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Diagnosing and

TB Meningitis Managing Tubercular


• Learning Objectives


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

By the end of this session you will be able to:


TB Meningitis
• Recognise the global problem of tuberculosis
• Learning Objectives
• Introduction
• Global problem • Describe the aetiology and pathogenesis of TB
• Aetiology and Meningitis
pathogenesis
• Clinical Features
• Complications and • Explain the clinical features, complications and
clinical outcome clinical outcomes of TB meningitis
• Diagnosis
• Microscopy and
culture • Be aware of the limitations of the available
• Imaging diagnostic tests for TB meningitis
• Therapy
• Key points
• Summary • List the therapeutic options available
• References/Further
reading
• Self assessment
Introduction
One third of the world's population is currently infected with tuberculosis (TB).
The causative agent is Mycobacterium tuberculosis which can cause both
TB Meningitis pulmonary and extra pulmonary disease. Men are affected more commonly
than women and the majority of patients are in the economically productive
• Learning Objectives age group. HIV and TB together form a lethal combination. Drug resistance to
• Introduction TB and particularly multidrug resistance pose a serious threat to TB control.
• Global problem
This session explores the pathogenesis, clinical features and management
• Aetiology and
strategy for TB meningitis. First, it examines the aetiology and pathogenesis of
pathogenesis TB meningitis. It then explains the clinical features, diagnostics, complications
• Clinical Features and clinical outcomes of TB Meningitis. Finally, it provides information on the
• Complications and drug treatment and drug resistance in TB meningitis. The first section begins
clinical outcome with an overview of the global problem of tuberculosis.
• Diagnosis
• Microscopy and
culture
• Imaging
• Therapy
• Key points
• Summary
• References/Further
reading
• Self assessment
Global Problem of Tuberculosis
In 1993, the WHO declared TB a global public health emergency. According to
TB Meningitis the World Heath Organization (WHO) (Global Tuberculosis Control, 2011), the
number of incident TB cases in 2010 were approximately 8.8 million globally.
• Learning Objectives 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
• Introduction
deaths reported by the WHO. Tuberculosis remains a disease of poverty. Africa
• Global problem
and Asia have the highest disease prevalence. The global incidence rate of
• Aetiology and tuberculosis is falling albeit very slowly.
pathogenesis
• Clinical Features
• Complications and
clinical outcome
• Diagnosis
• Microscopy and
culture
• Imaging
• Therapy
• Key points
• Summary
• References/Further
reading
• Self assessment
Global Problem of Tuberculosis

