Personal View

Tuberculous meningitis: a uniform case definition for use in

clinical research
Suzaan Marais, Guy Thwaites, Johan F Schoeman, M Estée Török, Usha K Misra, Kameshwar Prasad, Peter R Donald, Robert J Wilkinson, Ben J Marais

Tuberculous meningitis causes substantial mortality and morbidity in children and adults. More research is urgently Lancet Infect Dis 2010;
needed to better understand the pathogenesis of disease and to improve its clinical management and outcome. A 10: 803–12
major stumbling block is the absence of standardised diagnostic criteria. The different case definitions used in various Published Online
September 6, 2010
studies makes comparison of research findings difficult, prevents the best use of existing data, and limits the
DOI:10.1016/S1473-
management of disease. To address this problem, a 3-day tuberculous meningitis workshop took place in Cape Town, 3099(10)70138-9
South Africa, and was attended by 41 international participants experienced in the research or management of Department of Medicine,
tuberculous meningitis. During the meeting, diagnostic criteria were assessed and discussed, after which a writing GF Jooste Hospital, Manenberg,
committee was appointed to finalise a consensus case definition for tuberculous meningitis for use in future clinical South Africa (S Marais MBChB,
research. We present the consensus case definition together with the rationale behind the recommendations. This Prof R J Wilkinson FRCP); Clinical
Infectious Diseases Research
case definition is applicable irrespective of the patient’s age, HIV infection status, or the resources available in the Initiative, Institute of
research setting. Consistent use of the proposed case definition will aid comparison of studies, improve scientific Infectious Diseases and
communication, and ultimately improve care. Molecular Medicine, and
Department of Medicine,
University of Cape Town, South
Introduction Indonesia) attended the meeting. Participants included Africa (S Marais, R J Wilkinson);
Tuberculous meningitis is the most severe form of paediatric and adult neurologists, neurosurgeons, Imperial College, London, UK
tuberculosis and causes substantial morbidity and infectious diseases specialists, microbiologists, (G Thwaites PhD, R J Wilkinson);
Department of Paediatrics and
mortality in adults and children.1–10 The outcome of this immunologists, pharmacologists, and clinical trialists.
Child Health, Faculty of Health
disease is especially grave in patients with HIV.11–14 13 international tuberculous meningitis experts, all of Sciences, Stellenbosch
Clinicians face substantial challenges in the diagnosis and whom have published on the disease in international University, South Africa
management of tuberculous meningitis:15 disease peer-reviewed journals during the past 5 years, presented (J F Schoeman MD,
Prof P R Donald FRCP,
pathogenesis is poorly understood; rapid, sensitive, and their research findings. On the final day of the meeting,
Prof B J Marais PhD);
affordable diagnostic tests are not available; and the best the existing diagnostic criteria were assessed and a Department of Infectious
management has not been established by randomised consensus case definition for tuberculous meningitis Diseases, Cambridge University
controlled trials. Further research is urgently needed, but was developed. A writing committee of nine members Hospitals NHS Foundation
Trust, Cambridge, UK
the low frequency with which a definitive diagnosis is was appointed to review the existing data and develop the
(M E Török PhD); Department of
established and the absence of a uniform clinical case final consensus statement. Neurology, Sanjay Gandhi Post
definition are major obstacles. Detection of acid-fast bacilli Graduate Institute of Medical
(AFB) and culture isolation of Mycobacterium tuberculosis Standardised clinical case definition Sciences, Lucknow, India
(Prof U K Misra MD);
from cerebrospinal fluid (CSF) have been reported with In the past 5 years, studies have used various case definitions Department of Neurology, All
high frequency in some studies16,17 but are the exception in for tuberculous meningitis (panel 1).1,3,4,8,10,11,17,18,20–24 In most India Institute of Medical
most.1,7,18,19 Diagnosis usually relies on clinical evidence, definitions, patients are given a definite, probable, or Sciences, New Delhi, India
which combines supportive clinical, laboratory, and possible tuberculous meningitis status depending on (Prof K Prasad FRCP); and
National Institute for Medical
radiological findings. Standardised diagnostic criteria for clinical, laboratory, and radiological findings. Definite Research, Mill Hill, London, UK
tuberculous meningitis have not been established, and tuberculous meningitis cases usually include patients with (R J Wilkinson)
most reports have used different case definitions. This AFB on CSF microscopy or M tuberculosis cultured from Correspondence to:
absence of standardisation makes comparison of research CSF or another CNS source. However, some studies also Dr Suzaan Marais, Department of
findings difficult, prevents the best use of the existing included patients with M tuberculosis identified from Medicine, GF Jooste Hospital,
Manenberg, 7764, South Africa
data, and limits progress in management. To address specimens such as gastric aspirates, urine, or sputum,11,24 suzaanmarais@gmail.com
these issues, an international tuberculous meningitis or with M tuberculosis identified by PCR8,25–27 or IgM ELISA.8
workshop took place in Cape Town, South Africa, in May, Criteria for probable or possible tuberculous meningitis
2009, to establish a consensus case definition for cases differ greatly between studies, especially between
tuberculous meningitis for use in future clinical research. studies done in children and adults. Some studies do not
We present the consensus case definition, which should distinguish between patients with confirmed and suspected
be uniformly applicable, irrespective of the patient’s age or tuberculous meningitis.4,7
HIV infection status or the resources available in the We propose that patients with suspected tuberculous
research setting. meningitis should be allocated to one of four diagnostic
The organisers of the meeting invited leading categories depending on the strength of clinical,
tuberculous meningitis researchers and clinicians with laboratory, or radiological findings. The proposed
experience managing patients with tuberculous categories are definite, probable, possible, and not
meningitis. 41 participants from seven countries (South tuberculous meningitis (figure 1). A patient suspected to
Africa, the UK, Vietnam, India, the USA, Malawi, and have tuberculous meningitis should be regarded as

