Guidelines versus ground lines: Tuberculosis of the central nervous system
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.263198
Source of Support: None, Conflict of Interest: None
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.
Keywords: CNS tuberculosis, online survey, practice guidelines
Central nervous system (CNS) tuberculosis (TB) comprises 15%–20% of the total cases of extra-pulmonary TB (EPTB). 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.,,, 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.
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.
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.
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].
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., 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., 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.,
Constitutional symptoms are well-recognized in all forms of TB including CNS TB. 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., 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., Previously, WHO 2011 and British Infection Society 2009 advocated the use of HRZE + HR as a primary regimen., 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., British Infection Society 2009 suggests therapy for 12 months. 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.,,
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. 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. 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.” 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. 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. Moreover, local resistance patterns are known to be different, the knowledge of which is vital.,
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. 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.
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.
1. There are multiple caveats in the therapeutics of the CNS TB which surfaced from this survey:
This survey thus helps identify areas of future work in CNS TB in India.
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
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2]