TB Meningitis
• Learning Objectives Figure 1: Estimated TB
• Introduction
incidence rates, 2010
• Global problem
• Aetiology and
pathogenesis
• Clinical Features
• Complications and
clinical outcome
• Diagnosis
• Microscopy and
Figure 2: Estimated
culture
HIV prevalence in new
• Imaging
TB cases, 2010
• Therapy
• Key points
• Summary
• References/Further
reading From: Global
• Self assessment Tuberculosis Control
2011, WHO, 2011.
Global Problem of Tuberculosis: Europe
and UK
TB Meningitis 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
• Learning Objectives 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
• Introduction
diagnosed with Tuberculosis.
• Global problem
• Aetiology and A report by Kruijshaar and Abubakar has demonstrated a rise in extra
pathogenesis pulmonary tuberculosis in the UK with the reported numbers of TB Meningitis
• Clinical Features cases exhibiting a steady increase
• Complications and
clinical outcome
• Diagnosis
• Microscopy and
culture
• Imaging
• Therapy
• Key points
• Summary
• References/Further
reading
• Self assessment
Aetiology and Pathogenesis of TB
Meningitis I
TB Meningitis Tuberculosis is caused by Mycobacterium
tuberculosis, an obligate aerobic bacterium.
• Learning Objectives
• Introduction After inhalation, the mycobacteria replicate in
the lung (in the alveolar macrophages – which
• Global problem
is why they are called facultative intracellular
• Aetiology and
pathogens). The mycobacteria then
pathogenesis disseminate to the regional lymph nodes
• Clinical Features forming the primary complex. Haematogenous
• Complications and dissemination also occurs throughout the body
clinical outcome and can result in seeding of M tuberculosis to
• Diagnosis other organs.
• Microscopy and
culture .
The next step depends on the host immune response. There may be
• Imaging complete elimination of the mycobacteria or the development of 'tubercles'.
• Therapy
• Key points Each tubercle has a caseous focus and is surrounded by a fibrous capsule.
• Summary If the host immunity wanes, viable bacteria can start proliferating in the
• References/Further tubercle which can then rupture resulting in the release of organisms and
reading their antigenic products.
• Self assessment
Aetiology and Pathogenesis of TB
Meningitis II
In the CNS, the tubercles are known as Rich foci. These are
TB Meningitis subependymal (in the sylvian fissure commonly) or sub pial.
• Learning Objectives
• Introduction Rupture of the Rich focus into the subarachnoid space results in TB
• Global problem Meningitis.
• Aetiology and
pathogenesis Rupture of a Rich focus located in the deeper parenchyma will result
• Clinical Features in a tuberculoma or abscess.
• Complications and
clinical outcome A robust inflammatory response occurs secondary to the rupture of
• Diagnosis the Rich focus. A thick gelatinous exudate infiltrating cortical and
• Microscopy and meningeal blood vessels is formed.
culture
• Imaging Adhesions due to the exudates can result in cranial nerve palsies.
• Therapy Adhesions in the Basal cisterns can result in hydrocephalus.
• Key points Vasculitis can cause strokes and encephalitis may result in
• Summary
increased intracranial pressure. CNS involvement is more likely to
• References/Further
occur in patients with miliary TB.
reading
• Self assessment
Clinical features

Clinical features are similar to any subacute meningoencephalitis.


