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| EDITORIAL |
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| Year : 2012 | Volume
: 60
| Issue : 2 | Page : 143-145 |
Multi-drug-resistant central nervous system tuberculosis
J. M. K. Murthy
The Institute of Neurological Sciences, CARE Hospital, Nampally, Hyderabad, India
| Date of Submission | 19-Apr-2012 |
| Date of Decision | 19-Apr-2012 |
| Date of Acceptance | 19-Apr-2012 |
| Date of Web Publication | 19-May-2012 |
Correspondence Address:
J. M. K. Murthy
The Institute of Neurological Sciences, CARE Hospital, Nampally, Hyderabad
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0028-3886.96381
How to cite this article:
Murthy J. Multi-drug-resistant central nervous system tuberculosis. Neurol India 2012;60:143-5 |
Global burden of tuberculosis (TB) is still high, particularly in the developing world. In 2010, there were 8.8 million (range, 8.5-9.2 million) incident cases of TB and 1.1 million (range, 0.9-1.2 million) deaths from TB among human immunodeficiency virus (HIV)-negative people, and an additional 0.35 million (range, 0.32-0.39 million) deaths form HIV-associated TB. [1] India is the largest TB burden country accounting for one-fifth of the global incidence, and the estimated incident cases of TB in 2010 was 2.3 million (range, 2.0-2.5 million). The prevalent cases were 3.0 million (range, 2.0-4.0 million). There were 0.32 million (range, 0.21-0.47 million) deaths related to TB. [1] The emergence of multi-drug-resistance tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis with resistance to at least to isoniazid and rifampicin, and more recently, extensively drug-resistance tuberculosis (XDR-TB), defined as M. tuberculosis strains with resistance to both isoniazid and rifampicin plus resistance to a fluoroquinolone and injectable second-line drugs, is a major threat to global TB control. Globally, MDR-TB accounts for 3.4% (CI 1.9-5.0) of new cases and 20% (CI 14-20) of re-treatment cases. In India, MDR-TB accounts for 2.1% (CI 1.5-2.7) of new cases and 15% (CI 13-17) of re-treatment cases. [1] Sixty-nine countries have reported at least one case of XDR-TB by the end of 2010 and there are an estimated 25,000 cases of XDR-TB emerging every year. [2] The incidence of central nervous system (CNS) TB generally reflects the incidence and prevalence of TB in the community. About 10% of patients who have TB develop CNS disease. [3] HIV infection predisposes to the development of extra-pulmonary TB, particularly tuberculous meningitis. [4] In India, the incidence of new cases of TB for the year 2010 was 185 per 100,000 population. [1] Based on this figure, the projected incidence rate for CNS TB would be 18.5 per 100,000 population. About 2% of the new cases of CNS TB would be due to MDR-TB.
In this issue of Neurology India, Turel and colleagues [5] have reported a infant with MDR tuberculous subdural empyema, who has been successfully treated. Drug-resistant TB commonly develops in the course of TB treatment, [6] most commonly due to inappropriate treatment, poor drug adherence, interrupted drug supply, or failing to complete the course of treatment. Drug resistance may also be caused by a genetic mutation that makes a drug ineffective against the mutant bacilli. In this child, it appears that the infection was with primary drug resistant M. tuberculosis. Infection with MDR-TB stains more often occurs in people with immunocompromised state. However, infection can occur, less commonly, also in immunocompetent individuals. [7] This child appears to be otherwise immunocompetent; however, she was not worked up for any immunodeficiency state. Clinically, it is extremely difficult to suspect MDR CNS TB, except when there is history of contact with an MDR-TB patient.
