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Corticosteroids for managing tuberculous meningitis (Review)
Prasad K, Singh MB, Ryan H
Prasad K, Singh MB, Ryan H.

Corticosteroids for managing tuberculous meningitis.
Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD002244.
DOI: 10.1002/14651858.CD002244.pub4.
www.cochranelibrary.com

Copyright © 2016 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on
behalf of The Cochrane Collaboration.
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TABLE OF CONTENTS
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 3
BACKGROUND.............................................................................................................................................................................................. 5
OBJECTIVES.................................................................................................................................................................................................. 5
METHODS..................................................................................................................................................................................................... 5
RESULTS........................................................................................................................................................................................................ 7
Figure 1.................................................................................................................................................................................................. 8
Figure 2.................................................................................................................................................................................................. 9
Figure 3.................................................................................................................................................................................................. 10
Figure 4.................................................................................................................................................................................................. 12
Figure 5.................................................................................................................................................................................................. 13
Figure 6.................................................................................................................................................................................................. 14
Figure 7.................................................................................................................................................................................................. 15
Figure 8.................................................................................................................................................................................................. 16
Figure 9.................................................................................................................................................................................................. 17
DISCUSSION.................................................................................................................................................................................................. 17
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 18
ACKNOWLEDGEMENTS................................................................................................................................................................................ 19
REFERENCES................................................................................................................................................................................................ 20
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 23
DATA AND ANALYSES.................................................................................................................................................................................... 37
Analysis 1.1. Comparison 1 Any corticosteroid versus control, Outcome 1 Death............................................................................ 38
Analysis 1.2. Comparison 1 Any corticosteroid versus control, Outcome 2 Disabling neurological deficit...................................... 39
Analysis 1.3. Comparison 1 Any corticosteroid versus control, Outcome 3 Death or disabling neurological deficit....................... 39
Analysis 1.4. Comparison 1 Any corticosteroid versus control, Outcome 4 Adverse events............................................................. 40
Analysis 2.1. Comparison 2 Any corticosteroid versus control: stratified by severity of illness, Outcome 1 Death......................... 41
Analysis 3.1. Comparison 3 Any corticosteroid versus control: stratified by HIV status, Outcome 1 Death..................................... 43
Analysis 3.2. Comparison 3 Any corticosteroid versus control: stratified by HIV status, Outcome 2 Disabling neurological 43
deficit.....................................................................................................................................................................................................
Analysis 3.3. Comparison 3 Any corticosteroid versus control: stratified by HIV status, Outcome 3 Death or disabling residual 44
neurological deficit...............................................................................................................................................................................
Analysis 4.1. Comparison 4 Sensitivity analysis, Outcome 1 Worst case scenario analysis.............................................................. 44
ADDITIONAL TABLES.................................................................................................................................................................................... 46
APPENDICES................................................................................................................................................................................................. 53
WHAT'S NEW................................................................................................................................................................................................. 53
HISTORY........................................................................................................................................................................................................ 54
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 54
DECLARATIONS OF INTEREST..................................................................................................................................................................... 54
SOURCES OF SUPPORT............................................................................................................................................................................... 54
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 54
INDEX TERMS............................................................................................................................................................................................... 55
Corticosteroids for managing tuberculous meningitis (Review) i

Copyright © 2016 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane
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[Intervention Review]
Corticosteroids for managing tuberculous meningitis
Kameshwar Prasad1, Mamta B Singh1, Hannah Ryan2
1Department of Neurology, All India Institute of Medical Sciences, New Delhi, India. 2Department of Clinical Sciences, Liverpool School of
Tropical Medicine, Liverpool, UK
Contact: Kameshwar Prasad, Department of Neurology, All India Institute of Medical Sciences, Ansarinagar, New Delhi, 110029, India.
[email protected].
Editorial group: Cochrane Infectious Diseases Group.

Publication status and date: Unchanged, published in Issue 4, 2016.
Citation: Prasad K, Singh MB, Ryan H. Corticosteroids for managing tuberculous meningitis. Cochrane Database of Systematic Reviews
2016, Issue 4. Art. No.: CD002244. DOI: 10.1002/14651858.CD002244.pub4.
Copyright © 2016 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The
Cochrane Collaboration. This is an open access article under the terms of the Creative Commons Attribution-Non-Commercial Licence,
which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for
commercial purposes.
ABSTRACT
Background
Tuberculous meningitis is a serious form of tuberculosis (TB) that affects the meninges that cover a person's brain and spinal cord. It is
associated with high death rates and with disability in people who survive. Corticosteroids have been used as an adjunct to antituberculous
drugs to treat people with tuberculous meningitis, but their role has been controversial.
Objectives
To evaluate the effects of corticosteroids as an adjunct to antituberculous treatment on death and severe disability in people with
tuberculous meningitis.
Search methods
We searched the Cochrane Infectious Diseases Group Specialized Register up to the 18 March 2016; CENTRAL; MEDLINE; EMBASE; LILACS;
and Current Controlled Trials. We also contacted researchers and organizations working in the field, and checked reference lists.
Selection criteria
Randomized controlled trials that compared corticosteroid plus antituberculous treatment with antituberculous treatment alone in people
with clinically diagnosed tuberculous meningitis and included death or disability as outcome measures.
Data collection and analysis

We independently assessed search results and methodological quality, and extracted data from the included trials. We analysed the data
using risk ratios (RR) with 95% confidence intervals (CIs) and used a fixed-effect model. We performed an intention-to-treat analysis, where
we included all participants randomized to treatment in the denominator. This analysis assumes that all participants who were lost to
follow-up have good outcomes. We carried out a sensitivity analysis to explore the impact of the missing data.
Main results
Nine trials that included 1337 participants (with 469 deaths) met the inclusion criteria.
At follow-up from three to 18 months, steroids reduce deaths by almost one quarter (RR 0.75, 95% CI 0.65 to 0.87; nine trials, 1337
participants, high quality evidence). Disabling neurological deficit is not common in survivors, and steroids may have little or no effect
on this outcome (RR 0.92, 95% CI 0.71 to 1.20; eight trials, 1314 participants, low quality evidence). There was no difference between
Corticosteroids for managing tuberculous meningitis (Review) 1

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groups in the incidence of adverse events, which included gastrointestinal bleeding, invasive bacterial infections, hyperglycaemia, and
liver dysfunction.
One trial followed up participants for five years. The effect on death was no longer apparent at this time-point (RR 0.93, 95% CI 0.78 to 1.12;
one trial, 545 participants, moderate quality evidence); and there was no difference in disabling neurological deficit detected (RR 0.91, 95%
CI 0.49 to 1.69; one trial, 545 participants, low quality evidence).
One trial included human immunodeficiency virus (HIV)-positive people. The stratified analysis by HIV status in this trial showed no
heterogeneity, with point estimates for death (RR 0.90, 95% CI 0.67 to 1.20; one trial, 98 participants) and disability (RR 1.23, 95% CI 0.08
to 19.07; one trial, 98 participants) similar to HIV-negative participants in the same trial.
Authors' conclusions
Corticosteroids reduce mortality from tuberculous meningitis, at least in the short term.
Corticosteroids may have no effect on the number of people who survive tuberculous meningitis with disabling neurological deficit, but
this outcome is less common than death, and the CI for the relative effect includes possible harm. However, this small possible harm is
unlikely to be quantitatively important when compared to the reduction in mortality.
The number of HIV-positive people included in the review is small, so we are not sure if the benefits in terms of reduced mortality are
preserved in this group of patients.
11 April 2019
Up to date
All studies incorporated from most recent search
All eligible published studies found in the last search (18 Mar, 2016) were included
PLAIN LANGUAGE SUMMARY
Corticosteroids for managing people with tuberculous meningitis
What is tuberculous meningitis and how might corticosteroids work?
Tuberculous meningitis is a serious form of tuberculosis that affects the meninges that cover the brain and spinal cord, causing headache,
coma and death. The clinical outcome is often poor even when people with tuberculous meningitis are treated with antituberculous drugs.
Corticosteroids are commonly used in addition to antituberculous drugs for treating people with the condition. These drugs help reduce
inflammation of the surface of the brain and associated blood vessels, and are thought to decrease pressure inside the brain, and thus
reduce the risk of death. Some clinicians are concerned that corticosteroids may improve survival, but result in more severely disabled
survivors.
What the evidence shows
We examined the evidence published up to 18 March 2016 and included nine trials with 1337 people that evaluated either dexamethasone,
methylprednisolone, or prednisolone given in addition to antituberculous drugs; one trial was of high quality, while the other trials had
uncertainties over study quality due to incomplete reporting.
The analysis shows that corticosteroids reduce the risk of death by a quarter at two months to two years after treatment was started (high
quality evidence). Corticosteroids make little or no difference to the number of people who survive TB meningitis with brain damage causing
disability (low quality evidence); because this event is uncommon, even taking the most pessimistic estimate from the analysis of a slight
increased risk with corticosteroids means this would not be quantitatively important when compared to the reduction in deaths.
One trial followed up participants for five years, by which time there was no difference in the effect on death between the two groups,
although the reason for this change over time is unknown.
Only one trial evaluated the effects of corticosteroids in human immunodeficiency virus (HIV)-positive people but the number is small so
we are not sure if the benefits in terms of fewer deaths are preserved in this group of patients.

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SUMMARY OF FINDINGS

Summary of findings for the main comparison. Any corticosteroid compared to control for tuberculous meningitis
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Any corticosteroid compared to control for tuberculous meningitis
Participant or population: adults or children with tuberculous meningitis on tuberculosis (TB) chemotherapy
Settings: hospital care
Intervention: any corticosteroid
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Comparison: placebo or no corticosteroid
Outcomes Illustrative comparative risks (95% CI) Relative effect Number of participants Quality of the evidence
(95% CI) (trials) (GRADE)
Assumed risk* Corresponding risk
Control Corticosteroid
Follow-up to 2 to 24 months
Death 41 per 100 31 per 100 RR 0.75 1337 ⊕⊕⊕⊕

(27 to 36) (9 trials) high 1,2,3,4,5
(0.65 to 0.87)
Disabling neurolog- 8 per 100 7 per 100 RR 0.92 1314 ⊕⊕⊝⊝6,7,8

ical deficit (6 to 10) low
(0.71 to 1.20) (8 trials)
Follow-up to 5 years
Death 47 per 100 44 per 100 RR 0.93 545 participants ⊕⊕⊕⊝9,10

(37 to 53) (0.78 to 1.12) (1 trial) moderate

Disabling neurolog- 15 per 100 14 per 100 RR 0.91 244 ⊕⊝⊝⊝10,11,12
ical deficit
(7 to 25) (0.49 to 1.69) (1 trial) very low
*The assumed risk is from the median control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and
the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; TB: tuberculosis.
GRADE Working Group grades of evidence.

