Tuberculous meningitis

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Abstract

Tuberculous menigitis (TBM) presents a major health burden around the world, especially in individuals with concomitant HIV infection, in whom mortality is nearly 50%. Here, members of the TBM International Research Consortium summarize our current understanding of TBM pathogenesis, diagnosis and management, and discuss key avenues for future research.

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Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections.

David M. Tobin, Francisco J. Roca, Sungwhan F. Oh … (2012)

Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A(4) hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B(4). We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation. Copyright © 2012 Elsevier Inc. All rights reserved.

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British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children.

Guy Thwaites, Martin Fisher, Cheryl Hemingway … (2009)

SUMMARY AND KEY RECOMMENDATIONS: The aim of these guidelines is to describe a practical but evidence-based approach to the diagnosis and treatment of central nervous system tuberculosis in children and adults. We have presented guidance on tuberculous meningitis (TBM), intra-cerebral tuberculoma without meningitis, and tuberculosis affecting the spinal cord. Our key recommendations are as follows: 1. TBM is a medical emergency. Treatment delay is strongly associated with death and empirical anti-tuberculosis therapy should be started promptly in all patients in whom the diagnosis of TBM is suspected. Do not wait for microbiological or molecular diagnostic confirmation. 2. The diagnosis of TBM is best made with lumbar puncture and examination of the cerebrospinal fluid (CSF). Suspect TBM if there is a CSF leucocytosis (predominantly lymphocytes), the CSF protein is raised, and the CSF:plasma glucose is <50%. The diagnostic yield of CSF microscopy and culture for Mycobacterium tuberculosis increases with the volume of CSF submitted; repeat the lumbar puncture if the diagnosis remains uncertain. 3. Imaging is essential for the diagnosis of cerebral tuberculoma and tuberculosis involving the spinal cord, although the radiological appearances do not confirm the diagnosis. A tissue diagnosis (by histopathology and mycobacterial culture) should be attempted whenever possible, either by biopsy of the lesion itself, or through diagnostic sampling from extra-neural sites of disease e.g. lung, gastric fluid, lymph nodes, liver, bone marrow. 4. Treatment for all forms of CNS tuberculosis should consist of 4 drugs (isoniazid, rifampicin, pyrazinamide, ethambutol) for 2 months followed by 2 drugs (isoniazid, rifampicin) for at least 10 months. Adjunctive corticosteroids (either dexamethasone or prednisolone) should be given to all patients with TBM, regardless of disease severity. 5. Children with CNS tuberculosis should ideally be managed by a paediatrician with familiarity and expertise in paediatric tuberculosis or otherwise with input from a paediatric infectious diseases unit. The Children's HIV Association of UK and Ireland (CHIVA) provide further guidance on the management of HIV-infected children (www.chiva.org.uk). 6. All patients with suspected or proven tuberculosis should be offered testing for HIV infection. The principles of CNS tuberculosis diagnosis and treatment are the same for HIV infected and uninfected individuals, although HIV infection broadens the differential diagnosis and anti-retroviral treatment complicates management. Tuberculosis in HIV infected patients should be managed either within specialist units by physicians with expertise in both HIV and tuberculosis, or in a combined approach between HIV and tuberculosis experts. The co-administration of anti-retroviral and anti-tuberculosis drugs should follow guidance issued by the British HIV association (www.bhiva.org).

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Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis.

Nitika Pant Pai, Alan Hubbard, Lee W Riley … (2003)

Conventional tests are not always helpful in making a diagnosis of tuberculous meningitis. We did a systematic review and meta-analysis to establish the summary accuracy of nucleic acid amplification (NAA) tests for tuberculous meningitis. We searched six electronic databases and contacted authors, experts, and manufacturers. Measures of diagnostic accuracy were pooled using a random effects model. 49 studies met our inclusion criteria. The summary estimates in 14 studies with commercial NAA tests were: sensitivity 0.56 (95% CI 0.46, 0.66), specificity 0.98 (0.97, 0.99), positive likelihood ratio 35.1 (19.0, 64.6), negative likelihood ratio 0.44 (0.33, 0.60), and diagnostic odds ratio 96.4 (42.8, 217.3). In the 35 studies with in-house ("home-brew") tests, the summary accuracy could not be established with confidence because of wide variability in test accuracy. On current evidence, commercial NAA tests show a potential role in confirming tuberculous meningitis diagnosis, although their overall low sensitivity precludes the use of these tests to rule out tuberculous meningitis with certainty.

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Journal

Title: Nature Reviews Neurology

Abbreviated Title: Nat Rev Neurol

Publisher: Springer Nature

ISSN (Print): 1759-4758

ISSN (Electronic): 1759-4766

Publication date Created: September 8 2017

Publication date (Print): September 8 2017

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Article

DOI: 10.1038/nrneurol.2017.120

PubMed ID: 28884751

SO-VID: ba591221-2bc2-4eb2-a119-b44245a10b57

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Tuberculous meningitis

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Most cited references 137

Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections.

British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children.

Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis.

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Cited by 179

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