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Table of Contents    
NI FEATURE: THE QUEST - ORIGINAL ARTICLE
Year : 2019  |  Volume : 67  |  Issue : 3  |  Page : 787-791

Guidelines versus ground lines: Tuberculosis of the central nervous system


1 Department of Neurology, Bombay Hospital, Mumbai, Maharashtra, India
2 Department of Neurology, Grant Medical College and Sir Jamshedjee Jeejeebhoy Group of Hospitals, Mumbai, Maharashtra, India
3 Department of Neurology, Deenanath Mangeshkar Hospital, Pune, Maharashtra, India
4 Department of Neurology, Brain and Mind Institute, Nagpur, Maharashtra, India
5 Department of Preventive and Social Medicine, Grant Medical College, Mumbai, Maharashtra, India
6 Department of Neurology, Sterling Hospital, Ahmedabad, Gujarat, India

Date of Web Publication23-Jul-2019

Correspondence Address:
Dr. Satish V Khadilkar
Room No. 110, First Floor, New Wing, Bombay Hospital Institute of Medical Sciences, 12, New Marine Lines, Mumbai - 400 020, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.263198

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 » Abstract 

Aim: This questionnaire-based national survey is aimed at understanding the patterns of practice of various aspects of central nervous system (CNS) tuberculosis (TB) among neurologists.
Settings and Design: Neurology department of a tertiary medical college.
Materials and Methods: A questionnaire was sent through email to all practicing neurologists in India. The responses were analyzed.
Statistical Analysis: Inferential statistics.
Results: In all, 144 responses were received (out of the 853 questionnaires sent). The major discrepancies were in the primary antitubercular drug regimen (HRZE + HR), duration for tubercular meningitis (TBM) [12 months] and tuberculoma (12–18 months) to develop, follow-up (varied), linezolid use (varied), proportion of drug-resistant cases (<25%), and not taking histological aids (91%). The cerebrospinal fluid (CSF) TB polymerase chain reaction (PCR) utility (75%), not using CSF adenosine deaminase [ADA] (58%), the strategy to stop antitubercular drugs, and the use of steroids (77%) were according to guidelines.
Conclusion: The present survey, for the first time, provides ground-level evidence of various aspects of CNS TB as practiced by neurologists in India. The major diversity was observed in therapeutics such as the choice of antitubercular drugs, its duration, linezolid use beyond the recommended duration, and knowledge of drug resistance. The monitoring aspects of CNS TB also showed variations. The investigational aspects of CNS TB such as using TB PCR, not using CSF ADA, and regular neuroimaging revealed a good clinical practice. Other CSF parameters require uniformity. This survey thus helps to identify areas of future work in CNS TB in India.


Keywords: CNS tuberculosis, online survey, practice guidelines
Key Message: This national survey of neurologists brings to attention the issues related to diagnosis, therapy, and monitoring aspects of TB of CNS, as practiced at ground level by neurologists in India. This will guide the direction of further work in CNS TB.


How to cite this article:
Khadilkar SV, Kadam ND, Kulkarni RV, Meshram CM, Meshram AR, Patel BA, Chheda AH. Guidelines versus ground lines: Tuberculosis of the central nervous system. Neurol India 2019;67:787-91

How to cite this URL:
Khadilkar SV, Kadam ND, Kulkarni RV, Meshram CM, Meshram AR, Patel BA, Chheda AH. Guidelines versus ground lines: Tuberculosis of the central nervous system. Neurol India [serial online] 2019 [cited 2019 Aug 21];67:787-91. Available from: http://www.neurologyindia.com/text.asp?2019/67/3/787/263198




Central nervous system (CNS) tuberculosis (TB) comprises 15%–20% of the total cases of extra-pulmonary TB (EPTB).[1] Pulmonary TB is diagnosed and managed with standard guidelines, but there has been a significant lack of uniformity in the management of EPTB, including CNS TB. Approaches toward the diagnosis and therapy of TB of the nervous system are known to vary, and various regimens are in vogue.[2],[3],[4],[5] The emergence of multiple drug-resistant tubercle bacilli has compounded these issues. Hence, there is a need to survey the current diagnostic and treatment patterns among neurologists in India, a country where TB is common.