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Panel 1: Examples of tuberculousis case definitions used for adults, children, or both in the past 5 years
Adults only iii) Clinical evidence of other extrapulmonary tuberculosis
Torok (2008)17 • Possible tuberculous meningitis: clinical meningitis and four or more of
• Patients: HIV seropositive, ≥15 years of age the following:
• Case definition includes definite and probable tuberculous meningitis i) History of tuberculousis
cases ii) Predominance of lymphocytes in the CSF
• Definite tuberculous meningitis: CSF smear positive for AFB and/or culture iii) Illness of more than 5 days in duration
positive for Mycobacterium tuberculosis iv) CSF to blood glucose ratio of less than 0·5
• Probable tuberculous meningitis: clinically suspected tuberculous v) Altered consciousness
meningitis plus one or more of the following four criteria: vi) Yellow CSF
i) CXR consistent with pulmonary tuberculosis vii) Focal neurological signs
ii) Other specimens (eg, sputum, lymph node, gastric washings) • Patients were subsequently reclassified as having definite tuberculous
positive for AFB meningitis if AFB were seen in or M tuberculosis was cultured from the CSF,
iii) Evidence of extrapulmonary tuberculosis and as not having tuberculous meningitis if another diagnosis was
iv) CT or MRI evidence of tuberculous meningitis confirmed by microbiological or histopathological assessment
• Patients were excluded if there was microbiological evidence of another
Adults and children
CNS infection.
Nagesh Babu (2008)21
Kalita (2007)8 • Case definition includes definite and presumptive tuberculous meningitis
• Patients: HIV seronegative, ≥13 years of age cases
• Case definition includes definite and suggestive tuberculous meningitis A) Clinical criteria: fever, headache, meningeal signs, and other clinical
cases. presentations of meningitis lasting for more than 2 weeks.
A) Clinical criteria: meningitic symptoms including fever, headache, B) CSF criteria: typical features including pleocytosis (>20 cells/μL),
and vomiting for 2 or more weeks lymphocytes >60%, protein >1 g/L, and CSF: blood glucose ratio of less
B) Supportive criteria: than 0·6
i) CSF cells ≥20/μL with predominant lymphocytes, protein ≥2 g/L C) Supportive criteria:
ii) CT scan evidence of exudates, infarctions, hydrocephalus, and i) Isolation of M tuberculosis from body secretion other than CSF in
tuberculoma in various combinations smear or culture
iii) Evidence of extra-CNS tuberculosis ii) CXR findings of pulmonary tuberculosis (reticulonodular pattern in
iv) Response to antituberculosis therapy upper lobes with or without cavitary lesions)
C) Exclusion criteria: malaria, septic, fungal, and carcinomatous iii) Hydrocephalous from brain CT scan
meningitides D) Negative bacterial and fungal cultures and negative India ink
• Definite tuberculous meningitis: A and C plus positive PCR for • Definite tuberculous meningitis diagnostic criteria not stated
M tuberculosis or IgM ELISA , or AFB in CSF smear or culture • Diagnosis of presumptive tuberculous meningitis requires A, B, one or
• Suggestive tuberculous meningitis: A, C, and three or more of B more of C, and D to be fulfilled
Thwaites (2004)10 Rafi (2007)23
• Patients: HIV seropositive and negative, >14 years of age • Patients: HIV seropositive and negative
• Case definition includes definite, probable, and possible tuberculous • Case definition includes culture-confirmed and clinical tuberculous
meningitis cases meningitis cases
• Definite tuberculous meningitis: clinical meningitis (nuchal rigidity and • Diagnosis of clinical tuberculous meningitis requires A, B, and C:
abnormal CSF parameters) and AFB in the CSF A) Clinical findings: headache, fever, and vomiting for more than 3 weeks
• Probable tuberculous meningitis: clinical meningitis and one or more of B) CSF findings: pleocytosis and high protein concentration
the following: C) Neuroimaging findings: the presence of a basal exudate with or
i) Suspected active pulmonary tuberculosis on the basis of CXR without hydrocephalus
ii) AFB found in any sample other than from the CSF (Continues on next page)

having possible or probable tuberculous meningitis, Definite tuberculous meningitis

