TB Meningitis Learning Objectives Introduction Global problem Aetiology and pathogenesis

1. Diagnosing and Managing Tubercular Meningitis Agam Jung Agam Jung is a consultant neurologist at Leeds Teaching Hospitals NHS trust. She also works as an honorary research associate at the Institute of Infection and Global Health, University of Liverpool. Dr Jung has a particular interest in TB meningitis and is leading a national multicentre case control trial examining the applicability of a diagnostic algorithm for TB meningitis. Edited by Prof Tom Solomon and Dr Agam Jung • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment This session will provide an overview of tubercular meningitis (TBM). The global burden of the disease, diagnostic and management issues as well as the neurological outcomes will be discussed.

2. Learning Objectives • By the end of this session you will be able to: • Recognise the global problem of tuberculosis • Describe the aetiology and pathogenesis of TB Meningitis • Explain the clinical features, complications and clinical outcomes of TB meningitis • Be aware of the limitations of the available diagnostic tests for TB meningitis • List the therapeutic options available • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment

3. Introduction One third of the world's population is currently infected with tuberculosis (TB). The causative agent is Mycobacterium tuberculosis which can cause both pulmonary and extra pulmonary disease. Men are affected more commonly than women and the majority of patients are in the economically productive age group. HIV and TB together form a lethal combination. Drug resistance to TB and particularly multidrug resistance pose a serious threat to TB control. This session explores the pathogenesis, clinical features and management strategy for TB meningitis. First, it examines the aetiology and pathogenesis of TB meningitis. It then explains the clinical features, diagnostics, complications and clinical outcomes of TB Meningitis. Finally, it provides information on the drug treatment and drug resistance in TB meningitis. The first section begins with an overview of the global problem of tuberculosis. • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment

4. Global Problem of Tuberculosis • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment In 1993, the WHO declared TB a global public health emergency. According to the World Heath Organization (WHO) (Global Tuberculosis Control, 2011), the number of incident TB cases in 2010 were approximately 8.8 million globally. Worldwide, TB mortality is very high and is the second leading cause of death from an infectious agent. In 2010, there were an estimated 1.2-1.5 million deaths reported by the WHO. Tuberculosis remains a disease of poverty. Africa and Asia have the highest disease prevalence. The global incidence rate of tuberculosis is falling albeit very slowly.

5. Global Problem of Tuberculosis • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment Figure 1: Estimated TB incidence rates, 2010 • Figure 2: Estimated HIV prevalence in new TB cases, 2010 From: Global Tuberculosis Control 2011, WHO, 2011.

6. Global Problem of Tuberculosis: Europe and UK • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment In the UK , there were 9040 cases of TB reported in 2009, the highest in 30 years. London had the highest rate of TB at 44.4/100,000. The majority of the patients are non UK born (73%). Social risk factors of homelessness, drug or alcohol excess and imprisonment have been associated with 1 in 10 patients diagnosed with Tuberculosis. A report by Kruijshaar and Abubakar has demonstrated a rise in extra pulmonary tuberculosis in the UK with the reported numbers of TB Meningitis cases exhibiting a steady increase

7. Aetiology and Pathogenesis of TB Meningitis I • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment Tuberculosis is caused by Mycobacterium tuberculosis, an obligate aerobic bacterium. After inhalation, the mycobacteria replicate in the lung (in the alveolar macrophages – which is why they are called facultative intracellular pathogens). The mycobacteria then disseminate to the regional lymph nodes forming the primary complex. Haematogenous dissemination also occurs throughout the body and can result in seeding of M tuberculosis to other organs. . • The next step depends on the host immune response. There may be complete elimination of the mycobacteria or the development of 'tubercles'. • Each tubercle has a caseous focus and is surrounded by a fibrous capsule. If the host immunity wanes, viable bacteria can start proliferating in the tubercle which can then rupture resulting in the release of organisms and their antigenic products.

8. Aetiology and Pathogenesis of TB Meningitis II • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment In the CNS, the tubercles are known as Rich foci. These are subependymal (in the sylvian fissure commonly) or sub pial. Rupture of the Rich focus into the subarachnoid space results in TB Meningitis. Rupture of a Rich focus located in the deeper parenchyma will result in a tuberculoma or abscess. • A robust inflammatory response occurs secondary to the rupture of the Rich focus. A thick gelatinous exudate infiltrating cortical and meningeal blood vessels is formed. • Adhesions due to the exudates can result in cranial nerve palsies. Adhesions in the Basal cisterns can result in hydrocephalus. Vasculitis can cause strokes and encephalitis may result in increased intracranial pressure. CNS involvement is more likely to occur in patients with miliary TB.