This questionnaire-based survey of neurologists at the national level was aimed at understanding the approach of Indian neurologists in diagnosing and treating this potentially life-threatening infectious disease.


 » Materials and Methods Top


The survey was carried out in the department of neurology of a tertiary care hospital from September 2016 to January 2017. The study was approved by the institutional ethics committee.

Inclusion criteria: All neurologists practicing in India were included.

Exclusion criteria: Those who were not willing to participate in the survey were excluded.

An online questionnaire comprising multiple choice questions directed toward understanding of clinical, diagnostic, therapeutic, monitoring, and other practices in CNS TB (appendix A) was sent to all neurologists whose data were available with the Indian Academy of Neurology. A total of 20 questions were included. The questionnaire was designed in such a way that the participants ticked on only one option per question. Anonymity of the responses was ensured. Responses were recorded electronically, tabulated manually, and treated as a sample size for further analysis.

Statistical methods

Appropriate statistical tests were applied to analyze the responses of each question. T-test was used to find the significance of responses with 95% confidence interval (CI). Statistical analysis was performed using statistical software (IBM), Statistical Package for the Social Sciences (SPSS) 22.


 » Results Top


Out of 853 neurologists, 144 responded to the questionnaire. The responses were analyzed in four groups. The groups were clinical and diagnostic, therapeutic, monitoring parameters, and other practices [Table 1].
Table 1: Responses to questionnaire

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 » Discussion Top


This questionnaire-based survey has raised many interesting observations about the variations in responses in relation to the diagnosis, therapeutics, monitoring, and other practices for CNS TB in India.

Group 1: Clinical and diagnostics parameters

Among this group, variations in responses were very significant.

The priority issue is of diagnostic aids which are currently used by neurologists to diagnose CNS TB. The survey detected large discrepancy in the acceptable values for diagnostic cerebrospinal fluid (CSF) cell counts and proteins [Table 1]. These variations in the responses were statistically significant [Table 2]. When compared with the established diagnostic criteria, the threshold of Indian neurologists towards assessing CSF cells and proteins seems to be low.[6],[7] This statistically significant low threshold for diagnosis may be a reflection of the fact that TB is endemic in India. Although this practice benefits in providing an increased therapy coverage, over-treatment is often an issue. Analysis of the responses for the use of CSF adenosine deaminase (ADA) and/or TB polymerase chain reaction (PCR) clearly showed that the majority of neurologists do not use CSF ADA marker, even though it is a recommended practice.[8],[9] The use of TB PCR (75%), on the other hand, is encouraging as the test has a sensitivity of 80.5% and a specificity of 97.8%, which makes it a mandatory test for all suspected CNS TB cases.[10],[11]
Table 2: Statistical analysis of each parameter with use of inferential statistics

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Constitutional symptoms are well-recognized in all forms of TB including CNS TB.[6] Yet, a large number of neurologists (63%) do not screen it routinely [Table 1] and [Table 2]. This may be because of their role as referral physicians. Also, neurologists (41%) consider the criterion of a 5-day duration as short, in variance with the literature.[7],[12] Some patients, hence, may not receive therapy on this basis.

Group 2: Therapeutic parameters

The most controversial aspect of the CNS TB is its treatment; the present survey is not an exception. There are variations in practice regarding the number of drugs used in both the intensive and continuation phases [Table 1]. This variability of responses was found to be statistically significant [Table 2]. Index TB guidelines 2016 and World Health Organization (WHO) 2014 guidelines give clear recommendation for the use of HRZ E or S + HR with an individualized variation in selection of the fourth drug.[2],[3] Previously, WHO 2011 and British Infection Society 2009 advocated the use of HRZE + HR as a primary regimen.[4],[5] This survey detects that a large number of neurologists are practicing older guidelines and there is need for awareness with regard to the recent changes.