depending on initial lumbar puncture or cerebral A diagnosis of definite tuberculous meningitis is made
imaging findings. Results from subsequent tests will when AFB are seen, M tuberculosis is cultured, or
determine the patient’s final diagnostic category—for M tuberculosis is detected by a reliable molecular method
example, a patient will move up to the definite tuberculous from the CSF in someone with symptoms or signs
meningitis category if M tuberculosis is cultured from suggestive of the disease. AFB seen in the context of
their CSF. Conversely, a patient will move down to the histological changes consistent with tuberculosis in the
not tuberculous meningitis category if evidence for an brain or spinal cord are also diagnostic for tuberculous
alternative diagnosis is identified (panel 2). meningitis (mostly seen on autopsy). Identification

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(Continued from previous page) B) CSF criteria:

i) Pleocytosis (>20 cells per μL) with lymphocyte predominance
3) Children only
(>50%)
van Well (2009)1
ii) Protein concentration greater than age-specific normal value;
• Patients: HIV seropositive and negative
especially >1·0 g/L
• Case definition includes definite and probable cases
iii) Chloride <120 mmol/L
• Definite tuberculous meningitis: M tuberculosis isolated from CSF
iv) Glucose concentration less than 60% of concentration in blood
• Probable tuberculous meningitis: clinical signs of meningitis plus
v) AFB on stains; negative India ink stains for cryptococcosis
characteristic CSF findings (macroscopically clear, pleocytosis, raised
vi) Culture positive for tuberculosis
protein, and reduced glucose), plus two or more of the following criteria:
• Definite tuberculous meningitis: culture-positive CSF for tuberculosis—ie,
i) Recent poor weight gain (crossing of percentiles on Road to Health card)
B(vi)
ii) Household contact with sputum smear-positive tuberculosis
• Probable tuberculous meningitis: A (iii) and two other positives from A
iii) CT scan compatible with tuberculous meningitis
and three positives from B
iv) CXR compatible with primary tuberculosis
• Patients are classified as not having tuberculous meningitis if criteria
v) Positive TST
are not met or if an alternative diagnosis is made by culture or trial
vi) Other clinical specimens positive for AFB
of therapy.
Andronikou (2006)20
Saitoh (2005)4
• Case definition includes definite and probable cases
• Diagnostic criteria for tuberculous meningitis:
A) Clinical criteria:
• CSF pleocytosis (≥10 cells per μL ) with one or more of the following:
i) Household tuberculosis contact
i) Positive CSF culture for M tuberculosis complex organisms
ii) Positive Mantoux tests (>15 mm)
(M tuberculosis or Mycobacterium bovis)
iii) Neurological features: depressed level of consciousness, focal
ii) Positive M tuberculosis PCR in CSF
neurological signs, raised intracranial pressure, seizures, or
iii) Positive CSF smear for AFB
meningism
iv) Positive gastric aspirate M tuberculosis culture or AFB smear
iv) Systemic upset (in combination with neurological findings):
v) Positive TST with clinical evidence of tuberculous meningitis including
failure to thrive, fever, night sweats, proven pulmonary
CT findings or close contact with individuals with known or suspected
tuberculosis, proven abdominal tuberculosis, or evidence of
tuberculosis.
extra-neurological involvement
v) Prolonged symptoms for more than 48h CSF=cerebrospinal fluid. AFB=acid fast bacilli. CXR=chest radiograph. TST=tuberculin skin test.

of M tuberculosis from CSF, either by detection of AFB or CSF molecular diagnostic methods, such as nucleic
culture, is difficult, but the chances of positive diagnosis acid amplification tests4,8,25–27 and M tuberculosis antibody
can be increased by doing more lumbar punctures. From detection assays,8 have previously been included in
an initial lumbar puncture sample, Kennedy and Fallon28 diagnostic criteria for tuberculous meningitis. Because
recorded the sensitivity of microscopy to be 37% and the of their highly variable sensitivity and specificity,
sensitivity of culture to be 52%. When up to four lumbar both antibody assays33–35 and in-house nucleic acid
punctures were done, the sensitivity of microscopy amplification tests18,23 are regarded as experimental.
increased to 87% and the sensitivity of culture increased Commercial nucleic acid amplification tests generally
to 83%. Increasing the volume of CSF obtained and show high specificities36 and can therefore be used
meticulous microscopy (for at least 30 min) further to establish a definitive diagnosis in someone with
increases the chance of positive diagnosis.16 Although the symptoms or signs suggestive of tuberculous
benefits of fluorescence microscopy to detect AFB from meningitis. However, more data are urgently needed to
sputum is well established,29 data on its sensitivity for the establish the robustness of these tests in field conditions;
detection of AFB from CSF are sparse.30 Light-emitting the specificities of both culture and PCR methods
diode fluorescence microscopy systems provide a simple might be compromised in areas endemic for
and inexpensive alternative to costly mercury vapour tuberculosis because of an increased risk of sample
bulbs,29 but further studies are needed to assess its cross-contamination.37 The Xpert MTB/RIF assay
application in the diagnosis of tuberculous meningitis. (Cepheid, CA, USA), is one of several methods that
The microscopic observation drug susceptibility assay is uses real-time PCR to amplify and detect M tuberculosis
a liquid culture method that detects characteristic and identify drug resistance. This is an easy, rapid
M tuberculosis morphology by use of an inverse light method that was sensitive and highly specific in initial
microscope.31 This technique, which enables simultaneous studies done in patients with pulmonary tuberculosis.38
detection of M tuberculosis and determination of drug Studies are underway to validate these findings and to
susceptibility, might prove a rapid and sensitive diagnostic determine this assay’s application in extrapulmonary
method for tuberculous meningitis.32 tuberculosis.