TB Meningitis
Non specific features such as headache, fever, malaise and weight
• Learning Objectives loss can be the presenting features as well as seizures, altered
• Introduction sensorium and focal neurodeficits. Movement disorders can also
• Global problem occur, more so in children.
• Aetiology and
pathogenesis
A history of recent tuberculosis contact should be sought as well as
• Clinical Features
travel to TB endemic regions of the world. Homelessness, drug and
• Complications and
clinical outcome
alcohol misuse, malnutrition and immunosuppression should
• Diagnosis increase the clinical index of suspicion.
• Microscopy and
culture Physical examination may reveal lymphadenopathy, papilloedema
• Imaging and evidence of ocular tuberculosis. Focal Neurological deficits,
• Therapy cranial nerve palsies as well as abnormal movements should be
• Key points specifically sought.
• Summary
• References/Further
reading
• Self assessment
Complications and Clinical
Outcomes
TB Meningitis The sequelae of TB meningitis include focal motor deficits, cognitive
impairment, seizures, cranial nerve palsies and optic atrophy. Rarer
• Learning Objectives complications of diabetes insipidus, hypothermia, hypopituitarism
• Introduction and precocious puberty have also been reported.
• Global problem
• Aetiology and Low GCS (Glasgow Coma Scale) and presence of focal neurodeficit
pathogenesis on admission are predictors of poor outcome. The severity of TB
• Clinical Features Meningitis can be graded by using the MRC score which uses focal
• Complications and neurological deficit and alteration in level of consciousness.
clinical outcome
• Diagnosis A grade I where there is no focal neurological deficit or alteration in
• Microscopy and the level of consciousness is associated with a better prognosis as
culture compared to a score of II or III. Younger age (<10 years) is also a
• Imaging predictor for increased mortality and morbidity. Previous Bacille
• Therapy
Calmette-Guérin (BCG) vaccination is thought to reduce the
• Key points
morbidity.
• Summary
• References/Further
reading
• Self assessment
Complications and Clinical
Outcomes
Patient compliance and prescription errors can contribute to the
TB Meningitis complications and poor outcomes. Adverse reactions to drugs can
result in treatment interruptions which in itself is an independent
• Learning Objectives
predictor of increased mortality. Hepatic toxicity is the most common
• Introduction
• Global problem adverse drug reaction. Hyponatraemia (low sodium) can also occur
• Aetiology and and if severe may cause coma and seizures.
pathogenesis Hydrocephalus, infarction and
• Clinical Features tuberculomas are the commonest
• Complications and causes for neurological
clinical outcome deterioration.
• Diagnosis
• Microscopy and
Paradoxical treatment reactions
culture
• Imaging due to an intense inflammatory
• Therapy reaction are well described e.g
• Key points expansion
• Summary
• References/Further
reading
• Self assessment
Diagnosis of TB meningitis
Early diagnosis of TB Meningitis is of paramount importance as
TB Meningitis delayed treatment has shown high mortality and morbidity. A high
index of clinical suspicion is vital.
• Learning Objectives
• Introduction Various diagnostic algorithms have been published to aid clinical
• Global problem diagnosis of TB meningitis, however their use is not recommended
• Aetiology and in HIV positive patients. At present, these algorithms have not been
pathogenesis validated for use in a low TB prevalence settings.
• Clinical Features
• Complications and An initial study on children was conducted in India (Kumar et al
clinical outcome
1999) to assess the correlation of the presenting clinical features
• Diagnosis
with a diagnosis of TB meningitis. This was followed by a study in
• Microscopy and
culture Vietnam in adult patients and a diagnostic algorithm was created
• Imaging based on the parameters of age, total blood white cell count, total
• Therapy CSF white cell count, CSF percentage neutrophils and the duration
• Key points of illness at the time of presentation. Each parameter was given a
• Summary weighted score. A total score of ≤ 4 is suggestive of TBM.
• References/Further
reading
• Self assessment
Limitations of the Available
Diagnostic Tests for TB Meningitis
TB Meningitis 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.
• Learning Objectives
• Introduction Co-infection with HIV does not significantly alter the CSF profile.
• Global problem Polymorphonuclear leucocytosis can be seen early on in the disease with a
• Aetiology and subsequent shift to lymphocyte predominance. Neutrophilia has also been
pathogenesis observed in patients on treatment and is thought to be secondary to a
• Clinical Features hypersensitivity reaction. Rarely, the CSF can be normal.
• Complications and
clinical outcome
• Diagnosis
• Microscopy and
culture
• Imaging
• Therapy
• Key points
• Summary
• References/Further
reading
• Self assessment
Microscopy and Culture
Identification by microscopy and
culture are the most widely available
TB Meningitis tools.

• Learning Objectives M.Tuberculosis is a gram positive rod


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

• Learning Objectives Culture on Lowenstein–Jensen


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

Brain imaging can provide useful


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

• Learning Objectives According to the NICE guidelines (March 2011), patients with
• Introduction active meningeal TB should be prescribed a treatment regime
• Global problem comprising four drugs for the first two months (isoniazid,
• Aetiology and pyrazinamide, rifampicin and a fourth drug such as ethambutol)
pathogenesis followed by isoniazid and rifampicin for the rest of the treatment
• Clinical Features
period.
• Complications and
clinical outcome
• Diagnosis
At present, the optimal drug regimen and duration is not
• Microscopy and established. Daily dosing and combination medications should be
culture considered.
• Imaging
• Therapy Aspects of possible drug resistance, poor compliance, disease
• Key points severity and variable CNS drug penetration should be borne in
• Summary mind while prescribing anti tubercular drugs.
• References/Further
reading
• Self assessment
Therapeutic Options
Adjunctive steroids are recommended in TBM.
TB Meningitis
Steroid doses should follow those used in proven trials. Tapering of
• Learning Objectives doses should be initiated within 2-3 weeks and done over 6-8 weeks.
• Introduction Glucocorticoid equivalent to 20 – 40 mg of Prednisolone for patients
• Global problem on rifampicin otherwise 10-20mg is recommended by NICE
• Aetiology and guidelines.
pathogenesis
• Clinical Features Benefits of steroid use in HIV positive individuals is not proven. In the
• Complications and case of multi-drug resistant TB (MDR-TB) experts should be involved
clinical outcome in the management. For advice email: mdrtbservice@lhch.nhs.uk.
• Diagnosis
• Microscopy and Complications of hydrocephalus
culture and tubercular abscess will need
• Imaging neurosurgical involvement.
• Therapy Ventriculoperitoneal shunts for
• Key points non communicating
• Summary hydrocephalus should be
• References/Further considered early rather than
reading later.
• Self assessment
Key Points
• Tuberculosis is a global emergency with very high morbidity and mortality

