Central Nervous System Tuberculosis: a Challenge in India

Central Nervous System Tuberculosis: a Challenge in India

Central nervous system tuberculosis: a challenge in India

Ravindra Kumar Garg

Hardeep Singh Malhotra

Department of Neurology

King George Medical University

Uttar Pradesh

Lucknow, India

Address for correspondence

Ravindra Kumar Garg

Department of Neurology

King George Medical University,

Uttar Pradesh, Lucknow

India PIN-226003

Phone: 91 9335901790

Email:

Fax No: 91 522 2258852

Abstract

Central nervous system tuberculosis is a serious form of tuberculosis. Exact incidence of central nervous system tuberculosis in India is not known.Tuberculous central nervous system involvement can occur in the form of tuberculous meningitis, tuberculous vasculitis, cerebral tuberculoma and rarely tuberculous brain abscess. Tuberculous involvement of the spinal cord, roots, and vertebrae can occur in the form of spinal meningitis, radiculomyelitis, spondylitis, or spinal cord infarction. Diagnosis of tuberculous meningitis and other forms of central nervous system tuberculosis is usually based on clinical features and characteristic cerebrospinal fluid and neuroimaging findings. Microbiological confirmation in cerebrospinal fluid (CSF) by conventional methods (Ziehl-Neelsen smear, culture and tuberculosis polymerase chain reaction) is usually difficult.The Xpert MTB/RIF assay (Cepheid, CA, USA) is a fully-automated nucleic acid amplification test that has also been found to be effective in CSF.The mortality rate for untreated tuberculous meningitis is almost 100%.A short intensified treatment regimen has recently been advocated. World Health Organization recommended 12 months treatment is far from satisfactory. A short intensified treatment regimen consisting of a higher isoniazid and rifampicin dosages, longer administration of pyrazinamide and substitution of ethambutol with ethionamide is being used in many countries. Adjunctive corticosteroids should routinely be used. Drug-resistant tuberculous meningitis is associated with a high mortality. Patients with HIV infection are 26 to 31 times more likely to develop active tuberculosis, including central nervous system tuberculosis.Bacillus Calmette-Guérin vaccination confers protection against tuberculous meningitis and disseminated tuberculosis in childhood but not in adults. Timely diagnosis of central nervous system tuberculosis is of key importance because delayed treatment is associated with higher morbidity and mortality.

Central nervous system tuberculosis is a serious form of tuberculosis and is associated with significant mortality and morbidity. Exact incidence of central nervous system tuberculosis in India is not exactly known. Globally, in 2013, 9 million people had tuberculosis and 1.5 million died from the disease. Total number tuberculosis cases notified in India in, 2013, was 1 415 617, among these 226 557 cases were of extrapulmonary tuberculosis.1Largely, incidence of central nervous system tuberculosis is in proportion of tuberculosis in the community. Some data from developed countries are available. For example,in USA, among 253,299 tuberculosis cases, 18.7% patients were having extrapulmonary tuberculosis. Meningeal tuberculosis was present in 5.4% of patients.2

Tuberculous central nervous system involvement can occur in the form of tuberculous meningitis, tuberculous vasculitis, cerebral tuberculomaand rarely tuberculous brain abscess. Tuberculous involvement of the spinal cord, roots, and vertebrae can occur in the form of spinal meningitis, radiculomyelitis, spondylitis, or spinal cord infarction.(Table) (Figure)

Tuberculous meningitis

Tuberculous meningitis is the most frequent form of central nervous system tuberculosis. Tuberculous meningitis constitutes approximately 1% of all forms of tuberculosis and definitely tuberculous meningitis is the commonest cause of meningitis in India.3