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will allow direct comparison in future tuberculous

Patient with suspected tuberculous meningitis meningitis studies. Thus, although the proposed case
definition requires formal validation in both retrospective
and prospective studies in various settings, its application
should encourage identification in reports of the most
important diagnostic variables and allow more accurate
Lumbar puncture Brain CT/MRI
comparison of the results of different studies.
Definite tuberculous
meningitis
Clinical criteria
The clinical presentation of tuberculous meningitis is
Probable tuberculous meningitis:
Diagnostic score ≥10/12 non-specific, especially in the early stages of disease.
Adults and children typically present with fever, headache,
Possible tuberculous meningitis: irritability, neck stiffness, and vomiting.1,5–7,11,39,40 These
Diagnostic score 6–9/6–11 symptoms do not, however, distinguish tuberculosis
from other forms of meningitis.5,19,39,41 Systemic symptoms
of M tuberculosis infection, such as lethargy, cough,
Not tuberculous meningitis: alternative cause identified
weight loss (or poor weight gain in children), and night
sweats might be suggestive of tuberculosis, but are also
Figure 1: Categories for patients with suspected tuberculous meningitis non-specific.1,6,7,11 Unfortunately, many patients present
Patients suspected of tuberculous meningitis enter a study after lumbar puncture or brain imaging has been done with advanced disease and neurological signs, such as
in those meeting required criteria. Patients then move up or down the diagnostic pyramid as subsequent results
convulsions, an abnormal mental state, cranial nerve
become available and are classified into definite, probable, possible, or not tuberculous meningitis according to
diagnostic criteria. Definite tuberculous meningitis: microbiological identification or evidence from commercial palsies, or limb paresis.1,6,7,11,12 Although patients with HIV
nucleic acid amplification tests of CNS Mycobacterium tuberculosis infection. Probable tuberculous meningitis: are more likely to present with disseminated tuberculosis
when imaging is available a diagnostic score of 12 or above is required, and when imaging is not available, a than patients without HIV,9,12 and might have clinical
diagnostic score of 10 or above is required. Possible tuberculous meningitis: when imaging is available a diagnostic
score of 6–11 is required, and when imaging is not available, a score of 6–9 is required.
features suggestive of HIV/AIDS,11,17 HIV infection does
not seem to affect the neurological presentation of
tuberculous meningitis.9,11,12
In summary, a diagnosis of definite tuberculous Four studies have attempted to define the clinical and
meningitis should be made when one or more of the laboratory features that distinguish tuberculous meningitis
following criteria are met: AFB seen in the CSF, from bacterial5,19,25,39 and other19 causes of meningitis. The
M tuberculosis cultured from CSF, or a CSF M tuberculosis- diagnostic value of headache to differentiate bacterial
positive commercial nucleic acid amplification test from meningitis from tuberculous meningitis showed
a patient who presents with symptoms or signs suggestive discrepant results.5,39 In one adult study, cranial nerve
of meningitis; or AFB seen in the context of histological palsies were more common in adult patients with
changes consistent with tuberculosis in the brain or tuberculous meningitis than in those with bacterial
spinal cord together with suggestive symptoms or signs meningitis.39 Optic atrophy, extra-pyramidal movements,
and CSF changes, or visible meningitis (on autopsy). and focal deficits were associated with tuberculous
meningitis in one paediatric study,19 but optic atrophy is a
Probable and possible tuberculous meningitis late occurrence and abnormal extra-pyramidal movements
We propose that the diagnosis of probable or possible are rare. None of these findings have been validated in
tuberculous meningitis be determined by a diagnostic patients with HIV, and cryptococcal meningitis shares
scoring system (table) that requires the presence of similar clinical features.42,43
symptoms or signs indicative of meningitis plus The average duration between symptom onset and
additional clinical, CSF, or imaging criteria, with tuberculous meningitis presentation is 5–30 days1,4–6,10,19 and
exclusion of the most likely alternative diagnoses. The does not differ between patients with and without HIV.12,44
number of points required for a diagnosis of probable Symptom duration of more than 4 days,25 5 days,5,39 or
tuberculous meningitis (≥12 when imaging is available 6 days19 has been used to discriminate between tuberculous
or ≥10 when imaging is not available) and the points meningitis and bacterial meningitis in HIV-seronegative
awarded in each category were decided by reviewing adults and paediatric patients, but cannot differentiate
studies that quantified the diagnostic contribution of tuberculous meningitis from cryptococcal meningitis,
specific variables5,19,25,39 and based on personal experience which also presents as subacute meningitis.41,45
and consensus. The guiding principle was to encourage a A history of recent close contact with a person with
uniform approach and to ensure diagnostic certainty of infectious tuberculosis (within the past 12 months) is an
the highest possible standard, irrespective of the available important clue to the diagnosis of tuberculous meningitis
resources. We have considered all available evidence on in children, affecting more than 50%.1,44,46,47 A positive
the differential diagnostic relevance of clinical variables tuberculin skin test also indicates probable M tuberculosis
to standardise definitions and establish uniformity that infection. However, the sensitivity of the tuberculin skin