High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
3

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Very low quality: we are very uncertain about the estimate.
1Not downgraded for risk of bias. There are few uncertainties regarding allocation concealment or sequence generation in one of the two largest studies, but the largest trial was
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high quality and effects between these two trials were consistent.
2Not downgraded for inconsistency: low statistical heterogeneity, and the forest plot shows a consistent benefit.
3Not downgraded for indirectness in relation to age: all the participants in Schoeman 1997 and 59% of the participants in Girgis 1991 were children, and the effect is consistent
with the other large trial, Thwaites 2004, which included participants aged 14 and over.
4Not downgraded for indirectness for HIV status: one trial included 98 HIV-positive participants, with no obvious qualitative heterogeneity when compared to HIV-negative
participants (Thwaites 2004). If making recommendations for HIV-positive participants only, a guidelines panel may wish to downgrade on indirectness.
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Trusted evidence.
5Not downgraded for serious imprecision: the overall meta-analysis is adequately powered to detect this effect, but is only adequately powered when the trials at unclear or
high risk of bias are included. The effect is clinically important.
6Downgraded by one for risk of bias: four of the eight trials were at high risk of bias due to lack of blinding of outcome assessors, which could impact on the interpretation of
assessments of disability.
7Not downgraded for indirectness: trials included children, adults, some HIV-positive people, and people from different continents.
8Downgraded by one for imprecision: effects range from clinically important benefits of 29% reduction to 20% increase in disability.
9Not downgraded on risk of bias or imprecision: number of participants followed up was high: 91% at five years.
10Downgraded by one for indirectness. This was a single trial conducted in a high quality health care unit in a population with high levels of infectious diseases endemicity and
poverty. The attenuation of the effect may be less marked in populations with lower exposure to infectious diseases and other causes of reduced life expectancy associated with
poverty. The authors were not able to establish the cause of death in most of the people who died after 9 months follow-up, and so it is not possible to assess whether these
deaths were related to tuberculous meningitis or to other causes.
11Not downgraded on risk of bias. Although the assessors were not blind to the allocation, and some assessments were conducted by telephone, the numbers of disabled
participants in the two groups were the same, and it is unlikely that systematic bias in the observers is present.
12Downgraded by two for imprecision. There were few events, and the confidence interval ranges from substantive harms to substantive benefits.


4

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BACKGROUND additional 5% to 40% of people who survive tuberculous meningitis

(Ramchandran 1986; Alarcón 1990; Jacobs 1990; Jacobs 1992).
Description of the condition
Indirect evidence from animal studies provides a biological
Tuberculous meningitis is an inflammation of the meninges, which basis for how corticosteroids could be effective (Feldman 1958).
are membranes that envelope a person's brain and the spinal cord. They may decrease inflammation, especially in the subarachnoid
It is caused by infection with one of several mycobacterial species space; reduce cerebral and spinal cord oedema, and intracranial
that belong to the Mycobacterium tuberculosis complex, which are pressure (Feldman 1958; Parsons 1988); and reduce inflammation
responsible for tuberculosis (TB) disease. Tuberculous meningitis of small blood vessels, and damage due to blood flow slowing
is a severe form of TB and accounts for many deaths (Tandon 1988). to the underlying brain tissue. However, corticosteroids could
It is a form of extrapulmonary TB (that is, TB that occurs outside also cause harm by suppressing the person's immune system.
the lungs). The World Health Organization (WHO) reported that 0.8 They may suppress the symptoms of TB infection but promote
million of the 5.4 million new TB cases reported worldwide in 2013 an unchecked growth of the bacteria and an increased bacterial
were extrapulmonary cases (WHO 2014). There is an association load, and reduce inflammation of the meninges, which will then
between extrapulmonary TB and human immunodeficiency virus reduce the ability of drugs to cross the blood-brain barrier
(HIV) infection, particularly in people with low CD4 cell counts and enter the subarachnoid space. Other adverse effects of
(Naing 2013). It appears that the higher risk of TB infection in HIV- corticosteroids include gastrointestinal haemorrhage, electrolyte
positive people means that tuberculous meningitis is also more imbalance, hyperglycaemia, hypertension, and increased risk of
common in this group (Berenguer 1992; Berger 1994). infections from other pathogens (D'Arcy-Hart 1950).
People with tuberculous meningitis usually present with The use of adjunctive corticosteroids is not known to result
headache, fever, vomiting, altered conscious level, and sometimes in disability in tuberculous meningitis, especially when used
convulsions. It is diagnosed clinically, with confirmation by for short periods of time as is the case in most clinical trials
microscopy and culture of cerebral spinal fluid (CSF) or a of this intervention. However, there is concern that although
polymerase chain reaction (PCR) test. The low sensitivity of the corticosteroids may save the lives of some people who have severe
diagnostic tests currently available presents a particular challenge tuberculous meningitis, they may not necessarily improve their
for clinicians, especially when treating children and HIV-positive quality of life, as some people may survive but be left with a severe
people. Early diagnosis and prompt treatment are the main disability, rendering them bed-bound and highly dependent. In
determinants of a good outcome in people with tuberculous other words, if corticosteroids increase the survival rate but not
meningitis (Thwaites 2013). disability-free survival, then corticosteroids might actually increase
a person's suffering.
The causes of death and disability in tuberculous meningitis are
multifactorial. The main pathological mechanisms are persistent Why it is important to do this review
or progressive raised intracranial pressure with or without
hydrocephalus, involvement of the optic nerves or optic chiasm Several randomized controlled trials (RCTs) have been conducted
leading to visual deficit, cranial neuropathies, arachnoiditis, on the effect of corticosteroids in managing people with
and vasculitis of the cerebral blood vessels leading to stroke. tuberculous meningitis. The conclusions from these trials, seen
Neurological disability related to antituberculous treatment may individually, appear inconsistent. One trial, Thwaites 2004, showed
occur due to optic neuritis related to ethambutol or isoniazid, which that dexamethasone increases survival rate. However, it also raised
sometimes causes permanent loss of vision, or isoniazid-related two questions: do people who survive because of dexamethasone
peripheral neuropathy. therapy tend to be left with severe disability, and are there
differential effects among subgroups of people with different
Tuberculous meningitis can be classified according to its severity. degrees of disease severity? The editorial that accompanied the
The British Medical Research Council (MRC) staging system trial, Quagliarello 2004, and several letters to the editor in response
categorizes patients into three stages (MRC 1948): stage I to this trial (Marras 2005; Seligman 2005) commented that the trial
(mild cases) for those without altered consciousness or focal did not have sufficient statistical power to answer these questions.
neurological signs; stage II (moderately advanced cases) for those We have prepared a meta-analysis that synthesizes the results from
with altered consciousness who are not comatose and those with all available RCTs to try and provide the necessary power to address
moderate neurological deficits (for example, single cranial nerve these questions.
palsies, paraparesis, and hemiparesis); and stage III (severe cases)
for comatose patients and those with multiple cranial nerve palsies, OBJECTIVES
and hemiplegia or paraplegia, or both.
To evaluate the effects of corticosteroids as an adjunct to
Description of the intervention antituberculous treatment on death and severe disability in people
with tuberculous meningitis.
Without anti-tuberculous treatment, people with tuberculous
meningitis die (Tandon 1988; Thwaites 2002). Streptomycin, one METHODS
of the earliest antituberculous drugs to be introduced, reportedly
reduced the case-fatality rate to 63% (Parsons 1988). Newer Criteria for considering studies for this review
antituberculous drugs − isoniazid, rifampicin, pyrazinamide, and
ethambutol − are associated with better survival, but mortality Types of studies
remains comparatively high. Reports of mortality rates vary Randomized controlled trials (RCTs).
from 20% to 32%, and permanent neurological deficits in an

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Types of participants Data collection and analysis

People of any age with clinically diagnosed tuberculous meningitis. For selection of studies and data extraction, we independently
conducted each step, and examined agreement between the review
Types of interventions authors. We resolved any disagreements through discussion.
Intervention
Selection of studies
Corticosteroid (hydrocortisone, prednisolone,
methylprednisolone, or dexamethasone) given orally, We independently screened the search results and retrieved the
intramuscularly, or intravenously plus antituberculous treatment. full-text articles of all potentially relevant trials. We examined each
trial report to ensure that we included multiple publications from
Control the same trial only once. We contacted trial authors for clarification
if a trial's eligibility was unclear. We resolved any disagreements
Antituberculous treatment (same as intervention) with or without through discussion and listed the excluded studies and the reasons
placebo. for their exclusion.
Types of outcome measures One of the review authors, KP, conducted one of the included trials
Primary outcomes (Prasad 2006), which was started at the same time as Prasad 2000
(the first edition of this Cochrane Review). As of March 2016, this
1. Death. trial had not been published, but the unpublished data is included
2. Persisting disabling neurological deficit at the end of follow-up. in this review. KP is also a co-author on Kumarvelu 1994. For both of
these studies, HR performed the description of studies, 'Risk of bias'
Adverse events assessments, data extraction, and interpretation in consultation
Adverse events as reported by the authors, including upper with the CIDG Co-ordinating Editor, Paul Garner.
gastrointestinal bleeding, invasive bacterial or fungal infections,
and hyperglycaemia. Data extraction and management
We independently extracted data on participant characteristics,
Search methods for identification of studies diagnostic criteria, disease severity, HIV status, antituberculous
We attempted to identify all relevant trials regardless of language drug regimen, corticosteroid regimen, and outcome measures
or publication status (published, unpublished, in press, and in using a pre-piloted data extraction form. We resolved
progress). disagreements through discussion and contacted the
corresponding trial author in the case of unclear or missing data.
Electronic searches We contacted the authors of Lardizabal 1998 to determine the
number of deaths in participants with stage II and III disease, and
We searched the following databases using the search terms and also the authors of Thwaites 2004 to determine the number of
strategy described in Appendix 1: Cochrane Infectious Diseases deaths in the five-year follow-up study (Török 2011).
Group Specialized Register (18 March 2016); Cochrane Central
Register of Controlled Trials (CENTRAL), published in the Cochrane For dichotomous outcomes, we recorded the number of
Library, up to Issue 2, February 2016; MEDLINE (1966 to 18 participants that experienced the event and the number of
March 2016); EMBASE (1974 to 18 March 2016); and LILACS participants randomized to each treatment group, and used them
(1982 to 18 March 2016). We also searched Current Controlled in the analysis. We also recorded number of participants analysed
Trials (www.controlled-trials.com; accessed 18 March 2016) using in each treatment arm, and used the discrepancy between the
'tuberculosis' and 'meningitis' as search terms. figures to calculate the number of participants lost to follow-up.
These figures allowed us to perform a worst-case scenario analysis
Searching other resources to investigate the effect of missing data.
Researchers
Assessment of risk of bias in included studies
We contacted the following organizations and individuals working
in the field: delegates at the Vth Annual Conference of Indian We independently assessed methodological quality using the
Cochrane 'Risk of bias' tool and reported the results in a 'Risk
Academy of Neurology, Madras, India, 1997; delegates at the XIIIth
of bias' table (Higgins 2011). Regarding generation of allocation
Global Joint Meeting of the International Clinical Epidemiology
sequence and allocation concealment, we classified each of these
Network and Field Epidemiology Training Program, Victoria Falls,
as either adequate, inadequate, or unclear according to Jüni 2001.
Zimbabwe, 1994; and members of the INDEX-TB Guidelines
We reported who was blinded in each trial, and assessed the risk
technical advisory committee, New Delhi, India, 2015.
of bias associated with blinding separately for the two primary
Reference lists outcomes. If at least 90% of participants were followed up to
the trial's completion we classified inclusion of all randomized
We also drew on existing reviews of this topic (Ramchandran 1986; participants as adequate; otherwise we classified inclusion as
Jacobs 1990; Geiman 1992), and checked the reference lists of all inadequate. We attempted to contact the trial authors if this
the trials identified by the above methods. information was not specified or if it was unclear. We resolved any
disagreements by discussion between the review authors.