Diagnosis of tuberculous meningitis is usually based on clinical features and characteristic cerebrospinal fluid and neuroimaging findings. Microbiological confirmation in cerebrospinal fluid (CSF) by conventional methods (Ziehl-Neelsen smear, culture and tuberculosis polymerase chain reaction) is usually difficult.An Internationalgroup of experts, recently, suggested that the patients with suspected tuberculous meningitis can be classified to one of four groups based on clinical, laboratory, and neuroimaging findings. The proposed categories are definite, probable, possible, and not tuberculous meningitis. Diagnosis definite tuberculous meningitis can be considered if acid-fast bacilli are demonstrated in CSF, bacilli are cultured, or Mycobacterium tuberculosis is detected in CSF polymerase chain reaction. The diagnosis of probable or possible tuberculous meningitis could be made with the help of a diagnostic scoring system that included the presence of suggestiveclinical features of tuberculous meningitis along with exclusion of other possible differential diagnoses.4 The characteristic neuroimaging features include basal meningeal enhancement, hydrocephalus, cerebral tuberculomas, cerebralinfarction and spinal arachnoiditis. It is often difficult to exclude fungal meningitis, sarcoidosis, or lymphoma and carcinomatous meningitis.5,6

Detection of Mycobacterium tuberculosisin CSF by conventional methods is considered possible approximately in 50% of patients. In a meta- analysis, frequency of CSF acid-fast-bacilli smear positivity was 8·9%, and frequency of CSF culture positivity for Mycobacterium tuberculosis was 35·1%.7Nucleic acid amplification assays are better methods because of their rapidity and high sensitivity.The diagnostic accuracy of newer commercial nucleic acid amplification tests against a CSFMycobacterium tuberculosis culture-positive gold standard were sensitivity 64% with specificity of 98%.The Xpert MTB/RIF assay (Cepheid, CA, USA) is a fully-automated nucleic acid amplification test that has also been found to be effective for CSF samples.In CSF, Xpert pooled sensitivity was found to be 80.5% in comparison with solid culture as gold standard.8Several newer tests, like modified Ziehl-Neelsen stain, interferon-gamma release assays and Mycobacterium tuberculosis antigen detection assays have all shown promise.In a study, intracellular Mycobacterium tuberculosiswas seen in 87.8% of the slides positive by the modified Ziehl-Neelsen stain in comparison to. 3.3% by conventional Ziehl-Neelsen stain.9

The mortality rate for untreated tuberculous meningitis is almost 100%.Early treatment of tuberculous meningitis is crucial to prevent deaths as well as disability. A systematic review and meta-analysis of childhood tuberculous meningitis studies demonstrated that among 1636 children risk of death was 19.3% and probability of survival without neurological sequelae was 36.7 %. Among survivors, risk of neurological sequelae was 53.9%.7Among adults, a case-fatality rate of 60 % has been estimated.

Hydrocephalus is a common complication of tuberculous meningitis and may account for life-threatening raised intracranial pressure. There are two types of hydrocephalus (communicating and non-Communicating types).Communicating hydrocephalus requires treatment with furosemide with or without acetazolamide.Non- communicating hydrocephalus or obstructive hydrocephalus require some CSF diversion procedure. An external ventricular drain, ventriculo-peritoneal shunting or endoscopic thirdventriculostomy are common procedures that are performed in these patients. Endoscopic third ventriculostomy is increasingly being used as an alternative treatment for post-tuberculous meningitis hydrocephalus. Neurosurgical procedures are performed in carefully selected patients of tuberculous meningitis showing rapid clinical deterioration and increasing ventricular size. However, exact role of CSF diversion procedures is not known. 3-5

Optochiasmatic tuberculous arachnoiditis is afairly commonform of tuberculous meningitis and often associated with profound vision loss. Exudates, if dominantly present in the interpeduncular, suprasellar and Sylvian cisterns, result in optochiasmatic arachnoiditis. Frequently, optochiasmatic arachnoiditis develop paradoxically while a patient is being treated with antituberculosis drugs. Characteristic magnetic resonance imaging (MRI) picture of optochiasmatic tuberculous arachnoiditis consists of confluent enhancing lesions that are present in the interpeduncular fossa, pontine cistern, and the perimesencephalic and suprasellar cisterns. Treatment of tuberculous optochiasmatic arachnoiditis is often difficult. In isolated case reports and in small series, corticosteroids, methyl prednisolone, thalidomide and hyaluronidase have been used but none was found satisfactory. 10

