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Table of Contents    
COMMENTARY
Year : 2018  |  Volume : 66  |  Issue : 6  |  Page : 1678-1679

Role of aspirin as an adjuvant therapy in tuberculous meningitis in adults: The time has come for a phase III randomized controlled trial


Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India

Date of Web Publication28-Nov-2018

Correspondence Address:
Dr. Ravi Yadav
Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.246225

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How to cite this article:
Yadav R. Role of aspirin as an adjuvant therapy in tuberculous meningitis in adults: The time has come for a phase III randomized controlled trial. Neurol India 2018;66:1678-9

How to cite this URL:
Yadav R. Role of aspirin as an adjuvant therapy in tuberculous meningitis in adults: The time has come for a phase III randomized controlled trial. Neurol India [serial online] 2018 [cited 2018 Dec 10];66:1678-9. Available from: http://www.neurologyindia.com/text.asp?2018/66/6/1678/246225




According to the World Health Organization, tuberculosis forms an important cause of death and disability worldwide.[1],[2] India accounts for almost a quarter of the cases of TB globally, and tuberculous meningitis (TBM) is a major neuroinfectious disease that affects a significant population all over the world.[1],[2] One of the important causes of mortality and morbidity from this disease is due to its ability to cause ischemic stroke due to the prothrombotic state as well as inflammation of the perforating arteries and blood vessels that predominantly involves the brainstem and the basal ganglia.[3],[4],[5] These are the main reasons for the cranial neuropathy and ischemic stroke in early TBM.[3],[4],[5] The main challenge for the treating physician is to minimize the development of focal neurological deficits and reduce the mortality. The armamentarium of treatment consists of antituberculous therapy (ATT) with corticosteroids and supportive treatment.[6] However, it takes some time for the drugs to clear the bacterial load and restore and settle the injury to tissues, which cause widespread exudates. Hence in the acute state, there have been various studies that have proven the role of the adjunctive use of corticosteroids to reduce the mortality and neurological deficits.[6] Most of the current guidelines recommend the use of steroids in the acute management of TBM.[6] However, because of the experience in stroke prevention and pathology, aspirin may also have an additive positive role in the treatment of TBM.[3],[4],[5] There have been very few studies which have systematically evaluated the role of aspirin in the treatment of TBM.

This study by Misra et al., addresses this important lacuna in the medical literature.[7] The study is retrospective in nature but provides valuable information of the possible benefit of adding aspirin as an add-on therapy with corticosteroids and ATT in the management of TBM. Misra et al., divided the patients into three groups. The first group received aspirin alone at a dose of 150 mg/day.[7] The second group received both aspirin and steroids, and the third group received only ATT without steroids. The patients were diagnosed by using clinical features, cerebrospinal fluid examination and imaging, and cultures. The patients were assessed by using Barthel's index at the beginning and the end of 3 months. The endpoint of death or disability was noted in the 153 patients recruited. Kaplan–Meier survival estimates were used to display the survival at the end of three months. The authors found that most of the patients were in stage II and III. The results showed that patients who did not receive any adjuvant treatment had a higher mortality while those who received both aspirin and steroids had lesser number of deaths despite having a more severe form of meningitis, although this difference was not statistically significant. Also, the proportion of patients with complete recovery was 40% in group II compared to 25% in group I and 17.1% in group III. The cumulative survival of the group with steroids plus aspirin was better than aspirin alone.[7]