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Measures of treatment effect Data synthesis

We used relative risk as the measure of treatment effect for analysis. We analysed the data using Review Manager (RevMan) (RevMan
2014). In view of the absence of significant heterogeneity we
Unit of analysis issues decided to perform a meta-analysis. We used risk ratios (RR)
There were no cluster RCTs. with 95% CIs and the fixed-effect model. We summarized the
adverse event data in tables and performed meta-analysis for
Dealing with missing data four types of treatment-related adverse event: gastrointestinal
bleeding, hyperglycaemia/glycosuria, invasive bacterial infection
The primary analysis is an intention-to-treat analysis where (all of which could be related to corticosteroid use), and hepatitis
all participants randomized to treatment are included in the (related to antituberculous treatment). We were unable to calculate
denominator. This analysis assumes that all losses to follow-up rate ratios or summary rate ratios because the person-time over
have good outcomes. We carried out a sensitivity analysis to which these events were observed was unavailable.
explore the impact of the missing data on the summary effect
estimate for death. Subgroup analysis and investigation of heterogeneity
Assessment of heterogeneity There was no significant heterogeneity to indicate investigation of
its potential sources.
We assessed heterogeneity by visually inspecting the forest plots to
determine closeness of point estimates with each other and overlap Sensitivity analysis
of confidence intervals (CIs). We used the Chi2 test with a P value of
0.10 to indicate statistical significance, and the I2 statistic to assess To explore the possible effect of losses to follow-up on the
heterogeneity with a value of 50% taken to indicate statistical effect estimate for the outcome death, we performed a worst
heterogeneity. We planned to investigate heterogeneity through case scenario analysis and compared it with an available case
the following subgroup analyses: drug resistance (susceptible analysis. We assumed all participants who had dropped out of
versus resistant M. tuberculosis); severity of illness (MRC stages I, II, the corticosteroid group had an unfavourable outcome whereas
and III); and HIV status (seropositive versus seronegative). those who had dropped out of the control group had a favourable
outcome, and compared these results to an available case analysis.
Assessment of reporting biases
RESULTS
We conducted visual inspection of the funnel plot of the trials for
any obvious asymmetry that could be evidence of publication bias. Description of studies
We included nine trials and excluded 18 trials (Figure 1;
Characteristics of included studies; Characteristics of excluded
studies).


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Figure 1. Study flow diagram.

Results of the search confirm the diagnosis by microbiological tests, but only Girgis 1991
reported the outcomes for culture-confirmed cases separately. We
The original version of this Cochrane Review, Prasad 2000, included
have described the diagnostic criteria used in each included trial in
six trials with 595 participants (574 with follow-up, 215 deaths).
Table 2.
The 2008 update, Prasad 2008, added one new trial with 545
The trials included young children (Schoeman 1997) or adults
participants (535 with follow-up, 199 deaths).
(Kumarvelu 1994; Chotmongkol 1996; Lardizabal 1998; Thwaites
In this update, we included two additional trials: Malhotra 2009 2004; Prasad 2006), or both (O'Toole 1969; Girgis 1991), and both
with 97 participants and Prasad 2006 with 87 participants, as well sexes. All trials used the British Medical Research Council (MRC)
as follow-up data from a previously included trial (Thwaites 2004). system, MRC 1948, to assess baseline severity; two trials included
only participants with stage II and III tuberculous meningitis
Included studies (Schoeman 1997; Lardizabal 1998), while the other trials included
participants with all stages of severity. Thwaites 2004 specifically
We have provided a description of the included RCTs in Table 1. reported the inclusion of HIV-positive and HIV-negative people,
Geographical location and time period while Chotmongkol 1996 and Malhotra 2009 specifically reported
excluding HIV-positive people.
The included trials were conducted in different time periods
(one in the 1960s, one in the 1980s, four in the 1990s, and two Only Thwaites 2004 reported on drug resistance. In this trial, M.
between 2001 and 2007) and in different geographical regions: tuberculosis was cultured from the cerebrospinal fluid (CSF) or
Thailand (Chotmongkol 1996); Egypt (Girgis 1991); India (O'Toole another site in 170 participants (31.2%), 85 from each group. M.
1969; Kumarvelu 1994; Prasad 2006; Malhotra 2009); Philippines tuberculosis isolates were tested for susceptibility to isoniazid,
(Lardizabal 1998); South Africa (Schoeman 1997); and Vietnam rifampicin, pyrazinamide, ethambutol, and streptomycin. Of 170
(Thwaites 2004). isolates, 99 (58.2%) were susceptible to all first-line drugs (51 in
the placebo group and 48 in the dexamethasone group); 60 (35.3%)
Participants were resistant to streptomycin, isoniazid, or both (29 in the placebo
group and 31 in the dexamethasone group); one was resistant to
All participants were enrolled on the basis of clinical diagnosis of
rifampicin alone (in the dexamethasone group); and 10 (5.9%) were
probable tuberculous meningitis. All included trials attempted to

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resistant to at least isoniazid and rifampicin (three in the placebo Thwaites 2004 followed up participants over a five-year period, and
group and seven in the dexamethasone group). reported the results separately in Török 2011.
Interventions Outcome measures

Six included trials used the corticosteroid dexamethasone and All nine trials reported death.
two trials used prednisolone (Chotmongkol 1996; Schoeman 1997).
One trial, Malhotra 2009, compared both dexamethasone and All but one trial reported on disabling neurological deficit in
methylprednisolone with placebo. We have described the dose some way, although there was substantial variation in methods
regimens of corticosteroids used in Table 3. of assessment of this outcome between the trials (O'Toole 1969).
We accepted the trial authors' definition of disability and, for the
Eight trials used three- or four-drug antituberculous regimens. purpose of analysis, classified residual deficits into disabling or
O'Toole 1969, the earliest trial, used a two-drug regimen consisting non-disabling (as shown in Table 4).
of isoniazid and streptomycin.
Five trials mentioned adverse events. The trials reported on
Duration of antituberculous treatment varied from six months a number of other immediate outcome measures we had not
(Chotmongkol 1996; Schoeman 1997), nine months (Thwaites considered in this Cochrane review (see 'Characteristics of included
2004; Prasad 2006; Malhotra 2009), 12 months (Kumarvelu 1994; studies' section).
Lardizabal 1998), to 24 months (Girgis 1991). In one trial, O'Toole
1969, the duration of antituberculous treatment was unclear. Excluded studies
We have listed the reasons for excluding 18 studies in the
Follow-up
'Characteristics of excluded studies' section.
Seven trials clearly described the follow-up period: two months
(Lardizabal 1998); three months (Kumarvelu 1994); six months Risk of bias in included studies
(Schoeman 1997); nine months (Thwaites 2004); 10 months
See the' Characteristics of included studies' section, which includes
(Malhotra 2009); two years (Girgis 1991); and 16 to 45 months
a 'Risk of bias' table for each included trial. We have summarized
(Chotmongkol 1996). It was unclear in O'Toole 1969 and Prasad
the results of the 'Risk of bias' assessments across all included trials
2006.
in Figure 2 and Figure 3 .

Figure 2. 'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages
across all included trials.


Collaboration.
Informed decisions.

Figure 3. 'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included trial.

Collaboration.
Informed decisions.

Allocation Incomplete outcome data

Five included trials reported adequate methods of randomization Four trials included over 90% of their randomized participants
using either computer generated sequences of random numbers in the analysis (Lardizabal 1998; Malhotra 2009; O'Toole 1969;
or random number tables (Girgis 1991; Kumarvelu 1994; Thwaites Thwaites 2004), and we assessed these trials as at low risk of bias.
2004; Prasad 2006; Malhotra 2009). The remaining included trials
did not clearly report the method of randomization. Kumarvelu 1994 included 87.24% of the participants after six
participants were lost to follow-up (4/24 in the corticosteroid group
We assessed four trials (O'Toole 1969; Chotmongkol 1996; Thwaites and 2/23 in the control group), and did not report on the reasons
2004; Prasad 2006) as having adequate allocation concealment, participants were lost to follow-up. We therefore assessed this trial
with participants allocated coded treatment packs. The remaining as high risk of bias.
trials did not clearly describe allocation concealment.
Four trials did not report losses to follow-up (Girgis 1991;
Chotmongkol 1996 reported an imbalance in the severity of disease Chotmongkol 1996; Schoeman 1997; Prasad 2006). We assessed
between the two groups, with the placebo group having a greater these trials as at unclear risk of bias.
number of cases with Grade I disease and the steroid group having
a greater number with Grade III disease. MRC stage 3 disease was Selective reporting
present in 6/29 participants (20.7%) in the prednisolone group, For two included trials we had access to a trial protocol (Thwaites
but 4/30 participants (13.3%) in the placebo group. Conversely, 2004; Prasad 2006). We assessed Thwaites 2004 as at low risk of
stage 1 disease was present in 3/29 participants (10.3%) in the bias as the trial authors reported on all outcomes stated in the
prednisolone group, but 6/30 participants (20%) in the placebo protocol in full. We assessed Prasad 2006 as at high risk of bias, as
group. Both favoured the placebo group. the definitions of the main outcomes were altered in the available
(unpublished) data set, and adverse events were not reported.
Blinding
Lardizabal 1998; Malhotra 2009 and Schoeman 1997 reported all
Four included trials had adequate blinding of participants and outcomes stated in the methods section in the results, so we
personnel (O'Toole 1969; Chotmongkol 1996; Thwaites 2004; assessed them as having low risk of bias. Chotmongkol 1996; Girgis
Prasad 2006). Participants and personnel were not blinded in the 1991; Kumarvelu 1994 and O'Toole 1969 did not state the outcome
remaining trials. measures in the results, so we assessed them as having unclear risk
of reporting bias.
We evaluated the blinding of outcome assessors separately for the
two primary outcome measures. Other potential sources of bias
For death, we assessed all included trials as at low risk of bias, apart All included trials based the inclusion of participants on a clinical
from Girgis 1991. We considered that all-cause death was unlikely diagnosis of tuberculous meningitis, due to the limitations of
to be affected by risk of bias relating to outcome assessment, microbiological tests to confirm the diagnosis. This means that the
and therefore we assessed included trials as at low risk of bias trials may have included some non-tuberculous meningitis cases.
regardless of blinding of outcome assessors for this outcome. We The direction of bias caused by such inclusions is not likely to favour
assessed Girgis 1991 as having unclear risk of bias because this corticosteroids.
trial reported death as a case fatality rate, meaning that death
was attributed specifically to tuberculous meningitis. The effect of Effects of interventions
misclassification of deaths as being due to tuberculous meningitis See: Summary of findings for the main comparison Any
when they were in fact due to another cause on the overall estimate corticosteroid compared to control for tuberculous meningitis
of mortality is unknown.
Comparison: any corticosteroid versus control
For disabling neurological deficit, we categorized unblinded
outcome assessments as high risk, given the subjectivity of such Death
assessments. Two trials blinded assessors of neurological disability All nine included trials reported on death (Figure 4). The two largest
and were assessed as low risk of bias (Schoeman 1997; Thwaites trials, Girgis 1991 and Thwaites 2004, had more than 150 deaths in
2004); and two trials had unblinded outcome assessors and were each, and the remaining trials were small trials with fewer deaths.
assessed as high risk of bias (Kumarvelu 1994; Malhotra 2009). Overall, the direction of effect indicated a benefit of steroids, with
no statistical heterogeneity: the I2 statistic was 0%.