Miliary tuberculosis is defined as a hematogenous spread of Mycobacterium tuberculosis resulting in widespread, visceral, caseous tubercle formations measuring 1–3 mm in diameter (the size of millet seeds) with imaging or pathologic evidence of pulmonary nodules.Disseminated tuberculosis is defined as a hematogenous spread of mycobacteria with active caseous tubercle formation in two or more extrapulmonary sites and with no pulmonary miliary nodular shadowing on X-ray. Both miliary and disseminated tuberculosis are associated with a variety of central nervous involvement like tuberculous meningitis, miliary (small and numerous) tuberculoma of brain, solitary cerebral or spinal tuberculomas. Disseminated tuberculosis is more frequent in HIV infected patients and is often associated with drug-resistant strains of Mycobacterium tuberculosis. Both of these conditions are associated with exceptionally high mortality.11

HIV and central nervous system tuberculosis

Patients with HIV infection are 26 to 31 times more likely to develop active tuberculosis, including central nervous system tuberculosis. Central nervous system tuberculosis is often part of miliary and disseminated tuberculosis.HIV-associated central nervous system tuberculosis is often difficult to diagnose and treat because of several reasons, like increased risk of other central nervous system infections and malignancies with similar clinical presentations, atypical cerebrospinal fluid findings, higher rates of drug-resistant tuberculous meningitis, unknown benefit of corticosteroids therapy, drug to drug interactions, exact timing of antiretroviral therapy in the course of central nervous system tuberculosis and frequent occurrences of immune reconstitution inflammatory syndrome, and association with an exceptionally highmortality. Tuberculous meningitis- immune reconstitution inflammatory syndrome is a frequent and severe complication of antiretroviral therapy in HIV-infected tuberculous meningitis patients. It is characterized by raised CSF neutrophil counts and a high frequency of Mycobacterium tuberculosis culture positivity.There are several clinical features that help in differentiating tuberculous meningitis from cryptococcal meningitis (two the most frequent opportunistic infections) in HIV-infected patients. Tuberculous meningitis is associated with more marked neck stiff ness, fever, altered sensorium, lower CSF pressure, and higher CSF leucocyte count. In addition, a CD4 cell count of less than 200 per microliter, a ratio of CSF to plasma glucose of 0.2 or less, a total number of CSF lymphocytes greater than 200 cells/mm3, and a negative CSF Cryptococcal antigen test.12,13

Tuberculoma brain

Intracranial tuberculomas are usually solitary and they might coexist with pulmonary tuberculosis or other forms of central nervous system tuberculosis. Imaging findings depend on the stage of tuberculoma, whether it is noncaseating or caseating with solid or liquid centre. In the differential diagnosis of a suspected brain tumour, particularly in tropical countries, tuberculomas and cysticercosis must also be considered. They are far more common than brain tumours and often mimic brain tumours clinically and on imaging. Stereotactic biopsy, examination of the CSF, immunological tests, chest X-ray, and family history of tuberculosis exposure may be helpful in making a correct diagnosis. Numerous other conditions can mimic tuberculomas on conventional imaging, including neurocysticercosis, fungal granulomas, and tumor like lymphomas, glioma, and metastases. Newer imaging techniques, like diffusion imaging, MR spectroscopy may help in differentiating tuberculomas form other mass lesions of the brain.MR spectroscopy shows prominent lipid peaks in tuberculomas as compared to other lesions such asmetastasis and glioma.

Tuberculous brain abscess

Tuberculous brain abscess is a rare form of central nervous system tuberculosis. Tuberculous abscesses tend to be larger than tuberculomas, often greater than 3 cm in diameter. It is characterized by an encapsulated collection of pus, containing viable acid-fast bacilli without evidence of tuberculous granuloma. Abscess walls are usually devoid of epitheloid and giant cells, which are characteristic of tuberculoma.Diagnosis usually requires brain biopsy.