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test is variable; reported sensitivities range from 17% to

32% in mixed adult and paediatric populations6,7 and 30% Panel 2: Consensus tuberculous meningitis diagnosis
to 77% in children.1,11,19,44,46 In infants, the sensitivity can be Clinical entry criteria
as high as 86%,48 but specificity would be reduced in • Symptoms and signs of meningitis including one or more of the following: headache,
settings with universal BCG vaccination because of irritability, vomiting, fever, neck stiffness, convulsions, focal neurological deficits,
cross-reacting immune responses, which tend to wane altered consciousness, or lethargy.
with time. An HIV infection in patients with tuberculosis49
or tuberculous meningitis44,50 reduces the likelihood of Tuberculous meningitis classification
positive tuberculin skin test results. Additionally, a Definite tuberculous meningitis
positive tuberculin skin test does not differentiate • Patients should fulfill criterion A or B:
M tuberculosis infection (which is a common event in A) Clinical entry criteria plus one or more of the following: acid-fast bacilli seen in the
tuberculosis endemic areas) from active disease.51 CSF; Mycobacterium tuberculosis cultured from the CSF; or a CSF positive
Peripheral blood interferon-gamma release assays are commercial nucleic acid amplification test.
useful in the diagnosis of tuberculosis infection.52 B) Acid-fast bacilli seen in the context of histological changes consistent with
Generally, these tests have higher specificity than do tuberculosis in the brain or spinal cord with suggestive symptoms or signs and CSF
tuberculin skin tests,53 although sensitivities vary and changes, or visible meningitis (on autopsy).
interferon-gamma release assays do not make the crucial Probable tuberculous meningitis
distinction between M tuberculosis infection and active • Clinical entry criteria plus a total diagnostic score of 10 or more points (when cerebral
disease. There is little data on the efficiency of the assays imaging is not available) or 12 or more points (when cerebral imaging is available)
in severe disease such as tuberculous meningitis, and plus exclusion of alternative diagnoses. At least 2 points should either come from CSF
their role in the diagnosis of children or patients with or cerebral imaging criteria.
HIV has not been established. In immunocompromised Possible tuberculous meningitis
adults with extrapulmonary tuberculosis these assays • Clinical entry criteria plus a total diagnostic score of 6–9 points (when cerebral
have a sensitivity of 88% (95% CI 68–97%) and a imaging is not available) or 6–11 points (when cerebral imaging is available) plus
specificity of 71% (51–86%),54 and in adult patients with exclusion of alternative diagnoses. Possible tuberculosis cannot be diagnosed or
tuberculous meningitis they have a sensitivity of 69% excluded without doing a lumbar puncture or cerebral imaging.
(51–83%) and a specificity of 57% (42–70%).55 However,
further studies are needed to validate these findings. The Not tuberculous meningitis
rate of false negatives in patients with HIV with active • Alternative diagnosis established, without a definitive diagnosis of tuberculous
tuberculosis increases as the CD4 cell count declines,56 meningitis or other convincing signs of dual disease.
which is of particular importance in such patients with CSF=cerebrospinal fluid.
tuberculous meningitis, many of whom present with
profound immunosuppression. A systematic review
of commercially available antibody detection tests without a definite tuberculous meningitis diagnosis,
concluded that such tests have no role in the diagnosis should, according to our consensus case definition, be
of extrapulmonary tuberculosis.57 classified as probable, possible, or not tuberculous
Response to tuberculosis treatment is generally included meningitis, depending on their total diagnostic score.
in classification systems8,22,24 but is an unreliable diagnostic Duration of neurological symptoms for more than 5 days
aid. In practice, many patients presenting with clinical is the most informative clinical criterion. A miliary picture
features of meningitis receive antimicrobial treatment for on chest radiograph, the presence of lethargy, or other
both tuberculous meningitis and bacterial meningitis. subtle signs in high-risk children (ie, children less than
Improvement of the patient’s health after treatment will 3 years of age with documented M tuberculosis exposure)
also not distinguish tuberculous meningitis from viral might also justify CSF examination or imaging studies.
meningitis, which usually resolves spontaneously. The score required for classification as probable
Conversely, no response to treatment does not preclude tuberculous meningitis will vary according to the
the diagnosis of tuberculous meningitis; patients with availability of cerebral imaging (≥12 when imaging is
multidrug-resistant tuberculous meningitis show little or available or ≥10 when imaging is not available) to encourage
no clinical improvement with standard tuberculosis a uniform approach and ensure diagnosis with the highest
treatment and their prognosis is poor.58,59 Furthermore, at possible certainty, irrespective of the resources available.
least 10% of patients with tuberculous meningitis have
paradoxical deterioration after treatment initiation.40,60 For CSF criteria
these reasons, we have not included response to treatment Routine analysis of CSF in most patients with tuberculous
in the consensus case definition. meningitis shows clear appearance, pleocytosis
In summary, all patients with features suggestive of (range=5–1000 cells per μL; median=50–450 cells per μL)
meningitis (one or more of the following: headache, with a lymphocyte predominance, a raised protein
irritability, vomiting, fever, neck stiffness, convulsions, concentration (0·5–3 g/L), and a low glucose
focal neurological deficits, or altered consciousness) and concentration (absolute value <2·2 mmol/L and a CSF to