Collaboration.
Informed decisions.

Figure 4. Forest plot of comparison: 1 Any corticosteroid versus control, outcome: 1.1 Death.

The pooled analysis found that there were 25% fewer deaths with Disabling neurological deficit
corticosteroids (RR 0.75, 95% CI 0.65 to 0.87; nine trials, 1337
Eight trials reported on disabling neurological deficit (Figure 5). In
participants, Analysis 1.1). The median death rate across trials was
both the intervention and control groups there were fewer events
41% without corticosteroids, which translates to a 10% absolute
compared with death, and there was no difference between the two
risk reduction with corticosteroids when applying this relative risk.
groups detected at two to 24 months follow-up (RR 0.92, 95% CI 0.71
This summary estimate of effect was deemed to be high quality
to 1.20; eight trials, 1314 participants, Analysis 1.2). This summary
evidence using the GRADE approach (see Summary of findings for
estimate of effect was deemed to be low quality using the GRADE
the main comparison).
approach, because half the trials were at high risk of bias due to lack
of blinding of outcome assessors and the estimate was imprecise.


Collaboration.
Informed decisions.

Figure 5. Forest plot of comparison: 1 Any corticosteroid versus control, outcome: 1.2 Disabling neurological deficit.

Death or disabling neurological deficit - combined outcome suggested that benefit of dexamethasone in MRC stage I disease
tended to persist longer with five-year probability of survival being
Eight trials reported data from which we could derive a combined
0.69 versus 0.55 (risk difference 0.14, 95% CI −0.01 to 0.29; P =
outcome incorporating death and disabling neurological deficit
0.07). However, the test of interaction between disease severity
(Chotmongkol 1996; Girgis 1991; Kumarvelu 1994; Lardizabal 1998;
and effect size was not statistically significant (P = 0.46 for zero to
Malhotra 2009; Prasad 2006; Schoeman 1997; Thwaites 2004). For
three months and P = 0.18 after three months). For disability, the
this outcome, the overall estimate showed a reduction in the risk of
follow-up study reported similar numbers with severe persistent
death or disabling residual neurological deficit with corticosteroids
neurological disability in both the steroid and non-steroid groups.
(RR 0.80, 95% CI 0.72 to 0.89; eight trials, 1314 participants, Analysis
1.3). This effect mirrors the results of the mortality analysis which is Adverse events
the main contributor of events.
Of the six included trials that mentioned adverse events (O'Toole
Outcome at five years 1969; Kumarvelu 1994; Chotmongkol 1996; Schoeman 1997;
Thwaites 2004; Malhotra 2009), three trials reported on incidence
Only one recently published trial, Thwaites 2004, reported the long-
(O'Toole 1969; Thwaites 2004; Malhotra 2009; Figure 6). O'Toole
term outcome of people with tuberculous meningitis randomized
1969 reported four different adverse events (gastrointestinal
to receive either dexamethasone or placebo. The primary long-
bleeding, glycosuria, infections, and hypothermia), which occurred
term outcome was survival during the five years follow-up, while
in both groups (Table 5). Thwaites 2004 reported on several adverse
secondary outcomes were status of disability and TB relapse. Fifty
events, which were divided into "severe" and other events (Table
participants (9.4%) were lost to follow-up by the end of the follow-
5). Malhotra 2009 reported incidences of hepatitis, anti-epileptic
up period. The participants in the dexamethasone arm fared better
toxicity, gastrointestinal bleeding, and paradoxical tuberculoma
on two-year survival rate (0.63 versus 0.55; risk difference 0.8, 95%
in both groups. Schoeman 1997 had "serious side effects" as
CI 0.00 to 0.16; P = 0.07), but this advantage was lost at five years
an outcome measure and reported "no serious side effects of
(0.54 versus 0.51; risk difference 0.03, 95% CI −0.06 to 0.12; P =
corticosteroid therapy".
0.51). Analysis of hazard ratios by stage of disease at presentation


Collaboration.
Informed decisions.

Figure 6. Forest plot of comparison: 1 Any corticosteroid versus control, outcome: 1.4 Adverse events.

Meta-analyses examining gastrointestinal bleeding, hepatitis, For severity of illness, we stratified the results on death by the
hyperglycaemia, and invasive bacterial infection did not severity of illness (MRC stages I, II, and III) in Figure 7. The effect of
demonstrate a difference in the incidence of these events between corticosteroids appeared to be consistent across all stages of the
the corticosteroid and placebo groups (Analysis 1.4). However, the disease although the analysis is relatively underpowered (stage I RR
meta-analysis is not sufficiently powered to detect a significant 0.50, 95% CI 0.29 to 0.85; six trials, 305 participants); stage II (RR
difference in adverse events between groups, so the results should 0.72, 95% CI 0.56 to 0.93; seven trials, 581 participants); and stage III
be interpreted with caution. (RR 0.69, 95% CI 0.54 to 0.88; eight trials, 651 participants, Analysis
2.1).
Subgroup analysis
We explored whether heterogeneity was explained within two main
pre-specified subgroups.


Collaboration.
Informed decisions.

Figure 7. Forest plot of comparison: 2 Any corticosteroid versus control: stratified by severity of illness, outcome:
2.1 Death.

For HIV status, one trial specifically mentioned that 98 of the did not detect any large differences, and so showed no apparent
included participants were HIV-positive (Thwaites 2004). Analyses effect of HIV status on the effect estimates, but the analysis is
stratifying the outcomes of death and disabling neurological deficit underpowered (Analysis 3.1; Analysis 3.2; Figure 8).


Collaboration.
Informed decisions.

Figure 8. Forest plot of comparison: 3 Any corticosteroid versus control: stratified by HIV status, outcome: 3.1
Death.

Sensitivity analysis were unavailable except for two trials (Prasad 2006; Thwaites 2004).
For five trials where the outcomes were not clearly specified in
Six trials reported on losses to follow-up (Kumarvelu 1994;
the methods section, we assessed the risk of reporting bias as
Lardizabal 1998; Malhotra 2009; O'Toole 1969; Schoeman 1997;
unclear. We assessed three trials as at low risk of reporting bias as
Thwaites 2004), with two trials reporting no losses to follow-
all outcomes specified in the protocol or methods were reported
up (Lardizabal 1998; O'Toole 1969). We performed a worst case
(Schoeman 1997; Thwaites 2004; Malhotra 2009). We assessed one
scenario analysis, assuming that all participants lost to follow-up
trial as at high risk of bias, as outcome definitions were changed
in the corticosteroid group died while those in the control group
in the reported data (unpublished), and adverse events were not
survived (Analysis 4.1). Under this extreme assumption, there was
reported (Prasad 2006). Overall, the main analysis is unlikely to
still a reduction in deaths with corticosteroids (RR 0.80, 95% CI 0.66
have been affected by reporting bias.
to 0.96), and the estimate was similar to the available case analysis
(RR 0.71, 95% CI 0.59 to 0.86). Thus, losses to follow-up are unlikely Publication bias
to have introduced bias in favour of corticosteroids.
We have presented a funnel plot of the included trials in Figure
Assessment of reporting biases 9. It refers to the outcome death and values below one favour
corticosteroids. There is no obvious evidence of publication bias,
Six included trials date to the period when registry of clinical trials
but the number of included trials was low.
was not mandatory or routine. Protocols of the included trials


Collaboration.
Informed decisions.

Figure 9. Funnel plot of risk ratio (RR) from the included trials with the log of their standard error (SE) values.