The diagnosis of MDR-TB and XDR-TB is hampered by the absence of effective and affordable rapid diagnostic techniques. Only molecular tests can detect the resistance fast, and WHO recommends line probe assay and Xpert MTB/RIF assay. The latter assay identifies rifampicin resistance, a marker for multi-drug resistance. [8],[9] However, this experience is limited to pulmonary TB. The place of these diagnostic techniques in CNS TB needs exploration. Treatment of MDR-TB must be done on the basis of sensitivity testing. Both MDR-TB and XDR-TB do not respond to the standard first-line anti-TB drugs and can take 2 years or more to treat with second-line drugs that are less potent, more toxic, and much more expensive. Use of drugs in patients with MDR-TB would depend on the drug susceptibility testing of the strain isolated from the patient or close contacts. Most of the experience of treatment of MDR-TB and XDR-TB is in patients with pulmonary TB. There is hardly any data on MDR-TB of CNS. [10],[11] Probably, the pulmonary regimens should work. Revised 2011 recommended regimen for pulmonary MDR-TB by WHO includes at least four second-line drugs certain to be effective: pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), and cycloserine or else PAS if cycloserine cannot be used. [1],[12],[13] Often, more than four drugs may be started if the susceptibility pattern is unknown or the effectiveness of one or more agents is questionable. Susceptibility testing for isoniazid, rifampicin, the fluoroquinolones, and the injectable agents is fairly reliable. For other agents, it is less reliable, and basing individualized treatments on drug sensitivity testing for these agents should be avoided. [1] The standardized regimen (STR) under Revised National Tuberculosis Control Programme (RNTCP) in India for pulmonary MRD-TB consists of an intensive phase of 6-9 months with six drugs, namely kanamycin, ofloxacin, ethionamide, pyrazinamide, ethambutol, and cycloserine, given daily. This is followed by a continuation phase of 18 months of four drugs, namely ofloxacin, ethinoamide, ethambutol, and cycloserine. [14] At the end of 6 months of treatment, if the culture remains positive, the intensive phase is extended for a further 3 months. With this regimen, cure rates of 61-70% have been reported in pulmonary TB from India [15],[16] and Nepal. [17] These patients need close monitoring as this regimen is associated with high incidence of adverse drug reactions. [16] Cure rates in MDR-TB range between 60% and 70%. [1] Of the 48 patients with XDR-TB reported by Mitnick and colleagues, [18] 29 (60.4%) patients completed treatment or were cured. These patients received daily, supervised therapy with an average of 5.3 ± 1.3 drugs, including cycloserine, an injectable drug, and a fluoroquinolone. In-hospital case fatality rate was 57% in patients with MDR tuberculous meningitis, with a significant functional impairment in most of the survivors. [10] The mortality was nearly 90% in patients with HIV-associated MDR tuberculous meningitis. [11]
There are 10 new or repurposed TB drugs in clinical trials that have the potential to shorten the treatment of drug-susceptible TB and improve the treatment of MDR-TB. New drugs in Phase IIb trials for newly diagnosed MDR-TB include TMC-207 (bedauiline) and OPC-67683 (delamanid). Compounds in Phase II trials include linezolid which is being tested for the treatment of XDR-TB. [1]
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| 3. | Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis: Estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 1999;282:677-86.
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| 4. | Bishburg E, Sunderam G, Reichman LB, Kapila R. Central nervous system tuberculosis with the acquired immunodeficiency syndrome and its related complex. Ann Intern Med 1986;105:210-3.
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| 5. | Turel MK, Moorthy RK, Rajshekhar V. Multi-drug-resistant tuberculous subdural empyema with secondary methicillin-resistant Staphylococcus aureus infection: An unusual presentation of cranial tuberculosis in an Infant. Neurol India 2012;60:20.
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| 8. | Lawn SD, Brooks SV, Kranzer K, Nicol MP, Whitelaw A, et al. Screening for HIV-associated tuberculosis and rifampicin resistance before antiretroviral therapy using the Xpert MTB/RIF assay: A prospective study. PLoS Med 2011;8:e1001067.
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| 12. | WHO Report: Treatment of tuberculosis guidelines. 4th ed. 2010 WHO/HTM/TB/2009.420.
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| 13. | WHO Report: Guidelines for the programmatic management of drug-resistance tuberculosis - 2011 update. WHO/HTM/2010.11.
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| 14. | Central TB Division (CTD), Directorate General of Health 2. Services, Ministry of Health and Family Welfare, Government of India. DOTS-plus guidelines. New Delhi: CTD; 2006.
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| 15. | Singla R, Sarin R, Khalid UK, Mathuria K, Singla N, Jaiswal A, et al. Seven-year DOTS-Plus pilot experience in India: Results, constraints and issues. Int J Tuberc Lung Dis 2009;13:976-81.
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| 16. | Joseph P, Desai VB, Mohan NC, Fredrick JS, Ramachandran R, Raman B, et al. Outcome of standardized treatment for patients with MDR-TB from Tamil Nadu, India. Indian J Med Res 2011;133:529-34.
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| 17. | Malla P, Kanitz EE, Akthar M, Falzon D, Feldmann K, Gunneberg C, et al. Ambulatory-based standardised therapy for multi-drug resistant tuberculosis: Experience from Nepal, 2005-2006. PLoS One 2009;4:08313.
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| 18. | Mitnick GD, Shin SS, Seung KJ, Rich ML, Atwood SS, Furin JJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008;359:563-74.
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