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Diagnostic score
Clinical criteria (Maximum category score=6)
Symptom duration of more than 5 days 4
Systemic symptoms suggestive of tuberculosis (one or more of the following): weight loss (or poor weight gain in children), 2
night sweats, or persistent cough for more than 2 weeks
History of recent (within past year) close contact with an individual with pulmonary tuberculosis or a positive TST or IGRA 2
(only in children <10 years of age)
Focal neurological deficit (excluding cranial nerve palsies) 1
Cranial nerve palsy 1
Altered consciousness 1
CSF criteria (Maximum category score=4)
Clear appearance 1
Cells: 10–500 per μl 1
Lymphocytic predominance (>50%) 1
Protein concentration greater than 1 g/L 1
CSF to plasma glucose ratio of less than 50% or an absolute CSF glucose concentration less than 2·2mmol/L 1
Cerebral imaging criteria (Maximum category score=6)
Hydrocephalus 1
Basal meningeal enhancement 2
Tuberculoma 2
Infarct 1
Pre-contrast basal hyperdensity 2
Evidence of tuberculosis elsewhere (Maximum category score=4)
Chest radiograph suggestive of active tuberculosis: signs of tuberculosis=2; miliary tuberculosis=4 2/4
CT/ MRI/ ultrasound evidence for tuberculosis outside the CNS 2
AFB identified or Mycobacterium tuberculosis cultured from another source—ie, sputum, lymph node, gastric washing, urine, 4
blood culture
Positive commercial M tuberculosis NAAT from extra-neural specimen 4
Exclusion of alternative diagnoses
An alternative diagnosis must be confirmed microbiologically (by stain, culture, or NAAT when appropriate), serologically
(eg, syphilis), or histopathologically (eg, lymphoma). The list of alternative diagnoses that should be considered, dependent
upon age, immune status, and geographical region, include: pyogenic bacterial meningitis, cryptococcal meningitis, syphilitic
meningitis, viral meningo-encephalitis, cerebral malaria, parasitic or eosinophilic meningitis (Angiostrongylus cantonesis,
Gnathostoma spinigerum, toxocariasis, cysticercosis), cerebral toxoplasmosis and bacterial brain abscess (space-occupying lesion
on cerebral imaging)and malignancy (eg, lymphoma)

TST=tuberculin skin test. IGRA=interferon-gamma release assay. NAAT=nucleic acid amplification test. AFB=acid-fast bacilli. The individual points for each criterion (one,
two, or four points) were determined by consensus and by considering their quantified diagnostic value as defined in studies.

Table: Diagnostic criteria for classification of definite, probable, possible, and not tuberculous meningitis

plasma ratio <50% [median=~27%]).1,5,6,13,17,19,61 Although determination can be of benefit as a rule-in or rule-out
lower CSF protein concentrations13,14 and white cell test when values of less than 4 U/L and greater than 8 U/L
counts13,14,62 have been described in patients with HIV, are used, it cannot discriminate between tuberculous
most studies show similar findings compared to patients meningitis and bacterial meningitis.66 False-positive
without HIV.11,12,44,63–65 Atypical CSF findings have been results can also be found in patients infected with
described in both groups, including normal CSF glucose, HIV who have other HIV-associated neurological
protein, cell count, or a neutrophil predominance.13,14,17,19,63–65 diseases, such as cryptococcal meningitis, lymphomatous
Rare cases of culture-proven tuberculous meningitis with meningitis, and cytomegalovirus disease.67
no other CSF abnormalities have also been reported.9 The specificity of tuberculous meningitis diagnosis can
CSF findings that favour the diagnosis of tuberculosis be increased by molecular diagnostic tests. A systematic
over bacterial meningitis include clear appearance,5 a review and meta-analysis of commercial nucleic acid
white-cell count less than or equal to 900–1000/μL,5,25,39 a amplification tests for the diagnosis of tuberculous
neutrophil content less than 30–75%,5,19,25,39 and a protein meningitis showed a combined average sensitivity of 56%
concentration greater than 1 g/L.5 These studies did not, and specificity of 98%.36 Because of its high specificity, a
however, include patients with HIV and cryptococcal positive commercial nucleic acid amplification test is
meningitis, many of whom have similar CSF findings.45 regarded as a definitive test in patients with suspected
Although CSF adenosine deaminase activity tuberculous meningitis, and offers particular value in

