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TB Meningitis
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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
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.
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.
Edited by Prof Tom Solomon and Dr Agam Jung
Learning Objectives
TB Meningitis
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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
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
Introduction
TB Meningitis
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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
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.
Global Problem of Tuberculosis
TB Meningitis
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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.
Global Problem of Tuberculosis
TB Meningitis
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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.
Global Problem of Tuberculosis: Europe
and UK
TB Meningitis
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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
Aetiology and Pathogenesis of TB
Meningitis I
TB Meningitis
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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.
Aetiology and Pathogenesis of TB
Meningitis II
TB Meningitis
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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.
Clinical features
TB Meningitis
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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.
Complications and Clinical
Outcomes
TB Meningitis
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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 Bacille
Calmette-Guérin (BCG) vaccination is thought to reduce the
morbidity.
Complications and Clinical
Outcomes
TB Meningitis
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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
Diagnosis of TB meningitis
TB Meningitis
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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.
Limitations of the Available
Diagnostic Tests for TB Meningitis
TB Meningitis
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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.
Microscopy and Culture
TB Meningitis
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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
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%.
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 Auramine Rhodamine
stains.
Culture
TB Meningitis
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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
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.
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.
Imaging
TB Meningitis
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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.
Imaging
TB Meningitis
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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
Therapeutic Options
TB Meningitis
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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.
Therapeutic Options
TB Meningitis
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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: [email protected].
Complications of hydrocephalus
and tubercular abscess will need
neurosurgical
involvement.
Ventriculoperitoneal shunts for
non
communicating
hydrocephalus
should
be
considered early rather than
later.
Key Points
TB Meningitis
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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
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Tuberculosis is a global emergency with very high morbidity and mortality
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Clinical judgement remains paramount in the diagnosis of TB meningitis
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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.
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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
Summary
TB Meningitis
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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:
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Recognise the global problem of tuberculosis
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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
References/ Further reading
TB Meningitis
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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.
Assessment: Question 1
TB Meningitis
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TB meningitis is a notifiable disease
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
True
False