Challenges in Diagnosing Tuberculous Meningitis

In 2015, there were approximately 10.4 million cases of tuberculosis (TB) worldwide, of which 1.8 million were fatal.¹ An estimated 81% of cases originate in 22 high-burden countries primarily located in Southeast Asia, Western Pacific, and Africa.² In 2012, there were 9951 new cases reported in the United States, and 7.7% of these individuals had HIV co-infection.³

“Tuberculosis is now the leading infectious cause of death in the world, with cases reported in every region,” says Jerome Chin, MD, MPH, PhD, a researcher and adjunct professor of neurology at New York University Langone Medical Center who studies central nervous system tuberculosis, and chair of the International Subcommittee of the American Academy of Neurology. “With increasing global migration and travel, high-income countries may see a rise in the incidence of tuberculosis,” he told Infectious Disease Advisor.

Tuberculous meningitis (TBM), the most lethal form of the disease, accounts for more than 100,000 new cases every year. The annual mortality rate is 25% in HIV-negative patients and more than 67% in patients co-infected with HIV-1.^4,5 Children and individuals with HIV co-infection are particularly vulnerable to poor TBM outcomes. The risk for death from TBM is much higher in patients with the multidrug-resistant (MDR) form of the disease, patients at the extremes of age, and in patients in whom first-line antitubercular treatment has been interrupted.⁴

Presentation & Diagnosis

Although TBM can be cured with prompt and adequate care, delayed diagnosis and treatment contribute significantly to the high mortality and morbidity rates associated with the disease. However, diagnosis is challenging due to nonspecific presentation and the time-consuming cultures required for confirmation. “Diagnosis of all forms of tuberculosis requires expert clinical experience since rapid identification of Mycobacterium tuberculosis is not always possible,” explained Dr Chin. “The best chance for a good outcome is the early initiation of anti-tuberculous therapy, and cultures are too slow for clinical decision-making.”

Signs and symptoms of TBM include those typical of meningitis such as fever, headache, and stiff neck. In the early stages of the disease, however, these signs may not be present.² The duration of symptoms may range from days to months before patients seek care. As TBM advances without treatment, roughly 50% of patients will develop cranial nerve palsies (primarily in the fifth and third cranial nerves), and 10% will develop hemiplegia or paraplegia.¹ These signs should point to TBM as the possible etiology of meningitis. Death is inevitable in most cases if treatment is not provided. The presentation of TBM may be abrupt in children under the age of 1 and individuals with advanced HIV co-infection, with rapid progression to severe coma, prostration, and death, as well as an elevated risk for active TB in other organs.¹

If TBM is suspected based on clinical presentation, cerebrospinal fluid (CSF) should be sent for routine analyses and microbiologic testing. Hallmark findings in the CSF of patients with TBM include pleocytosis with lymphocytic predominance, high protein levels, and low glucose levels, according to a 2014 paper Dr Chin published in Neurology Clinical Practice.² For example, a study of 88 HIV-negative patients with TBM diagnosed by positive CSF culture revealed the following median values: cell count (136/µL), mononuclear cell percentage (63%), protein concentration (160 mg/dL), and CSF glucose/blood glucose ratio (0.13).⁶ “Since MTB cultures can take several weeks or longer to detect growth, a presumptive diagnosis of TBM in cases with a negative CSF Ziehl-Neelsen (ZN) stain needs to be made without waiting for the results of CSF MTB culture,” Dr Chin states in his paper.

Rapid POC Testing

The introduction of nucleic acid amplification testing represents a major advance in timely TB detection. In 2010, the World Health Organization (WHO) endorsed the first point-of-care assay for TB, the Xpert MTB/RIF assay. The test also detects mutations indicative of rifampicin resistance, which strongly suggests multidrug-resistant (MDR) TB, and results are available in less than 2 hours. The assay has become a front-line diagnostic test, and testing for MDR-TB increased 3- to 8-fold worldwide from 2010 to 2016.⁷

“Rapid point-of-care testing for MTB nucleic acids using the Xpert MTB/RIF technology is widely available and can rule in but not rule out tuberculosis,” notes Dr Chin. Although sensitivity is high for smear-positive samples, pooled study results show an overall sensitivity of approximately 60% and specificity of nearly 100%.¹ A next-generation version of the test, the Xpert MTB/RIF Ultra, has recently been introduced and has a reported sensitivity of 95%.⁸

A TBM diagnosis may be corroborated by contrast-enhanced brain computed tomography (CT) or magnetic resonance imaging (MRI) scans, which can identify common TBM features such as basal meningeal exudates, infarcts, tuberculomas, and hydrocephalus, either alone or in combination.^1,2

Treatment and Future Needs

In patients with suspected TBM based on clinical presentation and other findings, treatment should be initiated without definitive proof. Treatment for TBM consists of the same drugs as those used for pulmonary TB (despite concerns about poor penetration of the blood-brain barrier), but for a much longer duration (10 to 12 months). “This long treatment course is difficult to complete for many patients, especially individuals living in resource-limited countries,” says Dr Chin, and this presents one of most pressing research needs in this area. “Clinical trials are needed to find a shorter and more effective course of treatment for tuberculous meningitis, and more education is needed to improve the ability of healthcare providers to make a clinical diagnosis of tuberculous meningitis.”

References

1. Wilkinson RJ, Rohlwink U, Misra UK, et al; Tuberculous Meningitis International Research Consortium. Tuberculous meningitis. Nat Review Neurol. 2017;13:581-598.
2. Chin JH. Tuberculous meningitis: diagnostic and therapeutic challenges. Neurol Clin Pract. 2014;4:199-205.
3. Centers for Disease Control and Prevention (CDC). Trends in tuberculosis: United States 2012. MMWR Morb Mortal Wkly Rep. 2013;62:201-205.
4. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 2004;351:1741-1751.
5. Török ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (hiv)–associated tuberculous meningitis. Clin Infect Dis; 2011;52(11):1374-1383.
6. Chaidir L, Ganiem AR, Vander Zanden A, et al. Comparison of real time IS6110-PCR, microscopy, and culture for diagnosis of tuberculous meningitis in a cohort of adult patients in Indonesia. PLoS One. 2012;7:e52001.
7. Chakravorty S, Simmons AM, Rowneki M, et al. The new Xpert MTB/RIF Ultra: improving detection of Mycobacterium tuberculosis and resistance to rifampin in an assay suitable for point-of-care testing. mBio. 2017;8:e00812-e00817.
8. World Health Organization. Meeting report of a technical expert consultation: non-inferiority analysis of Xpert MTB/RIF Ultra compared to Xpert MTB/RIF. WHO. 2017. www.who.int/tb/publications/2017/XpertUltra/en/. Accessed November 6, 2017.