DISCUSSION corticosteroids was not significantly different between HIV-positive
and HIV-negative participants, but the trial lacked the power to
Summary of main results detect such a difference if one did exist due to the low number of
HIV-positive participants.
See 'Summary of findings' table 1 (Summary of findings for the
main comparison). Though the included trials varied in their use of bacteriological
confirmation of diagnosis, there is reasonable evidence to suggest
Nine trials met the inclusion criteria. At follow-up from 2 to
that the trial participants had tuberculous meningitis. Moreover,
24 months, steroids reduce deaths by one quarter. Disabling
the intention-to-treat analysis in clinically diagnosed participants
neurological deficit is less common in survivors, and steroids
provides assurance that use of corticosteroids on the basis of
may have little or no effect on this outcome; even taking the
clinical diagnosis does more good than harm. This is important
upper confidence limit of 20% increased risk, this is probably not
because the decision to use corticosteroids is usually taken on a
quantitatively important when compared to the reduced mortality.
purely clinical basis when culture reports are unavailable and it is
There was no difference between groups in the incidence of adverse
the balance of benefit and risk of such a decision that needs to
events, which included gastrointestinal bleeding, invasive bacterial
be determined to set a clinical policy. The proportion of confirmed
infections, hyperglycaemia and hepatitis, although adverse events
cases is mentioned only to provide confidence in the clinical
were not reported in all studies.
diagnosis made by the investigators. Separate analysis of culture-
One trial followed up participants for five years. The effect on death positive cases is probably less relevant for clinical decision making.
and was no longer apparent at this time-point, and there was no
All included trials were conducted in high TB burden settings, in
difference in disabling neurological deficit detected.
specialist referral hospitals.
One trial included human immunodeficiency virus (HIV)-positive
people. The stratified analysis by HIV status in this trial showed
Quality of the evidence
no heterogeneity, with point estimates for death similar to HIV- We used the GRADE approach to assess the quality of the evidence
negative participants in the same trial. for the two primary outcomes at two to 24 months follow-up,
and at five years follow-up (Summary of findings for the main
Overall completeness and applicability of evidence comparison).
The trials included male and female children and adults, most
We graded the quality of the estimate of effect for the outcome
of whom were HIV-negative. Thwaites 2004 reported that they
death at two to 24 months follow-up as high. We assessed
included 98 HIV-positive participants, but they did not stratify
the estimate of effect as being at low risk of bias, as while
the randomization for this subgroup; therefore the results for
there are some included trials that did not clearly report on the
this subgroup should be interpreted with caution. The effect of
randomization method or allocation concealment, or both, the two
Collaboration.
Informed decisions.

largest included trials had few concerns and showed a consistent The use of dexamethasone in the zebrafish morphants rescued
effect. The trials provided evidence of benefit for all age groups. high-LTA4H animals but led to increased susceptibility in low-
Although only one trial reported on outcomes for people living with LTA4H animals (Tobin 2012). In people, the LTA4H transcription
HIV, there was no obvious qualitative heterogeneity. We did not find level is regulated by a polymorphism in the gene promoter at SNP
any serious imprecision. We graded the estimate of effect for death rs17525495, with rs17525495 TT associated with high LTA4H protein
at five years follow-up as moderate, and downgraded by one for expression, rs17525495 CC associated with low expression, and
indirectness as the data came from a single trial conducted in a rs17525495 CT intermediate expression. Genotyping performed
high quality healthcare unit in a setting with high levels of endemic on 182 participants from a series of clinical studies in
infectious diseases and poverty. Vietnam demonstrated that people with the TT genotype (high
LTA4H, hyperinflammatory) had the highest mortality amongst
We assessed the quality of the estimate of effect for the outcome participants who did not receive dexamethasone, but the lowest
disabling neurological deficit as low quality. The lack of blinding in the dexamethasone group; the people with the CC genotype
of outcome assessors of disabling neurological deficit in four of (low LTA4H, hypoinflammatory) had the highest mortality in the
the eight trials reporting this outcome led us to downgrade the dexamethasone group (Tobin 2012). These results suggest that
quality of evidence by one for risk of bias. There was imprecision LTA4H genotype may have an important influence on whether or
of this estimate relating to the small number of events, which led not steroids are effective in tuberculous meningitis, at least in this
us to downgrade by one. We graded the estimate of effect for population.
disabling neurological deficit at five years follow-up as very low
quality, and downgraded by one for indirectness as the data was Further investigation into the relationship between LTA4H
from a single trial (as for the outcome death, see above) and by two expression in people, dexamethasone use, and outcomes in
for imprecision as there were few events and the CI ranged from people with TB meningitis is needed to determine whether
substantive harms to substantive benefits of corticosteroids. dexamethasone use is associated with harm in the subset of people
with LTA4H deficiency, and whether genotyping people for LTA4H
Potential biases in the review process at diagnosis is useful to guide treatment with corticosteroids.
Other drugs that target parts of this inflammatory pathway, such
We have attempted to limit bias in the review process.
as thalidomide, adulimumab and infliximab, have been used as
The Cochrane Infectious Diseases Group Information Specialist
rescue therapy in people with severe inflammatory complications
conducted the literature search, and it is unlikely that these
of TB meningitis, but few clinical trials have been conducted on the
searches missed any major trials; however, we cannot rule out
use of these agents, and all these potent immunosuppressive drugs
the possibility that we missed some small unpublished trials. The
have the potential to cause harm as well as benefit (Schoeman
funnel plot did not assist with this because there were too few
2001; Schoeman 2004; Schoeman 2010; Jorge 2012; Lee 2012;
included trials. To limit bias in the trial selection process and
Molton 2015).
data extraction, we independently examined the search results,
determined study selection, and extracted data.
AUTHORS' CONCLUSIONS
Agreements and disagreements with other studies or
Implications for practice
reviews
There is high quality evidence of the benefit of corticosteroids
Several TB guidelines recommend the use of corticosteroids as an in preventing death in people with tuberculous meningitis. This
adjunct to treatment of TB meningitis internationally (CDC 2003; effect is probably attenuated over time, as five-year follow-up
BSI 2009; SNHS 2010; NICE 2011). data from one trial suggests this, but there may be confounding
factors leading to this observation. Corticosteroids appear to
Questions remain about the mechanism by which corticosteroids
reduce mortality in people with TB meningitis, regardless of the
improve clinical outcomes, and advances in understanding of
British Medical Research Council (MRC) stage at presentation.
these mechanisms have led to a suggestion that some people
Corticosteroids may have no effect on rates of disabling
may benefit from corticosteroids while others do not, and
neurological deficit in people who survive TB meningitis, but
some may even be adversely affected by steroids (Thwaites
the confidence interval around this estimate includes increased
2013). Leukotriene A4 hydrolase (LTA4H) has been implicated
risk of this outcome. However, given the benefit associated
in the pathogenesis of mycobacterial infection through its
with reduced risk of death, this is unlikely to be quantitatively
effect on the equilibrium between pro- and anti-inflammatory
important when considering whether or not to use corticosteroids
eicosanoids. Tobin et al. showed that both low- and high-LTA4H
in patients with TB meningitis. There is uncertainty about whether
expression zebrafish morphants show increased mycobacterial
or not corticosteroids are beneficial for HIV-positive people with
bacterial burden compared with wildtype controls (Tobin 2010;
TB meningitis due to the lack of direct evidence in this group.
Tobin 2012). Low-LTA4H expression led to increased lipoxin
Corticosteroids may not be associated with increased risk of
A4 production and dampening of the early tissue necrosis
adverse events, but there is uncertainty related to the limited
factor-alpha (TNF-α) response, and high-LTA4H morphants
reporting of adverse events in the included trials.
showed increased macrophage lysis despite early control of
intracellular mycobacterial replication by TNF-α, with subsequent
Implications for research
extracellular mycobacterial growth. Both of these states led to
uncontrolled mycobacterial replication. Thus, hypersusceptibility Further research is unlikely to add to certainty about the effect of
to mycobacterial infection is associated with both inadequate and corticosteroids in people with tuberculous meningitis who are HIV-
excessive inflammatory responses. negative in preventing death.

Collaboration.
Informed decisions.

In people that are immunosuppressed, such as people living ACKNOWLEDGEMENTS

with HIV, it is unclear whether corticosteroids are of benefit. As
corticosteroids could lead to greater risk of harm in these people, We thank Estée Török and Marcel Wolbers for providing additional
further research would be useful to provide clear guidance for data from the follow-up study of participants from Thwaites 2004,
treatment. and Artemio Roxas Jr. for providing access to Lardizabal 1998.
Hannah Ryan, Paul Garner, and the editorial base for the Cochrane
Another question that remains unanswered is the optimum choice Infectious Diseases Group are funded by the UK Department for
of corticosteroid drug and dosing regimen. Given the fact that International Development (DFID) in a grant related to evidence
use of corticosteroids carries the risk of adverse events, and that synthesis for the benefit of developing countries (Grant: 5242).
many of these are dose-dependent, further research examining this The views expressed in this review do not necessarily reflect UK
question would be beneficial. government policy. We thank the All India Institute of Medical
Sciences, New Delhi, India for providing infrastructure support.

Collaboration.
Informed decisions.

REFERENCES

References to studies included in this review tuberculous meningitis in adolescents and adults. New England
Journal of Medicine 2004;351(17):1741-51.
Chotmongkol 1996 {published data only}
Chotmongkol V, Jitpimolmard S, Thavornpitak Y. Corticosteroid Török ME, Nguyen DB, Tran TH, Nguyen TB, Thwaites GE,
in tuberculous meningitis. Journal of the Medical Association of Hoang TQ, et al. Dexamethasone and long-term outcome of
Thailand 1996;79(2):83-90. tuberculous meningitis in Vietnamese adults and adolescents.
PLoS One 2011;6(12):e27821.
Girgis 1991 {published data only}
Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA.
Dexamethasone adjunctive treatment for tuberculous References to studies excluded from this review
meningitis. Pediatric Infectious Disease Journal Donald 2004 {published data only}
1991;10(3):179-83.
Donald PR, Schoeman JF. Tuberculous meningitis. New England
Kumarvelu 1994 {published and unpublished data} Journal of Medicine 2004;351(17):1719-20.
Kumarvelu S, Prasad K, Khosla A, Behari M, Ahuja GK. Escobar 1975 {published data only}
Randomized controlled trial of dexamethasone in tuberculous
Escobar JA, Belsey MA, Dueñas A, Medina P. Mortality from
meningitis. Tubercle and Lung Disease 1994;75(3):203-7.
tuberculous meningitis reduced by steroid therapy. Pediatrics
Lardizabal 1998 {unpublished data only} 1975;56(6):1050-5.
Lardizabal DV, Roxas AA. Dexamethasone as adjunctive therapy Freiman 1970 {published data only}
in adult patients with probable TB meningitis stage II and stage
Frieman I, Geefhuysen J. Evaluation of intrathecal therapy with
III: An open randomised controlled trial. Philippines Journal of
streptomycin and hydrocortisone in tuberculous meningitis.
Neurology 1998;4:4-10.
Journal of Pediatrics 1970;76(6):895-901.
Malhotra 2009 {published data only}
Girgis 1983 {published data only}
Malhotra HS, Garg RK, Singh MK, Agarwal A, Verma R.
Girgis NI, Farid Z, Hanna LS, Yassin MW, Wallace CK. The use
Corticosteroids (dexamethasone versus intravenous
of dexamethasone in preventing ocular complications in
methylprednisolone) in patients with tuberculous meningitis.
tuberculous meningitis. Transactions of the Royal Society of
Annals of Tropical Medicine and Parasitology 2009;103(7):625-34.
Tropical Medicine and Hygiene 1983;77(5):658-9.
O'Toole 1969 {published data only}
Heemskerk 2016 {published data only}
O'Toole RD, Thornton GF, Mukherjee MK, Nath RL.
Heemskerk AD, Bang ND, Mai NT, Chau TT, Phu NH, Loc PP,
Dexamethasone in tuberculous meningitis. Relationship of
Chau NV, Hien TT, Dung NH, Lan NT, Lan NH, Lan NN, Phong
cerebrospinal fluid effects to therapeutic efficacy. Annals of
le T, Vien NN, Hien NQ, Yen NT, Ha DT, Day JN, Caws M,
Internal Medicine 1969;70(1):39-48.
Merson L, Thinh TT, Wolbers M, Thwaites GE, Farrar JJ.
Prasad 2006 {unpublished data only} Intensified Antituberculosis Therapy in Adults with Tuberculous
Meningitis. New England Journal of Medicine 14th January
Prasad K. A randomized controlled trial to study the
2016;374(2):124-134.
effectiveness of dexamethasone as an adjunct to standard
antituberculous treatment in patients with clinically presumed Hockaday 1966 {published data only}
tuberculous meningitis: 10-year follow-up study (as supplied 7
Hockaday JM, Smith HM. Corticosteroids as an adjuvant
June 2015). Data on file.
to the chemotherapy of tuberculous meningitis. Tubercle
Schoeman 1997 {published data only} 1966;47(1):75-91.
Schoeman JF, Van Zyl LE, Laubscher JA, Donald PR. Effect Kalita 2001 {published data only}
of corticosteroids on intracranial pressure, computed
Kalita J, Misra UK. Effect of methyl prednisolone on sensory
tomographic findings, and clinical outcome in young children
motor functions in tuberculous meningitis. Neurology India
with tuberculous meningitis. Pediatrics 1997;99(2):226-31.
2001;49(3):267-71.
Thwaites 2004 {published data only}
Kapur 1969 {published data only}
Simmons CP, Thwaites GE, Quyen NT, Chau TT, Mai PP, Dung NT,
Kapur S. Evaluation of treatment of tuberculous meningitis
et al. The clinical benefit of adjunctive dexamethasone in
since the use of steroids as an adjuvant. Indian Pediatrics
tuberculous meningitis is not associated with measurable
1969;6(3):166-71.
attenuation of peripheral or local immune responses. Journal of
Immunology 2005;175(1):579-90. Karak 1998 {published data only}
* Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Karak B, Garg RK. Corticosteroids in tuberculous meningitis.
Nguyen TC, et al. Dexamethasone for the treatment of Indian Pediatrics 1998;35(2):193-4.

