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Table of Contents    
COMMENTARY
Year : 2019  |  Volume : 67  |  Issue : 4  |  Page : 1003-1005

Tuberculous Meningitis – Adjunctive Therapy: Corticosteroids, Aspirin, or Both


CARE Institute of Neurosciences, COPD, CARE Hospitals, Banjara Hills, Hyderabad, Telangana, India

Date of Web Publication10-Sep-2019

Correspondence Address:
Dr. J M K Murthy
Chief of Neurology, CARE Institute of Neurosciences,COPD, CARE Hospitals, Banjara Hills, Hyderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.266280

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How to cite this article:
Murthy J M. Tuberculous Meningitis – Adjunctive Therapy: Corticosteroids, Aspirin, or Both. Neurol India 2019;67:1003-5

How to cite this URL:
Murthy J M. Tuberculous Meningitis – Adjunctive Therapy: Corticosteroids, Aspirin, or Both. Neurol India [serial online] 2019 [cited 2019 Nov 20];67:1003-5. Available from: http://www.neurologyindia.com/text.asp?2019/67/4/1003/266280




Tuberculosis is a global health problem, and tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis. TBM is associated with a high frequency of neurologic sequelae and mortality if not treated promptly. Much of the neurologic sequelae of TBM are considered to be due to an overexuberant host response. Intracerebral inflammation is an important determinant of TBM outcome, and cerebral infarction is the most common cause of long-term neurological disability owing to TBM.[1]

Cerebral infarction is a common complication of TBM.[2] Up to 57% of patients with TBM undergo magnetic resonance imaging (MRI) or diffusion-weighted imaging cerebral infarction.[3] Similar is the prevalence in the autopsy-proven cases of TBM in adults (22%–56%).[4],[5],[6],[7] The prevalence is much higher in autopsy-proven cases in children (up to 80%).[8],[9] Most infarcts occur in the so-called “TB zone” of the medial lenticulostriate and thalamoperforating vessels.[2] Cerebral infarction can be asymptomatic or present in clinically diverse ways.[1],[2] In an Indian study, 8% of strokes in young have been attributed to vascular complications of TBM.[10] Cerebral infarcts are associated with poor outcome in patients with TBM.[11]

In TBM, cerebral infarction is due to several mechanisms. Vasculitis is the common pathology. The spectrum of vascular pathology in TBM is classified into infiltrative, proliferative, and necrotizing, either in relatively pure form or in combination. Cerebral infarction in TBM is most common and severe in late stage, a phase which appears to correspond to the intimal proliferative stage of cerebral vessel pathology. There is some evidence that vasospasm may mediate cerebral infarction early in the course of the disease.[2] In TBM, both increased procoagulant and decreased anticoagulant activities have been documented in children with stage II and III meningitis.[12] However, the role of vessel thrombosis in causing cerebral infarction in TBM is unclear.[2] The role of cytokines especially tumor necrosis factor, vascular endothelial growth factor, and matrix metalloproteinases in the blood–brain barrier (BBB) damage, attracting leucocytes, and release of vasoactive autocoids have been suggested.[13]

Corticosteroids have anti-inflammatory effects. In addition, corticosteroids have been shown to improve the compromised BBB.[14] Of the corticosteroids, dexamethasone has the most potent anti-inflammatory properties and the longest biological half-life. Use of adjunctive corticosteroid treatment for TBM is base on the notion that dampening of the inflammatory response can lessen morbidity and mortality.

The Cochrane systemic review showed that adjunctive corticosteroids increase survival in HIV-negative children and adults with TBM, but not found to reduce long-term neurological disability.[15] The beneficial effects of corticosteroids in TBM include reduced inflammation of meninges and blood vessel and also cerebral oedema.[15] Treatment of corticosteroids in preventing cerebral infarction is uncertain. A computed tomography–based study suggested that corticosteroid treatment does not affect the burden of basal ganglia infarction,[16] whereas a serial MRI scan study showed reduction in the burden of cerebral infarction by half in patients treated by dexamethasone when compared with the control group.[17]

Aspirin has antiplatelet, antiaggregant, anti-inflammatory, and antioxidant properties. The antithrombotic action of aspirin is due to inhibition of platelet function by acetylation of the platelet cyclooxygenase (COX) at the functionally important amino acid serine 529. This prevents the access of the substrate (arachidonic acid) to the catalytic site of the enzyme at tyrosine 385 and results in an irreversible inhibition of platelet-dependent thromboxane formation. Aspirin is the “gold” standard antiplatelet for the prevention of arterial thrombosis.[18] Anti-inflammatory action of aspirin is due to its inhibition of the enzyme COX which leads to the formation of prostaglandins that cause inflammation.[19] The rationale of using aspirin in TBM is that it might improve outcome by reducing the incidence of brain infarction by its antithrombotic property.

Several small trials have suggested that the use of aspirin in TBM is safe and might improve outcome by reducing the incidence of cerebral infarctions.[20],[21],[22],[23],[24] Rizvi et al.[25] did a systematic review of the role of aspirin in TBM, published in this issue of Neurology India. The analysis included 546 patients with TBM (both children and adults). The primary outcome measures were death or new infarcts confirmed by MRI. Of the 546 patients included in the study, 315 patients received aspirin and 231 patients received placebo. The addition of aspirin to antituberculosis drug regimen did not significantly reduce mortality [Relative risk (RR) = 0.66 (0.42–1.02); low-quality evidence] but significantly reduced the risk of new infarcts [RR = 0.52 (0.29–0.92); moderate-quality evidence]. Aspirin did not differ from placebo with regard to adverse events.

A recent retrospective study showed better survival in patients with TBM receiving aspirin and corticosteroids as adjunctive therapy besides antituberculous therapy when compared with patients receiving aspirin alone and none as adjunctive therapy. This effect was seen despite the presence of severe meningitis in this group of patients. However, the survival benefit was insignificant (hazard ratio 1.55; 95% confidential interval 0.96–26.49; P = 0.07). These observations suggest that aspirin with corticosteroids adjunctive treatment might be beneficial in reducing mortality in TBM. In this study, recurrence of cerebral infarction was not one of the outcome measures.[24]

The natural course of TBM is quite variable. Several pathological processes determine the outcomes in TBM. Intracerebral inflammation is an important determinant of TBM outcome. Vascular compromise is common complication of TBM and leads to ischemia, infarction, and raised intracranial pressure. Cerebral infarction is the most common cause of long-term neurological disability due to TBM.[1] These observations suggest that addition of anti-inflammatory and antithrombotic medications as adjunctive therapies might be beneficial in patients with TBM. The evidence for survival benefit for adjunctive corticosteroid therapy is robust in HIV-negative patients with TBM.[15] The conclusion of the analysis by Rizvi et al.[25] is that aspirin as adjunctive therapy reduces the risk of new cerebral infarction in patients with TBM but does not affect mortality (moderate to low level of evidence). This observation suggests that the beneficial effects of adjunctive corticosteroids on survival may be augmented by aspirin. However, there are no high-quality data for the beneficial effects of this combination as adjunctive therapy in TBM. Till such time, all the HIV-negative patients with TBM should receive the benefit of adjunctive corticosteroid therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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