catering to approxi-
mately 100 million population of North India. The patients Neuroimaging
were enrolled from October 2012 to January 2014. Insti-
tutional Ethics Committee of the university approved the Gadolinium-enhanced brain MRI was performed with a
study. Written informed consent was obtained from all the Signa Excite 1.5 tesla instrument (General Electric Medi-
patients or their legal guardians. cal Systems, Milwaukee, WI, USA). An experienced neu-
roradiologist unaware of treatment and patient outcome
Inclusion criteria reviewed the MR scans. Neuroimaging features recorded
were abnormal enhancement of the leptomeninges, tuber-
In this prospective follow-up study, we enrolled consecu- culomas, hydrocephalus (communicating or non-communi-
tive patients with suspected tuberculous meningitis who cating), and infarcts.
were 14 years of age or older. These patients had pre-
sented with clinical evidence of tuberculous meningitis Bacteriological confirmation
and had characteristic CSF abnormalities (mononuclear
cell pleocytosis, low glucose levels, elevated protein lev- CSF microscopy for tuberculosis was done by Ziehl–
els). All included patients fulfilled the consensus tuber- Neelsen staining. CSF culture was done by solid culture
culous meningitis criteria. According to these criteria, method, on Lowenstein Jensen media. Drug susceptibility
patients were categorized into definite, probable, and testing was done. Growth was monitored for 8 weeks and
possible tuberculous meningitis groups, depending on a the mycobacterial species identified in positive cultures.
13
Predictors and prognostic impact
PCR was done by real-time PCR. DNA amplification of score of 15 with neurological deficit (cranial nerve palsies)
mpt64 gene for Mycobacterium tuberculosis was done by or Glasgow Coma Scale score of 11–14, and patients with
real-time DNA detection technique [7]. stage III had Glasgow coma scale score <10 or multiple
cranial nerve palsies, hemiplegia, or paraplegia [8]. Dis-
Disease severity ability assessment was done using modified Barthel index,
which is a 20-point scoring system. A score of ≤12 indi-
All patients were assessed by Glasgow Coma Scale, modi- cated a poor functional status (death scored as zero) while a
fied tuberculous meningitis staging criteria by Thwaites score of >12 indicated a good functional status.
and co-workers, and modified Barthel index scoring sys-
tem. According to the staging criteria given by Thwaites Treatment
and co-workers: patients with stage I disease had a Glas-
gow Coma Scale score of 15 with no focal neurologic Patients were treated with anti-tuberculosis treatment pro-
signs, patients with stage II had a Glasgow Coma Scale tocol recommended by the World Health Organization.
13
S. K. Jha et al.
13
Predictors and prognostic impact
Table 1 Baseline epidemiological, clinical, and neuroimaging characteristics of patients with tuberculous meningitis (n = 118)
Characteristics Definite TBM (n = 43) Patients with probable + possible TBM (n = 75) p value
Table 2 Outcome assessment at 6 months stage III (p = 0.004) were independently associated with
Definite TBM (n = 43) Patients with prob- p value poor outcome (Table 3).
able + possible TBM
(n = 75)
MBI ≤ 12 13 14 0.001
Discussion
MBI > 12 17 54
In this study, approximately one-third of patients with
Death 13 7
suspected tuberculous meningitis had microbiologi-
p value = death or MBI ≤12 versus MBI >12 cal confirmation of their clinical diagnosis. Our anal-
MBI modified Barthel index, TBM tuberculous meningitis ysis revealed that three factors (severe disability at
13
S. K. Jha et al.
13
Predictors and prognostic impact
ethionamide has been shown to produce a higher concen- meningitis in a cohort of adult patients in Indonesia. PLoS ONE.
tration of anti-tuberculosis drugs in the CSF. This short 2012;7:e52001.
5. Nhu NT, Heemskerk D, Thu do DA, Chau TT, Mai NT, Nghia
intensified treatment was found to be safe and effective HD, et al. Evaluation of GeneXpert MTB/RIF for diagnosis of
in children with drug-susceptible tuberculous meningitis tuberculous meningitis. J Clin Microbiol. 2014;52:226–33.
[16]. These newer anti-tuberculosis regimens should be 6. Marais S, Thwaites G, Schoeman JF, Török ME, Misra UK,
subjected to rigorous randomized controlled trials before Prasad K, et al. Tuberculous meningitis: a uniform case definition
for use in clinical research. Lancet Infect Dis. 2010;10:803–12.
they can be recommended for every-day practice. Benefit 7. Bhanu NV, Singh UB, Chakraborty M, Suresh N, Arora J, Rana
of adding a fluoroquinolone (levofloxacin or moxifloxacin) T, et al. Improved diagnostic value of PCR in the diagnosis of
should also be investigated. female genital tuberculosis leading to infertility. J Med Micro-
Low yield of mycobacterial culture, lack of a group biol. 2005;54(Pt 10):927–31.
8. Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT,
comprising HIV co-infected patients, and deficient data Nguyen TC, et al. Dexamethasone for the treatment of tuber-
regarding multidrug resistance were major limitations of culous meningitis in adolescents and adults. N Engl J Med.
our study. The diagnosis of probable or possible tubercu- 2004;351:1741–51.
lous meningitis is determined by a diagnostic scoring sys- 9. World Health Organization. Treatment of tuberculosis: guidelines.
4th ed. (WHO/HTM/TB/2009.420) World Health Organization,
tem and such cases may have other diagnoses. Although http://whqlibdoc.who.int/publications/2010/9789241547833_
HIV infection does not alter the neurological features of eng.pdf (2010). Accessed 25 Sept 2014.
tuberculous meningitis, it significantly reduces the sur- 10. Thwaites GE, Chau TT, Stepniewska K, Phu NH, Chuong LV,
vival rate [17]. Presence of HIV co-infected patients Sinh DX, et al. Diagnosis of adult tuberculous meningitis by use
of clinical and laboratory features. Lancet. 2002;360:1287–92.
in our study would have shed more light on this aspect. 11. Thwaites GE, Chau TT, Farrar JJ. Improving the bacterio-
Drug-resistant tuberculous meningitis is a serious and fast- logical diagnosis of tuberculous meningitis. J Clin Microbiol.
increasing clinical problem which is associated with a high 2004;42:378–9.
mortality [18]. 12. Feng GD, Shi M, Ma L, Chen P, Wang BJ, Zhang M, et al. Diag-
nostic accuracy of intracellular Mycobacterium tuberculosis
In conclusion severe disability, cerebrospinal fluid cells detection for tuberculous meningitis. Am J Respir Crit Care Med.
>100 mm3, and basal exudates are significantly related to 2014;189:475–81.
the presence of microbiologically confirmed definite tuber- 13. Thwaites GE, van Toorn R, Schoeman J. Tuberculous men-
culous meningitis. Microbiologically confirmed tubercu- ingitis: more questions, still too few answers. Lancet Neurol.
2013;12:999–1010.
lous meningitis is associated with poorer outcome. 14. Botha H, Ackerman C, Candy S, Carr JA, Griffith-Richards S,
Bateman KJ. Reliability and diagnostic performance of CT imag-
Conflict of interest None for all the authors. ing criteria in the diagnosis of tuberculous meningitis. PLoS
ONE. 2012;7:e38982.
15. Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der
Ven AJ, et al. Intensified regimen containing rifampicin and mox-
References ifloxacin for tuberculous meningitis: an open-label, randomised
controlled phase 2 trial. Lancet Infect Dis. 2013;13:27–35.
1. Graham SM, Donald PR. Death and disability: the outcomes of 16. Turkova A, Seddon JA, Nunn AJ, Gibb DM. Phillips PP. Short
tuberculous meningitis. Lancet Infect Dis. 2014;14:902–4. intensified treatment in children with drug-susceptible tubercu-
2. Chin JH. Tuberculous meningitis: diagnostic and therapeutic lous meningitis. Pediatr Infect Dis J. 2014;33:993.
challenges. Neurol Clin Pract. 2014;4:199–205. 17. Thwaites GE, Duc Bang N, Huy Dung N, Thi Quy H, Thi Tuong
3. Chiang SS, Khan FA, Milstein MB, Tolman AW, Benedetti A, Oanh D, Thi Cam Thoa N, et al. The influence of HIV infection on
Starke JR, et al. Treatment outcomes of childhood tuberculous clinical presentation, response to treatment, and outcome in adults
meningitis: a systematic review and meta-analysis. Lancet Infect with tuberculous meningitis. J Infect Dis. 2005;192:2134–41.
Dis. 2014;14:947–57. 18. Garg RK, Jain A, Malhotra HS, Agrawal A, Garg R. Drug-
4. Chaidir L, Ganiem AR, Vander Zanden A, Muhsinin S, Kusuman- resistant tuberculous meningitis. Expert Rev Anti Infect Ther.
ingrum T, Kusumadewi I, et al. Comparison of real time IS6110- 2013;11:605–21.
PCR, microscopy, and culture for diagnosis of tuberculous
13