Collaboration.
Informed decisions.

Lepper 1963 {published data only} BSI 2009

Lepper MH, Spies HW. The present status of the treatment of Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J,
tuberculosis of the central nervous system. Annals of the New British Infection Society. British Infection Society guidelines
York Academy of Sciences 1963;106:106-23. for the diagnosis and treatment of tuberculosis of the central
nervous system in adults and children. Journal of Infection
Marras 2005 {published data only} 2009;59(3):167-87.
Marras TK. Dexamethasone for tuberculous meningitis. New
England Journal of Medicine 2005;352(6):628-30. CDC 2003
Centers for Disease Control and Prevention. Treatment of
Quagliarello 2004 {published data only} Tuberculosis, American Thoracic Society, CDC, and Infectious
Quagliarello V. Adjunctive steroids for tuberculous meningitis Diseases Society of America. MMWR 2003;52(RR-11):1-77.
- more evidence, more questions. New England Journal of
Medicine 2004;351(17):1792-4. D'Arcy-Hart 1950
D'Arcy-Hart P, Rees RJ. Enhancing effect of cortisone on
Seligman 2005 {published data only} tuberculosis in the mouse. Lancet 1950;2(6630):391-5.
Seligman SJ. Dexamethasone for tuberculous meningitis. New
England Journal of Medicine 2005;352(6):628-30. Feldman 1958
Feldman S, Behar AJ, Weber D. Experimental tuberculous
Shah 2014 {published data only} meningitis in rabbits. 1. Results of treatment with
Shah I, Meshram L. High dose versus low dose steroids in antituberculous drugs separately and in combination with
children with tuberculous meningitis. Journal of Clinical cortisone. A. M. A. Archives of Pathology 1958;65(3):343-54.
Neuroscience 2014;21(5):761-4.
Geiman 1992
Vagenakis 2005 {published data only} Geiman BJ, Smith AL. Dexamethasone and bacterial meningitis.
Vagenakis AG, Kyriazopoulou V. Dexamethasone for A meta-analysis of randomized controlled trials. Western
tuberculous meningitis. New England Journal of Medicine Journal of Medicine 1992;157(1):27-31.
2005;352(6):628-30.
Higgins 2011
Voljavec 1960 {published data only} Higgins JPT, Green S (editors). Cochrane Handbook for
Volijavec BF, Corpe RF. The influence of corticosteroid Systematic Reviews of Interventions Version 5.1.0 [updated
hormones in the treatment of tuberculous meningitis March 2011]. The Cochrane Collaboration, 2011. Available from
in Negroes. American Review of Respiratory Disease www.cochrane-handbook.org.
1960;81(4):539-45.
Jacobs 1990
Wasz-Höckert 1963 {published data only} Jacobs RF, Sunakorn P. Tuberculous meningitis in children: an
Wosz-Höckert O. Modern treatment and late prognosis of evaluation of chemotherapeutic regimens. American Review of
tuberculous meningitis. Acta Paediatrica 1963;52 Suppl Respiratory Disease 1990;141 Suppl:A337.
141:93-102.
Jacobs 1992
Weiss 1965 {published data only} Jacobs RF, Sunakorn P, Chotpitayasunonah T, Pope S,
Weiss W, Flippin HF. The changing incidence of and prognosis Kelleher K. Intensive short course chemotherapy for
of tuberculous meningitis. American Journal of the Medical tuberculous meningitis. Pediatric Infectious Disease Journal
Sciences 1965;250:46-59. 1992;11(3):194-8.
Jorge 2012
Additional references Jorge JH, Graciela C, Pablo AP, Luis SH. A life-threatening
Alarcón 1990 central nervous system-tuberculosis inflammatory reaction
nonresponsive to corticosteroids and successfully controlled
Alarcón F, Escalante L, Pérez Y, Banda H, Chacón G, Dueñas G. by infliximab in a young patient with a variant of juvenile
Tuberculous meningitis. Short course of chemotherapy. Archives idiopathic arthritis. Journal of Clinical Rheumatology
of Neurology 1990;47(12):1313-7. 2012;18(4):189-91.
Berenguer 1992 Jüni 2001
Berenguer J, Moreno S, Laguna F, Vicente T, Adrados M, Jüni P, Altman DG, Egger M. Systematic reviews in health
Ortega A, et al. Tuberculous meningitis in patients infected with care: Assessing the quality of controlled clinical trials. BMJ
the human immunodeficiency virus. New England Journal of 2001;323(7303):42-6.
Medicine 1992;326(10):668-72.
Lee 2012
Berger 1994
Lee HS, Lee Y, Lee SO, et al Choi SH, Kim YS, Woo JH, et al.
Berger JR. Tuberculous meningitis. Current Opinion in Neurology Adalimumab treatment may replace or enhance the activity of
1994;7(3):191-200.

Collaboration.
Informed decisions.

steroids in steroid-refractory tuberculous meningitis. Journal of Schoeman 2010

Infection and Chemotherapy 2012;18(4):555–7. Schoeman JF, Andronikou S, Stefan DC, Freeman N,
van Toorn R. Tuberculous meningitis-related optic neuritis:
Lefebvre 2011
recovery of vision with thalidomide in four consecutive cases.
Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching Journal of Child Neurology 2010;25(7):822–8.
for studies. In: Green S, Higgins JPT (editors). The Cochrane
Handbook for Systematic Reviews of Interventions Version SNHS 2010
5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Working Group of the Clinical Practice Guideline on the
Available from www.cochrane-handbook.org. The Cochrane Diagnosis, Treatment and Prevention of Tuberculosis. Centro
Collaboration. Cochrane Iberoamericano (Iberoamerican Cochrane Centre),
coordinator. Clinical Practice Guideline on the Diagnosis,
Molton 2015
Treatment and Prevention of Tuberculosis. Quality Plan for the
Molton JS, Huggan PJ, Archuleta S. Infliximab therapy in two Spanish National Healthcare System of the Spanish Ministry
cases of severe neurotuberculosis paradoxical reaction. Medical for Health, Social Policy and Equality; Agència d’Informació,
Journal of Australia 2015;202(3):156-7. Avaluació i Qualitat en Salut de Catalunya (AIAQS - Agency for
Information, Evaluation, and Quality in Health of Catalonia).
MRC 1948
Ministry of Science and Innovation, Spain, 2010.
Medical Research Council Report. Streptomycin treatment of
tuberculous meningitis. Lancet 1948;1(6503):582-96. Tandon 1988
Tandon PN, Bhatia R, Bhargava S. Tuberculous meningitis. In:
Naing 2013
Harris AA editor(s). Handbook of Clinical Neurology. Vol. 8,
Naing C, Mak JW, Maung M, Wong SF, Kassim AI. Meta-analysis: Amsterdam: Elsevier Science Publishers, 1988:195-226.
the association between HIV infection and extrapulmonary
tuberculosis. Lung 2013;191(1):27-34. Thwaites 2002
Thwaites GE, Chau TT, Stepniewska K, Phu NH, Chuong LV,
NICE 2011
Sinh DX, et al. Diagnosis of adult tuberculous meningitis
National Institute for Health and Care Excellence (NICE). by use of clinical and laboratory features. Lancet
Tuberculosis: Clinical diagnosis and management of 2002;360(9342):1287-92.
tuberculosis, and measures for its prevention and control. NICE
clinical guidelines 117. Manchester: NICE, March 2011. Thwaites 2013
Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis:
Parsons 1988
more questions, still too few answers. Lancet Neurology
Parsons M. Tuberculous Meningitis: Tuberculomas and Spinal 2013;12(10):999-1010.
Tuberculosis - A Handbook for Clinicians (Oxford Medical
Publications). 2nd Edition. Oxford: Oxford University Press, Tobin 2010
1988:32-62. Tobin DM, Vary JC Jr, Ray JP, Walsh GS, Dunstan SJ, Bang ND,
et al. The lta4h locus modulates susceptibility to mycobacterial
Ramchandran 1986
infection in zebrafish and humans. Cell 2010;140(5):717-30.
Ramachandran P, Duraipandian M, Nagarajan M, Prabhakar R,
Ramakrishnan CV, Tripathy SP. Three chemotherapy studies of Tobin 2012
tuberculous meningitis in children. Tubercle 1986;67(1):17-29. Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP,
et al. Host genotype-specific therapies can optimize the
RevMan 2014 [Computer program]
inflammatory response to mycobacterial infections. Cell
The Nordic Cochrane Centre, The Cochrane Collaboration. 2012;148(3):434-46.
Review Manager (RevMan). Version 5.3. Copenhagen: The
Nordic Cochrane Centre, The Cochrane Collaboration, 2014. Török 2011
Török ME, Nguyen DB, Tran TH, Nguyen TB, Thwaites GE,
Schoeman 2001
Hoang TQ, et al. Dexamethasone and long-term outcome of
Schoeman JF, Ravenscroft A, Hartzenberg HB. Possible role of tuberculous meningitis in Vietnamese adults and adolescents.
adjunctive thalidomide therapy in the resolution of a massive PLoS One 2011;6(12):e27821.
intracranial tuberculous abscess. Child's Nervous System
2001;17(6):370-2. WHO 2014
World Health Organization. Global Tuberculosis Report 2014.
Schoeman 2004
Geneva: World Health Organization, 2014.
Schoeman JF, Springer P, van Rensburg AJ, Swanevelder S,
Hanekom WA, Haslett PA, et al. Adjunctive thalidomide therapy
for childhood tuberculous meningitis: results of a randomized
study. Journal of Child Neurology 2004;19(4):250-7.