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patients who have previously received tuberculosis

A B C
treatment.68 Detection of M tuberculosis antigens30,69,70 and
antibodies35,70 in CSF, and CSF interferon-gamma release
assays26,55,71 might be useful, but these results require
verification in large studies from various settings.
In the consensus case definition, a maximum score of
four points is assigned to CSF criteria that include: a
clear CSF appearance; a leucocyte count of 10–500 cells
per μL; a lymphocyte predominance (>50%); a protein
concentration greater than 1 g/L; and a CSF to plasma
glucose ratio of less than 50% or an absolute CSF
glucose concentration of less than 2·2 mmol/L. A
commercial M tuberculosis nucleic acid amplification Figure 2: Cerebral imaging abnormalities observed in tuberculous meningitis
test is regarded as a definitive diagnostic test for Non-contrast CT scan showing hyperdense material occupying the suprasellar and middle cerebral artery cisterns
and hydrocephalus with periventricular lucency (A). Post-contrast CT scan showing basal meningeal enhancement
tuberculosis. At present, insufficient evidence exists for and multiple right-sided suprasellar rim-enhancing lesions (B). MRI flair sequence showing bilateral basal ganglia
the inclusion of CSF antibody or interferon-gamma infarcts (C). Adapted from Reference 76 with permisson from Springer.
release assay tests.
no difference on imaging between the adults with and
Cerebral imaging criteria without HIV.64 Alternative causes of meningitis, such as
The contribution of cerebral imaging to the diagnosis of cryptococcal meningitis, cytomegalovirus encephalitis,
tuberculous meningitis is well established, although its toxoplasmosis, sarcoidosis, meningeal metastases, and
performance is not essential to establish a diagnosis of lymphoma, which are more common in patients with
definite or probable disease. Abnormalities are most HIV, can result in similar radiological findings.61
frequently detected in patients with severe disease.72 On The consensus case definition recommends that, when
CT, hydrocephalus and basal meningeal enhancement possible, CT or MRI brain scans should be done as part
are the most common radiological features of tuberculous of the assessment for tuberculous meningitis.
meningitis. About 80% of children have hydrocephalus3,72–74 Recommended supportive diagnostic criteria include:
and 75% basal meningeal enhancement;1,3,75 whereas hydrocephalus, basal meningeal enhancement, infarcts,
about 45% of adolescents and adults have hydrocephalus7,8,72 tuberculoma, and pre-contrast basal hyperdensity (on
and 8–34% basal meningeal enhancement.7,8,72 Infarcts CT imaging).
(8–44% of cases)1,3,7,8,72–74 and tuberculoma (8–31%)1,3,7,8,73,74
are also seen in many cases (figure 2). Andronikou76 Evidence of tuberculosis elsewhere
recorded the presence of a pre-contrast hyperdensity in The presence of tuberculosis outside the CNS increases
the basal cisterns to be 100% specific of tuberculous the likelihood of tuberculous meningitis. Suggestive chest
meningitis in children, but this finding has not been radiograph abnormalities are seen in 33–60%1,6,7,27,65,72 of
validated in other studies. The combination of basal patients. A higher incidence of abnormal chest radiograph
meningeal enhancement, infarcts, and hydrocephalus findings,11 and extrapulmonary tuberculosis12 have been
also had 100% specificity; basal meningeal enhancement identified in association with HIV infection. Additional
was the most sensitive feature (89%). Kumar74 reported imaging (ie, chest CT scan80 and abdominal ultrasound3,65)
similar results. MRI has higher sensitivity than CT for can be useful to identify involvement of other organs.
the detection of abnormalities such as meningeal Taking samples from sites of infection other than the
enhancement, infarcts, and tuberculomas,77,78 especially CNS, such as lung, lymph node, liver, bone marrow,
of lesions involving the brainstem. Thwaites79 reported urine, ascitic fluid, and gastric fluid, further increases the
MRI findings in adult patients with tuberculous chance of a positive diagnosis.7,47 Gastric aspiration or
meningitis; 82% had basal meningeal enhancement and induced sputum are particularly useful in children; in
hydrocephalus was seen in 77% of cases. In the same one study,47 M tuberculosis was isolated in 68% of children
study, tuberculoma developed in 74% of patients during with tuberculous meningitis. Positive M tuberculosis blood
treatment, most of which were asymptomatic. Children11,44 cultures seem very rare, even in immunocompromised
and adults14,27,63 with tuberculous meningitis and HIV patients with tuberculous meningitis.59
show less hydrocephalus11,14 and basal meningeal The consensus case definition states that every effort
enhancement,11,14 and a higher frequency of infarcts,27 should be made to identify tuberculosis outside of the
gyral enhancement,44 and mass lesions compared with CNS. To do so, and when appropriate, clinicians should
patients who do not have HIV.63 Patients with HIV and use: radiological features of tuberculosis on chest
tuberculous meningitis are also more likely to have radiography, CT, MRI, or ultrasound; isolation of
cerebral atrophy,11,14 which can be difficult to distinguish M tuberculosis from sputum, gastric aspirates, lymph
from communicating hydrocephalus. However, these nodes, ascitic fluid, urine, blood, bone marrow, or any
findings are not consistent and some authors recorded other clinical specimen.