Spinal involvement

Spinal involvement manifests in several forms, like tuberculous radiculomyelitis, spinal tuberculoma, myelitis, syringomyelia, vertebral tuberculosis and very rarely spinal tuberculous abscess. Frequently, tuberculous spinal arachnoiditis develop paradoxically while patient is being adequately treated with antituberculous drugs. Infrequently, spinal cord involvement may even be asymptomatic. Spinal cord and spinal nerve involvement is demonstrated by diffuse enhancement of cord parenchyma, nerve roots and meninges, on contrast-enhanced MR. High cerebrospinal fluid protein was a risk factor for development of spinal arachnoiditis. The most important differential diagnosis of tuberculous arachnoiditis is meningeal carcinomatosis.

Treatment

The World Health Organization currently recommends 2 months regimen of isoniazid, rifampicin, pyrazinamide and streptomycin followed by 10 months of isoniazid and rifampicin. The total duration of treatment is 12 months. World Health Organization recommended antituberculous treatment regimen for central nervous system tuberculosis is far from satisfactory. A short intensified treatment regimen has recently been advocated. The short intensified treatment regimen consists of a higher isoniazid and rifampicin dosages, longer administration of pyrazinamide and substitution of ethambutol with ethionamide (6RHZEth for HIV-uninfected and 9RHZEth for HIV-infected patients)provides higher CSF concentrations of antituberculosis drugs for the entire duration of treatment. Alternatively, a treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks of antituberculosis treatment is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease.14,15Though, some ill-designed studies reported satisfactory results of intermittent antituberculosis treatment regimen, advocated by Revised National Tuberculosis Control Programme guidelines, intermittent antituberculosis therapy has no place in the management of tuberculous meningitis.16The important prognostic factors of tuberculous meningitis include early diagnosis and treatment, severe grade of disease, presence of complications like vision loss, stroke, hydrocephalus, myeloradiculopathy, high CSF protein and cell count, hyponatremia and co-infection with HIV.

Adjunctive corticosteroids should routinely be used in all patients of tuberculous meningitis. Thwaitesand co-workers comprehensively demonstrated that corticosteroids reduced mortality but no effect was shown on neurological disability.17 Extended follow up these same patients showed that beneficial effect of corticosteroids did not last long. The dexamethasone group had a similar proportion of severely disabled patients among survivors at five years as the placebo group and there was no significant association between dexamethasone treatment and disability status at five years. Another adjunctive treatment, aspirin resulted in absolute risk reduction of stroke in 19.1% of patients and significant reduction in mortality compared to placebo (21.7% Vs 43.4%). Subsequently, a significant association of polymorphisms in theLTA4Hgene (a gene responsible for eicosanoid synthesis) with susceptibility to extra-pulmonarytuberculosis, including tuberculous meningitis was demonstrated. 3,5,6

Drug-resistant tuberculous meningitis

Drug-resistant tuberculous meningitis is associated with a high mortality. HIV infected patients with drug-resistant tuberculous meningitis have severe clinical manifestations with exceptionally high mortality. Globally, an estimated 3.5% of new cases and 20.5% of previously treated cases have Multidrug-resistant tuberculosis. Drug-resistant tuberculous meningitishas been reported from many countries. In India there drug-resistant tuberculous meningitis, so far, has not appeared as major problem but there is a need to keep constant vigil. If case is encountered with multidrug-resistant tuberculous meningitis, treatment with second-line drugs with good penetration of the CSF should be preferred. 18

Paradoxical reaction

Many paradoxical complications appear during the treatment of tuberculous meningitis. Paradoxical reaction is defined as the worsening of a pre-existing lesion or the appearance of new lesion in a patient whose clinical symptoms initially improved with antituberculosis treatment. A variety of paradoxical complications have been reported in patients with tuberculous meningitis including expansion of existing cerebral tuberculomas, and appearance of new tuberculomas, hydrocephalus, and optochiasmatic and spinal arachnoiditis. The exact mechanism of paradoxical reactions is uncertain; an exaggerated immune reaction against Mycobacterium tuberculosis-associated antigens is the most accepted theory. Corticosteroids are considered to have a beneficial effect in the management of paradoxical reactions. 19