Collaboration.
Informed decisions.

References to other published versions of this review Prasad 2008

Prasad 2000 Prasad K, Singh MB. Corticosteroids for managing tuberculous
meningitis. Cochrane Database of Systematic Reviews 2008,
Prasad K, Volmink J, Menon GR. Steroids for treating
Issue 1. [DOI: 10.1002/14651858.CD002244.pub3]
tuberculous meningitis. Cochrane Database of Systematic
Reviews 2000, Issue 3. [DOI: 10.1002/14651858.CD002244]
* Indicates the major publication for the study
Prasad 2006
Prasad K, Volmink J, Menon GR. Steroids for treating
tuberculous meningitis. Cochrane Database of Systematic
Reviews 2006, Issue 1. [DOI: 10.1002/14651858.CD002244.pub2]

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Chotmongkol 1996
Methods Randomized parallel group study.
Length of follow-up: 6 months but post-study follow-up continued for 16 to 45 months (mean = 30
months).
Participants Setting: Sringarind Hospital, Khon Kaen, Thailand - tertiary referral centre.
Number of participants: 59 participants; 27 females, 32 males; 29 received prednisolone, 30 received no

steroid.
Inclusion criteria: age > 15 years; clinically diagnosed tuberculous meningitis (characteristic clinical
features with typical CSF profile consisting of lymphocytic meningitis with low glucose level and elevat-
ed protein), all stages of disease included.
Exclusion criteria: children <15 years old, HIV-positive, VDRL positive for syphilis, cryptococcal antigen
positive, CSF positive for bacterial or fungal infection on latex agglutination or culture, malignant cells
in CSF.
HIV status: HIV-positive participants excluded.
Interventions 1. Antituberculous treatment (ATT) plus prednisolone orally on tapering dosage for 5 weeks (week 1 =
60 mg, week 2 = 45 mg, week 3 = 30 mg; week 4 = 20 mg, week 5 = 10 mg).
2. ATT alone.
ATT: isoniazid oral (300 mg), rifampicin oral (600 mg, 450 mg for those weighing < 50 kg), pyrazinamide
oral (1500 mg), and streptomycin intramuscular (750 mg) for the first 2 months; followed by isoniazid
and rifampicin in above dosage for 4 months.
Outcomes 1. Death at the end of 6 months.

2. Residual neurological deficits at the end of 6 months.
3. Time until resolution of fever.
4. Time until disappearance of headache.
Adverse events recorded were gastrointestinal bleeding and hyperglycaemia.
Notes Date: July 1990 to December 1992.
Trialists: Department of Medicine, Khon Kaen University, Thailand; no collaborators.
There was baseline prognostic imbalance in favour of placebo group: MRC stage 3 disease was present
in 6/29 (20.7%) in prednisolone group, but 4/30 (13.3%) in placebo group. Conversely, stage 1 dis-
ease was present in 3/29 (10.3%) in prednisolone group, whereas 6/30 (20%) in placebo group. Both
favoured the placebo group.

Collaboration.
Informed decisions.

Chotmongkol 1996 (Continued)
Ziehl-Nielsen staining of CSF for AFBs or culture positive for M. tuberculosis, or both, in 4/29 in the pred-
nisolone group and 1/30 in the placebo group.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Unclear risk Block randomization by a block size of 4, but insufficient information on se-
tion (selection bias) quence generation.
Allocation concealment Low risk "Patients were randomised to receive prednisolone or placebo by a block size
(selection bias) of four using coded treatment A and B."
Blinding of participants Low risk Blinding with use of placebo.

and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- Low risk Blinding of outcome assessors was not specified, but this is unlikely to intro-
sessment (death) duce bias for all-cause mortality.
Blinding of outcome as- Unclear risk Blinding of outcome assessors was not specified, so impact on assessment of
sessment (disabling neu- neurological deficits during follow-up was unclear.
rological deficit at the end
of follow-up)
Incomplete outcome data Unclear risk Losses to follow-up were not reported.
(attrition bias)
All outcomes
Selective reporting (re- Unclear risk The protocol was unavailable, and outcomes were not clearly specified in the
porting bias) methods.

Girgis 1991
Methods Randomized parallel group, 2-arm study with allocation ratio: 1:1.
Length of follow-up: 24 months.
Participants Setting: Abbassia Fever Hospital, Cairo, Egypt - tertiary referral centre.
Number of participants: 280 participants; 158 males, 122 females; 145 received dexamethasone, 135 re-
ceived no steroid.
Age: all ages included, 37% aged 0 to 5 years, 22% aged 5 to 16 years.
Inclusion criteria: clinically diagnosed tuberculous meningitis based on history and examination (dura-
tion of illness > 30 days, consisting of fever, headache, vomiting, altered sensorium, generalized weak-
ness or cranial nerve deficits); comparison of first and second CSF findings; and a poor response to an-
tibacterial therapy for 48 hrs.
Exclusion criteria: not reported.
HIV status: not reported.
Interventions 1. ATT plus dexamethasone given intramuscularly (12 mg/day to adults and 8 mg/day to children weigh-
ing < 25 kg) for 3 weeks and then tapered during the next 3 weeks).
2. ATT alone.

Collaboration.
Informed decisions.

Girgis 1991 (Continued)
ATT: isoniazid (10 mg/kg/day, maximum 600 mg) intramuscularly for 2 weeks then orally for 2 years,
streptomycin intramuscular (25 mg/kg/day, maximum 1000 mg) for 6 weeks, and ethambutol oral (25
mg/kg/day, maximum 1200 mg) for 6 weeks, then 15 mg/kg/day for 2 years.
Outcomes 1. Death during 2-year follow-up.

2. Residual neurological sequelae.
3. Neurological complications developing during therapy.
4. CSF leucocytes, glucose, and protein on day 15 and day 30 after initiation of treatment.
Trial authors reported case-fatality rate, which by definition includes all deaths caused by tuberculous
meningitis, but not deaths attributed to other causes. They did not report whether any death during
the follow-up period was considered to be due to any cause other than tuberculous meningitis.
Notes Date: 1982 to 1987.
Trialists: United States Naval Medical Research Unit No. 3, Cairo, Egypt; no collaborators.
160/280 CSF culture positive for M. tuberculosis.
Risk of bias
Random sequence genera- Low risk Pre-designed 1-to-1 number randomization chart.
tion (selection bias)
Allocation concealment Unclear risk Insufficient information.

(selection bias)
Blinding of participants Unclear risk No attempt at blinding, but the impact on mortality is unclear.
mance bias)
All outcomes
Blinding of outcome as- Unclear risk Outcome assessors were not blinded, and impact on risk of bias for case fatali-
sessment (death) ty rate is unclear as this is a measure of death attributed to tuberculous menin-
gitis only.
Blinding of outcome as- High risk Outcome assessors were not blinded, so risk of bias in assessment of neuro-
sessment (disabling neu- logical deficit during follow-up is high.
of follow-up)
Incomplete outcome data Unclear risk Losses to follow-up were not reported.
(attrition bias)
All outcomes
Selective reporting (re- Unclear risk The protocol was unavailable and outcomes were not clearly specified in the
porting bias) methods.

Kumarvelu 1994
Methods Randomized parallel group 2-arm study with allocation ratio 1:1.
Participants Setting: all India Institute of Medical Sciences (AIIMS), New Delhi, India - tertiary referral centre.

Collaboration.
Informed decisions.

Kumarvelu 1994 (Continued)
Number of participants: 47 participants; 22 females, 25 males; 24 received dexamethasone, 23 received
no steroid.
Inclusion criteria: aged over 10 years; clinically diagnosed tuberculous meningitis (meeting any 3 of the
following criteria).
1. Fever, headache, neck stiffness for 2 weeks.

2. CSF profile of > 20 cells/mm3 predominantly lymphocytes, protein > 1 g/L, and sugar < 2/3 of corre-
sponding blood sugar with no malignant cells on cytological examination and bacteria/fungi on cul-
ture.
3. Head contrast-enhanced CT showing basal exudates or hydrocephalus.
4. Clinical, radiological, or histological evidence of extracranial TB).
All stages of severity and any duration of disease included.
Exclusion criteria: aged < 10 years, received ATT for more than 4 weeks prior to admission, received cor-
ticosteroids before admission.
Interventions 1. ATT plus dexamethasone (intravenous 16 mg/day in 4 divided doses for 7 days, then oral tablet 8 mg/
day for 21 doses, and in children 0.6 mg/kg/day for 7 days, reducing to 0.3 mg/kg/day for 21 days).
2. ATT alone.
ATT: rifampicin (450 mg), isoniazid (300 mg), and pyrazinamide (1500 mg) all oral daily; for those weigh-
ing < 30 kg 15 mg/kg, 10 mg/kg, and 30 mg/kg respectively.
Duration of treatment: 1 year.
Outcomes 1. Death at 3 months.

2. Major sequelae (totally dependent for activities of daily living) at 3 months.
3. Minor sequelae (activities of daily living with no or minimal assistance) at 3 months.
4. Adverse effects.
5. Time to recover from altered sensorium, from fever, and from headache.
Notes Location: India.
Date: March 1991 to March 1992.
Trialists: Department of Neurology, All India Institute of Medical Sciences, New Delhi, India; no collabo-
rators.
Number of participants that were CSF culture positive for M. tuberculosis was not stated.
Risk of bias
Random sequence genera- Low risk Used random numbers from Fisher's table.
Allocation concealment High risk Not done.

(selection bias)
Blinding of participants Unclear risk No blinding but its impact on mortality remains unclear.
mance bias)
All outcomes

Collaboration.
Informed decisions.

