reminiscences from Indian Pediatrics: A tale
of 50 years |
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Indian Pediatr 2016;53:
416-417 |
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Tubercular Meningitis – A Tale of 50
Years
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Preeti Singh and *Anju
Seth
From the Department of Pediatrics, Lady Hardinge Medical College, New
Delhi, India.
Email: *[email protected]
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In
1966, the 34-paged May issue of Indian Pediatrics had four
original articles besides two case reports, current literature, notes
and news. Amongst these, we decided to review the original article on
tubercular meningitis as despite the advances in diagnosis and
management, it still continues to be a major scourge responsible for
mortality and morbidity in Indian children.
The Past
The article by Manchanda, et al. [1], in
May 1966 issue of Indian Pediatrics, is a retrospective review of
records of tuberculosis (TB) cases in children (age <14 y) admitted at
VJ Hospital, Amritsar from 1955 to 1965. Of 21,728 pediatric admissions
over 10 years, 742 (3.4%) were due to TB, of which 249 (33.6%) were
complicated by tubercular meningitis (TBM). Amongst the cases with TBM,
75.1% were boys, 57.5% were aged below 3 years, 71.9% were from urban
areas, and 50% were in clinical stage III at admission. The mortality
rate was 51% (127/249); 65.4% of the deaths were in children aged below
5 years, and 80% of those who died were in clinical stage 3 at
admission. The chief causes of death were progressive hydrocephalus,
bulbar palsy and hyperpyrexia. Of the 122 cases who were discharged, 70
were designated as relieved, while 52 (20.9%) were in such a poor state
that authors thought they were unlikely to have survived. Thus, the
presumed mortality was 71.9%. The follow-up data was available in 49 of
the 70 survivors. Of these, 28 were labelled as cured (11.2%) without
sequelae while 21 had sequelae, including hemiplegia (8), generalized
rigidity (3), facial palsy (1), deafness (3), optic atrophy (6),
choreoathetoid movements (2), hypotonia (1), hydrocephalus (2) and
behaviour disturbances (3). The article did not describe the diagnostic
criteria for TBM or the treatment given to the included cases.
Historical background and past knowledge: The
earliest published clinical vignette on TBM is credited to Robert Whyth
in 1768 for his treatise ‘Dropsy in the brain’ [2]. The patho-physiology
of TBM was unravelled by Arnold Rich and McCordock in 1933 [3]. Before
the mid-20th century, childhood TB was uniformly fatal. The introduction
of isoniazid in early 1950’s revolutionized the treatment of TB. For
nearly two decades, the standard treatment comprised of combination of
isoniazid and streptomycin, following which rifampicin was introduced.
Still, the mortality was very high, and significant proportions were
left with physical and mental disabilities due to delay in treatment
initiation and poor compliance. To strengthen the fight against TB, the
Government of India launched "District Tuberculosis Control Programme"
in 1962 which focussed on prevention, control and management of the
disease in both urban as well as rural areas. At the time of publication
of this article [1], there existed wide disparity in the reported
incidence (0.5-13%) of TBM in India, and its true situation was
difficult to determine because of diagnostic uncertainties and poor case
notification. In most cases, the diagnosis was presumptive, based on
clinical suspicion and circumstantial evidence as bacteriological
confirmation was often not possible.
The Present
In India, pediatric TB has received attention as a
major public health problem, especially during the last two decades.
After lymphadenopathy, TBM is second commonest cause of extra-pulmonary
TB affecting children < 3 years of age [4]. TB-Immune reconstitution
inflammatory syndrome (IRIS) has emerged as a dreaded complication in
HIV-TB co-infection due to restoration of immune function after
initiation of anti-retroviral therapy.
The diagnosis of TBM in children in most
resource-limited settings with high disease prevalence is still based on
comprehensive clinical assessment along with supportive investigations
such as a positive tuberculin skin test, a family history of
tuberculosis, and/radiological evidence of pulmonary TB. The
bacteriological confirmation is not always possible due to poor
sensitivity of Z-N staining of acid fast bacilli in CSF and low yield
and delay in processing culture results. The diagnostic precision in CSF
cultures has however improved by concordant use of L-J medium and
Automated Culture Systems. The advent of Cartridge-based Nucleic Acid
Amplification Test (CBNAAT) like Xpert MTB/Rif/Gene Xpert has enhanced
the diagnostic yield from various body specimens, including CSF. The
Xpert for CSF specimens offer higher sensitivity (59-84%) and
specificity (73-89%) than conventional tools [5]. It is endorsed by WHO
[6] and recommended as preferred initial test in suspected TBM, MDR-TB,
co-infection with HIV and severe illness. CSF biomarkers
(interleukin-13, vascular endothelial growth factor and cathelicidin
LL-37) have a huge potential for improving diagnosis and management but
are still in experimental phase [7]. Neuro-imaging has a significant
adjunctive role in diagnosis of TBM especially at an early stage of
disease, in cases of diagnostic dilemma and to detect complications.