TB Meningitis • Clinical judgement remains paramount in the diagnosis of TB meningitis

• Learning Objectives • There is no perfect test to diagnose TB meningitis


• Introduction
• High index of suspicion along with the use of a combination of tests is
• Global problem
required to guide diagnosis
• Aetiology and
pathogenesis • Treatment should be continued with 4 drugs for a minimum of 12 months. If
• Clinical Features in doubt seek expert advice early.
• Complications and
clinical outcome • Steroids are a useful adjunct in the management
• Diagnosis
• Microscopy and • Management of patients with co-existent HIV should be done in collaboration
culture with experts in HIV
• Imaging
• Therapy • Untreated, TB meningitis is fatal. Despite treatment, there are significant
• Key points neurological sequelae
• Summary
• References/Further • There are many unresolved issues with the diagnosis and management of
TB meningitis
reading
• Self assessment
Summary
Having completed this session you will now be able to:
TB Meningitis
• Recognise the global problem of tuberculosis
• Learning Objectives
• Introduction • Describe the aetiology and pathogenesis of TB Meningitis
• Global problem
• Aetiology and • Explain the clinical features, complications and clinical outcomes
pathogenesis
of TB meningitis
• Clinical Features
• Complications and
• Be aware of the limitations of the available diagnostic tests for TB
clinical outcome
• Diagnosis meningitis
• Microscopy and
culture • List the therapeutic options available
• Imaging
• Therapy
• Key points
• Summary
• References/Further
reading
• Self assessment
References/ Further reading
• World Health Organization Health Topics: Tuberculosis.
NICE guidelines.
TB Meningitis • British HIV Association guidelines for the treatment of TB/HIV coinfection
2010.
• Learning Objectives • Rock et al Clinical Microbiology Reviews, Apr. 2008, p. 243–261 Central
• Introduction Nervous System Tuberculosis: Pathogenesis and Clinical Aspects.
• Global problem • Kalita J et al European Journal of Neurology 2007, 14: 33–37 .Predictors of
long-term neurological sequelae of tuberculous meningitis: a multivariate analysis.
• Aetiology and
• Tuberculosis in the UK: Annual report on tuberculosis surveillance in the UK,
pathogenesis
2010. London: Health Protection Agency Centre for Infections, October 2010.
• Clinical Features • Kruijshaar and Abubakar . Thorax .2009;64:1090-1095 Increase in
• Complications and extrapulmonary tuberculosis in England and Wales 1999–2006.
clinical outcome • Nicholas A Be et al. Current Molecular Medicine 2009, 9, 94-99. Pathogenesis
• Diagnosis of Central Nervous System Tuberculosis
• Microscopy and • British Infection Society guidelines for the diagnosis and treatment of
culture tuberculosis of the central nervous system in adults and children. Thwaites G et al
• Imaging Journal of Infection (2009) 59, 167e187
• Therapy • Thwaites GE.2002.The diagnosis and management of tuberculous meningitis..
• Key points Practical Neurology, 2, 250–261
• Summary • Kumar R, Singh SN, Kohli N (1999) A diagnostic rule for tuberculous
• References/Further meningitis. Archives of the diseases of childhood, 81, 221–4.
reading
• Self assessment
Assessment: Question 1

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