BCG vaccination and central nervous system tuberculosis

Prevention of tuberculosis remains the most important factor to reduce the incidence of central nervous system tuberculosis. Several systematic review, meta-analyses, and meta-regression analysis have suggested that Bacillus Calmette-Guérin (BCG) vaccination provides significant protection against tuberculous meningitis and disseminated tuberculosis in childhood.These studies further observed that BCG vaccine failed to provide sufficient protection against tuberculosis in adults. Protection benefit of BCGvaccination of HIV-positive individuals is not precisely known.The severity or prognosis of tuberculous meningitis in BCG vaccinated adults does not seem to differ from that of non-vaccinated patients.6

Conclusion

Early recognition and timely treatment of central nervous system tuberculosisis of great importancebecause if it is not recognised early central nervous system tuberculosis is associated with considerable mortality and morbidity.

References

  1. World Health Organization. Global tuberculosis report 2014.Downloaded from:
  1. Peto HM, Pratt RH, Harrington TA, LoBue PA, Armstrong LR. Epidemiology of extrapulmonary tuberculosis in the United States, 1993-2006.Clin Infect Dis 2009;49:1350-7.
  1. Thwaites GE. Advances in the diagnosis and treatment of tuberculous meningitis. Curr Opin Neurol 2013; 26:295-300.
  1. Marais S,ThwaitesG, Schoeman JF, Török ME, Misra UK, Prasad K, et al. Tuberculous meningitis: a uniform case definition for use in clinical research.Lancet Infect Dis. 2010;10:803-12.
  1. Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol 2013;12:999-1010.
  1. Garg RK. Tuberculous meningitis. Acta Neurol Scand. 2010;122:75-90.
  1. Chiang SS, Khan FA, Milstein MB, Tolman AW, Benedetti A, Starke JR, et al. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2014 Aug 6. pii: S1473-3099(14)70852-7.
  1. Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, SteingartKR.Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J 2014;44:435-46.
  1. Feng GD, Shi M, Ma L, Chen P, Wang BJ, Zhang M, et al. Diagnostic accuracy of intracellular mycobacterium tuberculosis detection for tuberculous meningitis. Am J Respir Crit Care Med 2014;189:475-81.
  1. Garg RK, Paliwal V, Malhotra HS. Tuberculous optochiasmatic arachnoiditis: a devastating form of tuberculous meningitis. Expert Rev Anti Infect Ther 2011;9:719-29.
  1. Garg RK, Sharma R, Kar AM, Kushwaha RA, Singh MK, Shukla R, et l.Neurological complications of miliary tuberculosis. Clin Neurol Neurosurg 2010;112:188-92.
  1. Chamie G, Marquez C, Luetkemeyer A. HIV-associated central nervous system tuberculosis. Semin Neurol 2014;34:103-15.
  1. Garg RK, Sinha MK.Tuberculous meningitis in patients infected with human immunodeficiency virus. J Neurol 2011;258:3-13.
  1. Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis 2013;13:27-35.
  1. Turkova A, Seddon JA, Nunn AJ, Gibb DM, Phillips PP. Short intensified treatment in Children with Drug-susceptible Tuberculous Meningitis. Pediatr Infect Dis J 2014;33:993.
  1. Iype T, Pillai AK, Cherian A, Nujum ZT, Pushpa C, Dae D, et al. Major outcomes of patients with tuberculous meningitis on directly observed thrice a week regime. Ann Indian Acad Neurol 2014;17:281-6.
  1. Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Nguyen TC, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351:1741-51.
  1. Garg RK, Jain A, Malhotra HS, Agrawal A, Garg R. Drug-resistant tuberculous meningitis. Expert Rev Anti Infect Ther 2013;11:605-21.
  1. Garg RK, Malhotra HS, Kumar N. Paradoxical reaction in HIV negative tuberculous meningitis. J Neurol Sci 2014;340:26-36.

Legends