There is significant variation among the existing guidelines and ground-level clinical practice in the duration of antitubercular therapy (ATT) in CNS TB [Table 1]. The index TB guideline advocates at least 9 months treatment for TBM, whereas WHO 2014 advocates at least 12months of therapy.[2],[9] British Infection Society 2009 suggests therapy for 12 months.[5] This survey showed that neurologists prefer a longer duration of treatment, extending up to 18 months or longer. This shows that a comparative evaluation of various durations will be essential to derive the optimal duration of therapy. Longer treatments are logically expected to increase the toxicity of ATT drugs and morbidity related to the disease. Whether they increase the efficacy is open to speculation. The survey brought out the need to establish treatment duration paradigms.

When choosing the second-line anti-TB drugs, linezolid seems to be used by a proportion of Indian neurologists. What is of concern is those who use it seem to continue it beyond the recommended duration. The awareness that the maximum recommended duration for linezolid is 4 weeks needs to be increased, as severe neuropathies are known to occur with the use of linezolid. The recommended place for the use of linezolid, for life-threatening TBM, also needs to be propagated. The use of steroids in all cases, regardless of severity, is noteworthy. This survey reiterates the same, and the Cochrane review database and a number of other published trials support it.[13],[14],[15]

Group 3: Monitoring parameters

Diversities of opinion regarding the radiological follow-up of CNS TB [Table 1] were evident in this survey. Very few neurologists see the need for frequent radiological follow-ups. Available guidelines stress on repeating neuroimaging at 3 and 9–12 months to monitor the response to treatment.[2] Follow-ups are also important in recognizing treatment failures (when lesions either increase in size or fail to reduce in size after 3–6 months of ATT despite appropriate dosing and a good adherence to the treatment protocol). This fact assumes importance, given the increasing emergence of drug-resistant CNS TB.

Another grey area is an end point of therapy. Randomized controlled trials to address this issue are not available.[16] For tuberculomas of the CNS, the WHO 2011 Report on Global TB Control states that “the treatment can be tailored according to the clinical and radiological response.”[4] Although in the present survey, the majority of neurologists opined that clinical and radiological improvement should be taken to decide on the end point, standardized regimens will need to be evolved with well-defined end points and a long-term follow-up.

Group 4: Other practices

The percentages of drug-resistant CNS TB cases seen by neurologists were fewer when compared with the estimates based on pulmonary TB [Table 1]. This may be because of the fact that the suspicion of multidrug-resistant (MDR) CNS TB is extremely difficult to maintain unless there is a history of contact with a MDR TB case.[17] A fact of concern is the lack of awareness of the local drug resistance pattern among neurologists. Such an unawareness needs urgent attention as MDR TB accounts for 2.1% of new cases and 15% of re-treatment cases.[18] Moreover, local resistance patterns are known to be different, the knowledge of which is vital.[19],[20]

Another underdeveloped area is the histological diagnosis in CNS tuberculoma. A majority of the surveyed neurologists refrain from obtaining a biopsy [Table 1]. The available literature emphasizes the role of brain biopsy to establish the definitive diagnosis of CNS granuloma, as imaging techniques have limitations.[21] The reluctance to biopsy may reflect issues related to lack of facilities for conducting a biopsy, as well as of pathological and bacteriological support to analyze the samples. This has perhaps resulted in underreporting of non-TB granulomas and an apparent increase in drug-resistant situations.


 » Conclusion Top


The present survey, for the first time, provides ground-level evidence about various aspects of CNS TB among Indian neurologists. Comparing the available guidelines with the ground lines provided by this survey, detects areas of concern and requirements for further work.

Highlights

1. There are multiple caveats in the therapeutics of the CNS TB which surfaced from this survey:

  1. Therapeutic regimens are variable
  2. Duration of therapy is longer than guidelines suggest
  3. Linezolid is used beyond the recommended duration
  4. Follow-up patterns are variable
  5. End points of therapy are undefined
  6. There is under-utilization of the histology to unequivocally establish the diagnosis.


This survey thus helps identify areas of future work in CNS TB in India.