9. Clinical features • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment • Clinical features are similar to any subacute meningoencephalitis. • Non specific features such as headache, fever, malaise and weight loss can be the presenting features as well as seizures, altered sensorium and focal neurodeficits. Movement disorders can also occur, more so in children. • A history of recent tuberculosis contact should be sought as well as travel to TB endemic regions of the world. Homelessness, drug and alcohol misuse, malnutrition and immunosuppression should increase the clinical index of suspicion. • Physical examination may reveal lymphadenopathy, papilloedema and evidence of ocular tuberculosis. Focal Neurological deficits, cranial nerve palsies as well as abnormal movements should be specifically sought.

10. Complications and Clinical Outcomes • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment The sequelae of TB meningitis include focal motor deficits, cognitive impairment, seizures, cranial nerve palsies and optic atrophy. Rarer complications of diabetes insipidus, hypothermia, hypopituitarism and precocious puberty have also been reported. Low GCS (Glasgow Coma Scale) and presence of focal neurodeficit on admission are predictors of poor outcome. The severity of TB Meningitis can be graded by using the MRC score which uses focal neurological deficit and alteration in level of consciousness. A grade I where there is no focal neurological deficit or alteration in the level of consciousness is associated with a better prognosis as compared to a score of II or III. Younger age (<10 years) is also a predictor for increased mortality and morbidity. Previous BacilleCalmette-Guérin (BCG) vaccination is thought to reduce the morbidity.

11. Complications and Clinical Outcomes • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment Patient compliance and prescription errors can contribute to the complications and poor outcomes. Adverse reactions to drugs can result in treatment interruptions which in itself is an independent predictor of increased mortality. Hepatic toxicity is the most common adverse drug reaction. Hyponatraemia (low sodium) can also occur and if severe may cause coma and seizures. • Hydrocephalus, infarction and tuberculomas are the commonest causes for neurological deterioration. • Paradoxical treatment reactions due to an intense inflammatory reaction are well described e.g expansion

12. Diagnosis of TB meningitis • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment Early diagnosis of TB Meningitis is of paramount importance as delayed treatment has shown high mortality and morbidity. A high index of clinical suspicion is vital. Various diagnostic algorithms have been published to aid clinical diagnosis of TB meningitis, however their use is not recommended in HIV positive patients. At present, these algorithms have not been validated for use in a low TB prevalence settings. An initial study on children was conducted in India (Kumar et al 1999) to assess the correlation of the presenting clinical features with a diagnosis of TB meningitis. This was followed by a study in Vietnam in adult patients and a diagnostic algorithm was created based on the parameters of age, total blood white cell count, total CSF white cell count, CSF percentage neutrophils and the duration of illness at the time of presentation. Each parameter was given a weighted score. A total score of ≤ 4 is suggestive of TBM.

13. Limitations of the Available Diagnostic Tests for TB Meningitis • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment CSF features can mimic those of many infectious and non infectious pathologies. Presence of a spinal block can result in very high levels of CSF protein. Co-infection with HIV does not significantly alter the CSF profile. Polymorphonuclear leucocytosis can be seen early on in the disease with a subsequent shift to lymphocyte predominance. Neutrophilia has also been observed in patients on treatment and is thought to be secondary to a hypersensitivity reaction. Rarely, the CSF can be normal.

14. Microscopy and Culture Identification by microscopy and culture are the most widely available tools. M.Tuberculosis is a gram positive rod which stains poorly due to the constituents of its thick cell wall. The mycolic acids in the cell wall are however able to retain dyes which are normally washed out from other microbes by the use of alcohol and acids. This acid-fast property is used in Ziehl Neilson staining to identify the mycobacterium. The sensitivity is variable ranging from 19% to 91%. • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment • Sensitivity can be improved by staining a larger volume (6 ml) or multiple samples of CSF. Spending more time on microscopy (30 minutes) and staining the clot has also been shown to increase the sensitivity. Other stains used are Kinyoun and AuramineRhodamine stains.

15. Culture Culture has so far been the gold standard for diagnosing TB meningitis and also allows drug susceptibility testing. Culture on Lowenstein–Jensen medium (LJ) media can take weeks due to the slow doubling time of 15 – 20 hours. The colonies grow in parallel serpentine cords. Semiautomated and automated systems have reduced culture times. • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment • Commercial nucleic acid amplification tests are good confirmatory tests, however are not effective in ruling out TB infection. In a meta analysis, polymerase chain reaction (PCR) has been shown to have a sensitivity of about 56% and a specificity of 98% for diagnosing TB meningitis. They are useful adjuncts in the diagnosis, particularly once treatment has commenced. • Antigen and antibody detection in the CSF may be useful particularly in resource poor settings, however, issues about variable sensitivity, cross reactivity and inability to differentiate between acute and previous infection remain. Other blood tests including full blood count, serum electrolytes and chest radiography should be performed.