As recommended by the WHO, British Infection Society,
as well as the current National guidelines for Pediatric TB [8],
treatment regimen of TBM consists of initial 2 months of isoniazid,
rifampicin, pyrazinamide, and ethambutol followed by 10 months of
isoniazid and rifampicin. Corticosteroids have an undisputed supportive
role in reducing mortality and morbidity from severe neurological
disability [9], and have been recommended by the above guidelines. The
addition of newer generation fluroquinolones to standard anti-tubercular
regimen or intensified regime of fluroquinolones with high dose
Rifampicin is shown to improve outcome [10]. The evolution of MDR-TB has
posed new challenges for which WHO has recently published guidelines
[11]. The Food and Drug Administration (FDA) approved new drug ‘Bedaquiline
fumarate’ for MDR-TB has been introduced in India on World Tuberculosis
Day, March 2016. Surgical interventions like ventriculo-peritoneal shunt
placement and endoscopic third ventriculostomy are now available in
cases of non-communicating hydrocephalus and failure of medical
management.
In the present era, prompt optimal treatment along
with good supportive care initiated in clinical stage 1 of TBM offers
almost universal survival. A recent meta-analysis on treatment outcomes
on children with TBM reported risk of mortality as 19·3% (95% CI 14·0,
26·1). Among survivors, risk of neurological disability was 53·9% (95%
CI 42·6, 64·9) while the probability of intact survival was 36·7% (95%
CI 27·9, 46·4) [12]. However, long term behavioral disinhibitions and
internalized emotional disorders may persist despite optimal management.
References
1. Manchanda SS, Lal H. Tuberculous meningitis in
children- a problem unsolved in India. Indian Pediatr.1966;3:167-76.
2. Ruhrah J. The history of tuberculous
meningitis. Medical Library and Historical Journal. 1904;2:160-5.
3. Rich AR, McCordock HA. The pathogenesis of
tuberculous meningitis. Bull Johns Hopkins Hosp.1933;52:5-37.
4. Marais BJ, Gie RP, Schaaf HS, Hesseling AC,
Enarson DA, Beyers N. The spectrum of childhood tuberculosis in a
highly endemic area. Int J Tuberc Lung Dis. 2006;10:732-8.
5. Patel VB, Theron G, Lenders L, Matinyena B,
Connolly C, Singh R, et al. Diagnostic accuracy of
quantitative PCR (XpertMTB/RIF) for tuberculous meningitis in a high
burden setting: A prospective study. PLoS Med. 2013;10:e1001536.
6. World Health Organization. Automated Real-Time
Nucleic Acid Amplification Technology for Rapid and Simultaneous
Detection of Tuberculosis and Rifampicin Resistance: Xpert MTB/RIF
System for the Diagnosis of Pulmonary and Extrapulmonary TB in
Adults and Children. Geneva, WHO, 2013.
7. Visser DH, Solomons RS, Ronacher K, van Well
GT, Heymans MW, Walzl G, et al. Host immune response to
tuberculous meningitis. Clin Infect Dis. 2015;60:177-87.
8. Kumar A, Gupta, D, Nagaraja SB, Singh V, Sethi
GR, Prasad J. Updated National Guidelines for Pediatric Tuberculosis
in India, 2012. Indian Pediatr. 2013;50:301-6.
9. Prasad K, Singh MB. Corticosteroids for
managing tuberculous meningitis. Cochrane Database Syst Rev.
2008;1:CD002244.
10. Thwaites GE, Bhavnani SM, Chau TT, Hammel JP,
Torok ME, Van Wart SA, et al. Randomized pharmacokinetic and
pharmacodynamic comparison of fluoroquinolones for tuberculous
meningitis. Antimicrob Agents Chemother. 2011;55:3244-53.
11. WHO Guidelines for the Programmatic
Management of Drug-Resistant Tuberculosis. 2011 Update. Available
from:http://www.who.int/tb/challenges/mdr/programmatic_guidelines_for_mdrtb/en/
Accessed March 10, 2016.
12. Chiang SS, Khan FA, Milstein MB, Tolman AW, Benedetti A, Starke
JR, et al. Treatment outcomes of childhood tuberculous
meningitis: A systematic review and meta-analysis. Lancet Infect Dis.
2014;14:947-57.
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