Acknowledgements

The authors thank the Indian Academy of Neurology for their support and Unichem Pharmaceuticals for their help in the facilitation of this survey.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120;316-53.  Back to cited text no. 1
    
2.
Central TB Division, Ministry of Health and Family Welfare, Government of India. Index Tb guidelines—Guidelines for extrapulmonary tuberculosis for India; 2016. Available from: http://www.icmr.nic.in/guidelines/TB/Index-TB%20Guidelines%20-%20green%. [Last accessed on 2017 Mar 09].  Back to cited text no. 2
    
3.
Van Loenhout-Rooyackers JH, Keyser A, Laheij RJ, Verbeek AL, van der Meer JW. Tuberculous meningitis: Is a 6-month treatment regimen sufficient? Int J Tuberc Lung Dis 2011;5:1028-35.  Back to cited text no. 3
    
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World Health Organization. Global Tuberculosis Control. Geneva, Switzerland: WHO; 2011.  Back to cited text no. 4
    
5.
Thwaites GF. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect 2009;59:167-87.  Back to cited text no. 5
    
6.
Marais S, Thwaites G, Schoeman JF, Török ME, Misra UK, Prasad K, et al. Tuberculous meningitis: A uniform case definition for use in clinical research. Lancet Infect Dis 2010;10;803-12.  Back to cited text no. 6
    
7.
Youssef FG, Afifi SA, Azab AM, Wasfy MM, Abdel-Aziz KM, Parker TM, et al. Differentiation of tuberculous meningitis from acute bacterial meningitis using simple clinical and laboratory parameters. Diagn Microbiol Infect Dis 2006; 55:275-8.  Back to cited text no. 7
    
8.
Chawla RK, Seth RK, Raj B, Saini AS. Adenosine deaminase levels in cerebrospinal fluid in tuberculosis and bacterial meningitis. Tubercle 1991;72;190-2.  Back to cited text no. 8
    
9.
Radhakrishnan VV, Mathai A. Detection of Mycobacterium tuberculosis antigen 5 in cerebrospinal fluid by inhibition ELISA and its diagnostic potential in tuberculous meningitis. J Infect Dis 1991;163:650-2.  Back to cited text no. 9
    
10.
Shankar P, Manjunath N, Srinivas, Mohan KK, Prasad K, Behari M, et al. Rapid diagnosis of tuberculous meningitis by polymerase chain reaction. Lancet 1991;337:5-7.  Back to cited text no. 10
    
11.
Takahashi T, Tamura M, Takasu T. The PCR-based diagnosis of central nervous system tuberculosis: Up to date. Tubercul Res Treat 2012;2012;:17.  Back to cited text no. 11
    
12.
Thwaites GE, Chau TT, Stepniewska K, Phu NH, Chuong LV, Sinh DX, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Lancet 2002; 360;1287-92.  Back to cited text no. 12
    
13.
Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008;23:CD002244.  Back to cited text no. 13
    
14.
Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Nguyen TC, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351;1741-51.  Back to cited text no. 14
    
15.
Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991;10;179-83.  Back to cited text no. 15
    
16.
Prasad K, Sahu JK. Duration of anti-tubercular treatment in tuberculous meningitis: Challenges and opportunity. Neurol India 2010;58;723-6.  Back to cited text no. 16
    
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Murthy J. Multi-drug-resistant central nervous system tuberculosis. Neurol India 2012;60:143-5.  Back to cited text no. 17
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WHO Report: Global Tuberculosis Control 2011. WHO/HTM/TB/2011.16.  Back to cited text no. 18
    
19.
Menon S, Dharmshale S, Chande C, Gohil A, Lilani S, Mohammad S, et al. Drug resistance profiles of Mycobacterium tuberculosis isolates to first line anti-tuberculous drugs: A five years study. Lung India 2012;29:227-31.  Back to cited text no. 19
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Dusthackeer A, Sekar G, Chidambaram S, Kumar V, Mehta P, Swaminathan S. Drug resistance among extrapulmonary TB patients: Six years experience from a supranational reference laboratory. Indian J Med Res 2015;142:568-74.  Back to cited text no. 20
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Bouchama A, Al-Kawi MZ, Kannan I. Brain biopsy in tuberculoma: The risks and benefits. Neurosurgery 1991;28:405-8.  Back to cited text no. 21
    



 
 
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