16. Imaging • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment Brain imaging can provide useful supplementary information (contrast enhanced MRI being superior to CT). Hydrocephalus, Basal meningeal enhancement, infarcts and tuberculomas have been identified as distinguishing features. Meningeal calcification and cerebral atrophy have been reported as long term sequelae. • Tuberculomas are low or high density, round or lobulated with a predilection for the frontal and parietal lobes. They may be single or multiple and may exhibit the target sign. The degree of surrounding oedema is inversely proportional to the age of the tuberculoma. • New or enlarging tuberculomas can occur despite adequate treatment.

17. Imaging • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment Left: Ring enhancing lesions Right: Sulcal leptomeningeal enhancement

18. Therapeutic Options • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment Treatment may need to be started prior to a confirmatory diagnosis. According to the NICE guidelines (March 2011), patients with active meningeal TB should be prescribed a treatment regime comprising four drugs for the first two months (isoniazid, pyrazinamide, rifampicin and a fourth drug such as ethambutol) followed by isoniazid and rifampicin for the rest of the treatment period. At present, the optimal drug regimen and duration is not established. Daily dosing and combination medications should be considered. Aspects of possible drug resistance, poor compliance, disease severity and variable CNS drug penetration should be borne in mind while prescribing anti tubercular drugs.

19. Therapeutic Options • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment • Adjunctive steroids are recommended in TBM. • Steroid doses should follow those used in proven trials. Tapering of doses should be initiated within 2-3 weeks and done over 6-8 weeks. Glucocorticoid equivalent to 20 – 40 mg of Prednisolone for patients on rifampicin otherwise 10-20mg is recommended by NICE guidelines. Benefits of steroid use in HIV positive individuals is not proven. In the case of multi-drug resistant TB (MDR-TB) experts should be involved in the management. For advice email: mdrtbservice@lhch.nhs.uk. Complications of hydrocephalus and tubercular abscess will need neurosurgical involvement. Ventriculoperitoneal shunts for non communicating hydrocephalus should be considered early rather than later.

20. Key Points • Tuberculosis is a global emergency with very high morbidity and mortality • Clinical judgement remains paramount in the diagnosis of TB meningitis • There is no perfect test to diagnose TB meningitis • High index of suspicion along with the use of a combination of tests is required to guide diagnosis • Treatment should be continued with 4 drugs for a minimum of 12 months. If in doubt seek expert advice early. • Steroids are a useful adjunct in the management • Management of patients with co-existent HIV should be done in collaboration with experts in HIV • Untreated, TB meningitis is fatal. Despite treatment, there are significant neurological sequelae • There are many unresolved issues with the diagnosis and management of TB meningitis • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment

21. Summary • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment • Having completed this session you will now be able to: • Recognise the global problem of tuberculosis • Describe the aetiology and pathogenesis of TB Meningitis • Explain the clinical features, complications and clinical outcomes of TB meningitis • Be aware of the limitations of the available diagnostic tests for TB meningitis • List the therapeutic options available

22. References/ Further reading • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment • World Health Organization Health Topics: Tuberculosis. • NICE guidelines. • British HIV Association guidelines for the treatment of TB/HIV coinfection 2010. • Rock et al Clinical Microbiology Reviews, Apr. 2008, p. 243–261 Central Nervous System Tuberculosis: Pathogenesis and Clinical Aspects. • Kalita J et al European Journal of Neurology 2007, 14: 33–37 .Predictors of long-term neurological sequelae of tuberculous meningitis: a multivariate analysis. • Tuberculosis in the UK: Annual report on tuberculosis surveillance in the UK, 2010. London: Health Protection Agency Centre for Infections, October 2010. • Kruijshaar and Abubakar . Thorax .2009;64:1090-1095 Increase in extrapulmonary tuberculosis in England and Wales 1999–2006. • Nicholas A Be et al. Current Molecular Medicine 2009, 9, 94-99. Pathogenesis of Central Nervous System Tuberculosis • British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. Thwaites G et al Journal of Infection (2009) 59, 167e187 • Thwaites GE.2002.The diagnosis and management of tuberculous meningitis.. Practical Neurology, 2, 250–261 • Kumar R, Singh SN, Kohli N (1999) A diagnostic rule for tuberculous meningitis. Archives of the diseases of childhood, 81, 221–4.

23. Assessment: Question 1 • TB Meningitis • Learning Objectives • Introduction • Global problem • Aetiology and pathogenesis • Clinical Features • Complications and clinical outcome • Diagnosis • Microscopy and culture • Imaging • Therapy • Key points • Summary • References/Further reading • Self assessment TB meningitis is a notifiable disease True False