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 Personal View

Exclusion of alternative diagnosis will improve methodological rigour, allow comparison of

The provision of an exhaustive list of possible differential data, promote scientific communication, and encourage
diagnoses for tuberculous meningitis is beyond the scope research collaboration. Strengthening the evidence base
of this article, but alternative conditions with which the is essential if we are to improve the standard of care, and,
disease is commonly confused, and which should be ultimately, the clinical outcome for patients with
actively considered, are listed in the table. The diagnosis tuberculous meningitis.
of severely immunocompromised individuals (eg, patients Contributors
with HIV/AIDS), in whom more than one infection could All authors contributed equally to the preparation and writing of this
be present, can be difficult. All patients should have a CSF Personal View.
Gram stain done (preferably with bacterial culture) to Conflicts of interest
exclude pyogenic bacterial meningitis. In patients with We declare that we have no conflicts of interest.
HIV, India ink microscopy (preferably with cryptococcal Acknowledgments
antigen latex agglutination test or fungal culture) should This Personal View arose from a tuberculous meningitis workshop hosted
by the Institute of Infectious Diseases and Molecular Medicine (IIDMM)
also be done. Additional alternative diagnostic in Cape Town, South Africa. The meeting was funded by the Clinical
investigations that should be considered depending on Infectious Diseases Research Initiative, IIDMM. SM receives funding
age, immune status, and geographical region include from the Perinatal HIV Research Unit from the United States Agency for
neurosyphilis (venereal disease research laboratory or International Development (USAID) and PEPFAR. RJW receives funding
from The Wellcome Trust (084323) and the Medical Research Council. We
rapid plasma reagin assay with or without the fluorescent thank Savvas Andronikou for providing the CT image showing
treponemal antibody absorption assay, micro- pre-contrast basal hyperdensity. The following people attended the
hemagglutination assay, or Treponema pallidum particle meeting: Tasnim Bana, Roland Eastman, Brian Eley, Graham Fieggen,
agglutination assay); viral meningoencephalitis (CSF viral Anthony Figaji, Jeanine Heckmann, Gregory Hussey, Gary Maartens,
Suzaan Marais, Helen McIlleron, Graeme Meintjes, Marc Mendelson,
PCR or culture); cerebral malaria (peripheral blood smears Alvin Ndondo, Mark Nicol, Dominique J Pepper, Jonathan Peter,
for malarial parasites); parasitic or eosinophilic meningitis Helen Van der Plas, Jo Wilmshurst, Kathryn Wood (University of Cape
(CSF serology for Angiostrongylus cantonensis, Gnathostoma Town, Cape Town, South Africa); Kathleen Bateman, Peter R Donald,
Franclo Henning, Richard Hewlett, Pieter Janse van Rensburg,
spinigerum, toxocariasis, and cysticercosis); cerebral
Ben J Marais, Johan F Schoeman, Priscilla Springer, Ronald Van Toorn
toxoplasmosis (cerebral imaging and positive serum (University of Stellenbosch, Cape Town, South Africa); Ahmed Bhigjee
serology for Toxoplasma gondii or histopathology); pyogenic (University of KwaZulu-Natal, Durban, South Africa); Maxine Caws,
bacterial brain abscess (cerebral imaging or histopathology); Anna D Heemskerk (Oxford University Clinical Research Unit, Ho Chi
Minh City, Vietnam); Macaya Douoguih, Lisa Beth Ferstenberg
and malignancy (cytology or histopathology).
(AERAS Global TB Vaccine Foundation, USA); Robert Heyderman
The consensus case definition recommends that an (Malawi- Liverpool-Wellcome Trust Clinical Research Programme,
alternative diagnosis should be confirmed Blantyre, Malawi); Usha K Misra (Sanjay Gandhi Postgraduate Institute
microbiologically (by stain, culture, or nucleic acid of Medical Sciences, Lucknow, India); Kameshwar Prasad (All India
Institute of Medical Sciences, New Delhi, India); Ahmad Rizal
amplification tests when appropriate), serologically
(Padjadjaran University, Bandung, Indonesia); Guy Thwaites,
(eg, syphilis), or histopathologically (eg, lymphoma). Robert J Wilkinson (Imperial College, London, UK); Estee Torok
(Cambridge University, Cambridge, UK), Reinout Van Crevel (Radboud
Conclusion University Nijmegen Medical Center, Nijmegen, Netherlands).
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