These findings are very significant and pave the way for a phase III prospective randomized control trial to test the hypothesis that the adjuvant therapy with aspirin and steroids is better than aspirin or steroids alone in reducing the morbidity and mortality of patients with TBM. Two important studies are worth mentioning at this point. Both of them were conducted before the study by Misra et al. Schoeman et al., in 2011 studied 146 children with TBM and randomized them in 3 groups.[8] One group received low dose aspirin (75 mg fixed dose), the second group received high dose aspirin (100 mg/kg), and the third group received a placebo. The administration of aspirin did not show a statistically significant benefit in reducing the mortality or morbidity between the treatment groups. There was one death linked to the use of aspirin. The findings of this study were negative, but it was a well-conducted study and had a double-blind hospital-based design.[8] The authors argued that one of the reasons for the failure could be that the etiology of arterial ischemic stroke in patients with TBM is poorly understood and the neuroimaging studies performed before instituting treatment would provide a better window for intervention.[8] The second study was performed in adult non-human immunodeficiency virus (HIV) affected patients in Vietnam by Mai et al., in 2018, which was a randomized, double-blind placebo-controlled phase 2 trial that used aspirin as an adjuvant therapy in patients with TBM.[9] They recruited 120 patients and randomized them into three groups. All the groups received ATT. There was a placebo group that received only ATT, a low dose aspirin group that received 81 mg of aspirin, and a high dose aspirin group that received 1000 mg of aspirin. This study had findings similar to the current study as they also used corticosteroids. The three-month mortality rates reduced, and the adverse events were also low. However, the study was not adequately powered to estimate the improvement obtained.[9]

Misra et al., also did an unblinded study in 2010 on 118 patients of TBM in a randomized, open-label design. They found that at the end of 3-month study period, there was a nonsignificant reduction in stroke but a statistically significant reduction in the 3-month mortality.[10]

These studies [Table 1] indicate that there may be a definite trend towards the beneficial role of aspirin as an add-on drug to corticosteroids along with ATT for the treatment of ischemic stroke in patients with TBM. Studies are needed to evaluate the beneficial role of other platelet aggregation inhibitors like clopidogrel and dipyridamole, as has been the case in ischemic stroke. Also, the safety data has to be refined further by larger double-blind randomized control trials.[11]
Table 1: List of main studies focusing on the role of aspirin in tuberculous meningitis

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  References Top

1.
Global Tuberculosis report 2018. Available from: https://www.who.int/tb/publications/global_report/en/. [Last accessed on 2018 Oct 30].  Back to cited text no. 1
    
2.
India TB Report 2018. Available from: https://tbcindia.gov.in/. [Last accessed on 2018 Oct 30].  Back to cited text no. 2
    
3.
Schoeman J, Mansvelt E, Springer P, van Rensburg AJ, Carlini S, Fourie E. Coagulant and fibrinolytic status in tuberculous meningitis. Pediatr Infect Dis J 2007;26:428-31.  Back to cited text no. 3
    
4.
Vani KR, Shankar SK, Das S, Asha T, Rao TV. Involvement of hypothalamous in tuberculous meningitis, pathological changes at autopsy. Ind J Tuberc 1991;38:149-53.  Back to cited text no. 4
    
5.
Lammie GA, Hewlett RH, Schoeman JF, Donald PR. Tuberculous cerebrovascular disease: A review. J Infect 2009;59:156-66.  Back to cited text no. 5
    
6.
Prasad K, Singh MB, Ryan H. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev. 2016 Apr 28;4:CD002244. Doi 10.1002/14651858.  Back to cited text no. 6
    
7.
Misra UK, Kalita J, Sagar B. Does adjunctive corticosteroid and aspirin therapy improve the outcome of tuberculous meningitis? Neurol India 2018;66:1672-7.  Back to cited text no. 7
  [Full text]  
8.
Schoeman JF, Janse van Rensburg A, Laubscher JA, Springer P. The role of aspirin in childhood tuberculous meningitis. J Child Neurol 2011;26:956-62.  Back to cited text no. 8
    
9.
Mai NT, Dobbs N, Phu NH, Colas RA, Thao LT, Thuong NT, et al. A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults. Elife. 2018 Feb 27;7. pii: e33478. doi: 10.7554/eLife.33478.  Back to cited text no. 9
    
10.
Misra UK, Kalita J, Maurya PK. Stroke in tuberculous meningitis. J Neurol Sci 2011;303:22-30.  Back to cited text no. 10
    
11.
Misra UK, Kalita J, Nair PP. Role of aspirin in tuberculous meningitis: A randomized open label placebo controlled trial. J Neurol Sci 2010;293:12-7.  Back to cited text no. 11
    



 
 
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