Kumarvelu 1994 (Continued)
Blinding of outcome as- Low risk Outcome assessors were not blinded, but this is unlikely to introduce bias for
sessment (death) all-cause mortality.
Blinding of outcome as- High risk Outcome assessors were not blinded, so the risk of bias in assessment of neu-
sessment (disabling neurological deficit during follow-up is high.
of follow-up)
Incomplete outcome data High risk Six out of 47 participants were lost to follow-up (4 in the treatment arm and 2
(attrition bias) in the control arm).
All outcomes
Selective reporting (re- Unclear risk Protocol unavailable and outcomes not clearly specified in the methods.
porting bias)

Lardizabal 1998
Methods Randomized parallel group, 2-arm study with allocation ratio 1:1
Length of follow-up: 2 months
Participants Setting: University of the Phillipines College of Medicine, tertiary care facility, single centre
Number of participants: 58 participants; 31 males and 27 females; 29 received dexamethasone, 29 re-

ceived no steroid.
Inclusion criteria: aged 18 years and above; probable tuberculous meningitis diagnosed using ASEAN
Neurological Association criteria based on the following.
1. Insidious onset fever for at least 1 week, headache and vomiting, with or without nuchal rigidity fol-
lowed by altered consciousness, cranial nerve palsies, or long tract signs.
2. CSF profile of lymphocyte predominance, elevated protein and reduced glucose.
3. CSF negative for cryptococcal antigen plus 1 or more of the following: basilar/meningeal enhance-
ment on contrast CT scanning, active pulmonary disease, positive purified protein derivative (PPD),
history of contact with TB; confirmed tuberculous meningitis based on positive CSF culture or mi-
croscopy, or both.
4. British MRC stages II and III disease.
Exclusion criteria
1. Aged under 18.

2. British MRC stage I TB meningitis, or bacterial or fungal meningitis diagnosed on CSF culture.
3. Pregnancy or lactation.
4. History of diabetes mellitus or hypertension.
5. Upper gastrointestinal bleeding, or history of peptic ulcer disease in the previous month.
6. Raised bilirubin, SGPT or serum creatinine.
Interventions 1. Antituberculous treatment plus dexamethasone (16 mg/day for 3 weeks (first 5 days intravenous
thereafter orally or via nasogastric tube); after 3 weeks corticosteroid was tapered by 4 mg decrements
every 5 days).
2. Antituberculous treatment alone.
Antituberculous treatment: rifampicin (10 to 15 mg/kg/day), isoniazid (5 to 10 mg/kg/day), pyrazi-

namide (15 to 30 mg/kg/day), and ethambutol (15 to 20 mg/kg/day) for the first 2 months; thereafter,
rifampicin and isoniazid only for 10 months; total treatment duration 12 months; route of administra-
tion was not stated.

Collaboration.
Informed decisions.

Lardizabal 1998 (Continued)
An H2-antagonist (famotidine or ranitidine) was given during the period of corticosteroid administra-
tion.
Outcomes 1. Death on days 15, 30, and 60 post-randomization.

2. Functional independence assessed by attending doctor on admission and 60 days after randomiza-
tion: Functional Independence Measure (FIM) used assesses self care, sphincter control, mobility, lo-
comotion, and social cognition on a 7-point scale.
3. Potential adverse reactions to corticosteroids including weakness, oedema, hypertension, eupho-
ria, psychosis, epigastric discomfort, Cushingoid facies, hirsutism, acne, insomnia, and increased ap-
petite.
Notes Location: Philippines.
Date: November 1996 to July 1997.
Trialists: University of Philippines, College of Medicine; no collaborators.
We contacted the trial authors to determine the number of deaths in participants with stage II and III
disease.
Risk of bias
Random sequence genera- Unclear risk Generation of allocation sequence was unclear.

(selection bias)
Blinding of participants Unclear risk No blinding but its impact on mortality remains unclear.
mance bias)
All outcomes
Blinding of outcome as- Low risk Outcome assessors were not blinded, but unlikely to introduce bias for all-
sessment (death) cause mortality.
Blinding of outcome as- High risk Outcome assessors were not blinded, so risk of bias in assessment of neuro-
sessment (disabling neu- logical deficit during follow-up is high.
of follow-up)
Incomplete outcome data Low risk No losses to follow-up, changes of treatment arm, or withdrawals. Outcomes
(attrition bias) were reported for all randomized participants.
All outcomes
Selective reporting (re- Low risk The protocol was unavailable, but all outcomes specified in the methods sec-
porting bias) tion are reported on in the results.

Malhotra 2009
Methods Randomized parallel group 3-arm study with allocation ratio 1:1:1.

Collaboration.
Informed decisions.

Malhotra 2009 (Continued)
Participants Setting: Chhatrapati Shahuji Maharaj Medical University (CSMMU), Lucknow, India - tertiary referral
centre.
Number of participants: 91 participants; 48 males, 43 females (6 participants randomized but lost to

follow-up); 32 randomized to dexamethasone (1 lost to follow-up), 33 randomized to methylpred-
nisolone (3 lost to follow-up), 32 randomized to no steroid (2 lost to follow-up).
Inclusion criteria: age > 14 years; meningitic syndrome; tuberculous meningitis defined as "definite" if
acid-fast bacilli were seen in CSF, "probable" if one or more than one of the following present: suspect-
ed active pulmonary TB on chest radiography, acid-fast bacilli in any specimen other than CSF, clinical
evidence of extrapulmonary TB, and "possible" if at least 4 of the following were present: history of TB,
predominance of lymphocytes in CSF, duration of illness > 5 days, radio of CSF to plasma glucose < 0.5,
altered consciousness, yellow CSF, or focal neurological signs.
Exclusion criteria: age < 14 years; HIV-positive; contraindication to corticosteroids; received corticos-
teroid or antituberculous drugs before presentation at the CSMMU, evidence of space occupying lesion
on CT brain, refused consent.
Interventions 1. ATT + dexamethasone (intravenous for 4 weeks as (at 0.4, 0.3, 0.2 and 0.1 mg/kg.day during weeks
1, 2, 3, 4 respectively); daily oral dose for following 4 weeks as 4, 3, 2, 1 mg/day on weeks 5, 6, 7, 8
respectively).
2. ATT + methylprednisolone (intravenous for 5 days (1 g/day for participants weighing > 50kg and 20
mg/kg/day for participant weighing < 50 kg).
3. ATT alone.
ATT: rifampicin (15 mg/kg/day), isoniazid (10 mg/kg/day), pyrazinamide (30 mg/kg/day) and either
ethambutol (20 mg/kg/day) or streptomycin (15 mg/kg/day) for 2 months and isoniazid (10 mg/kg/
day) for 7 months.
Outcomes Assessed at 6 months post-randomization.
1. Death or severe disability.

2. Adverse events: hepatitis; anti-epileptic toxicity, gastro-intestinal bleeding, paradoxical tuberculoma.
3. Deterioration in vision, development of new focal neurological deficit and new-onset seizures.
Notes Date: January 2006 to July 2007.
Trialists: CSMMU, Lucknow, Department of Neurology, Uttar Pradesh, India.
97/126 acid-fast stain/culture positive forM. tuberculosis.
Risk of bias
Random sequence genera- Low risk Random allocation using computer-generated randomization sheet.

(selection bias)
Blinding of participants Unclear risk No blinding, but the impact on mortality is unclear.
mance bias)
All outcomes
Blinding of outcome as- Low risk Outcome assessors were not blinded, but this is unlikely to introduce bias for
sessment (death) all cause mortality.

Collaboration.
Informed decisions.

Malhotra 2009 (Continued)
Blinding of outcome as- High risk Outcome assessors were not blinded, so the risk of bias in assessment of neu-
sessment (disabling neurological deficit during follow-up is high.
of follow-up)
Incomplete outcome data Low risk Six out of 97 participants were lost to follow-up (1 in dexamethasone, 3 in
(attrition bias) methylprednisolone, and 2 in the control arm).
All outcomes
Selective reporting (re- Low risk The protocol was unavailable, but all outcomes specified in the methods were
porting bias) reported.

O'Toole 1969
Length of follow-up: unclear.
Participants Setting: Infectious Diseases Hospital, Calcutta, India - tertiary referral centre.
Number of participants: 23 participants in total, 11 females, 12 males; 11 received dexamethasone, 12

received no steroid.
Inclusion criteria: not explicitly specified, but the trial authors state that due to the trial institution's ad-
missions policy only participants with a short history or acute signs and symptoms of meningitis were
selected; due to limited bed availability only moderate to severely unwell participants were included
(MRC Stage II and III). All age groups were included. Treatment allocation was stratified for age and dis-
ease severity.
Interventions 1. ATT plus dexamethasone given for up to 4 weeks in an adult dose of 9 mg/day during the first week, 6
mg/day during the second week, 3 mg/day during the third week, and 1.5 mg/day during the 4th week;
dose for children was calculated according to their body surface area (no more details available).
2. ATT alone.
ATT: isoniazid intramuscular or oral (10 mg/kg/day, except in children < 2 years of age who received 20
mg/kg/day) and streptomycin (20 mg/kg/day, maximum 1 g), duration not specified.
Outcomes 1. Death at the end of follow-up (duration unclear).

2. Number with elevated CSF opening pressure on days 1, 4, 7, and 14.
3. CSF sugar, protein, and cell count on days 1, 4, 7, 14, 21, and 28 in decreasing number of participants,
depending apparently on the surviving number. Number with residual deficits not given. Surviving
participants all been described as "significantly improved".
4. Adverse events recorded: upper gastrointestinal bleed, invasive bacterial infection, hypoglycaemia,
and hypothermia.
5. Resolution of CSF findings.
Notes Date: February 1966 to March 1967.
Trialists: Calcutta School of Tropical Medicine and the Infectious Disease Hospital, Calcutta, India, in
collaboration with Johns Hopkins University, Baltimore, USA.
16/23 participants had either smear (2) or culture (9), or both smear and culture (5) positive for tuber-
cle bacillus; remaining 7 participants had clinical features consistent with the diagnosis of tuberculous
meningitis and CSF profile consisting of elevated white cell count and protein, decreased glucose, and

Collaboration.
Informed decisions.

O'Toole 1969 (Continued)
negative India ink smear for Cryptococcus; the trial authors intended to include only moderately ad-
vanced (stage II) and severe (stage III) cases, but 1 case of stage I was entered in the treatment group.
Risk of bias
Random sequence genera- Unclear risk Insufficient information.

Allocation concealment Low risk "New admissions to the study were assigned their drug by matching age and
(selection bias) stage of disease then selecting the next unused coded preparation in that
prognostic category."
Blinding of participants Low risk Blinding unlikely to have been broken.

mance bias)
All outcomes
Blinding of outcome as- Low risk Blinding of outcome assessors was not specified, but this was unlikely to intro-
Blinding of outcome as- Low risk Neurological deficit was not reported on in this trial.
sessment (disabling neu-
of follow-up)
Incomplete outcome data Low risk All outcomes reported in 23/23 participants.
(attrition bias)
All outcomes
Selective reporting (re- Unclear risk The protocol was unavailable and outcomes not clearly specified in the meth-
porting bias) ods.

Prasad 2006
Methods Double-blind, randomized, concurrent placebo-controlled parallel group trial.
Length of follow-up: 18 months. A 10-year follow-up was planned, but not completed.
Participants Setting: All India Institute of Medical Sciences, New Delhi, India - tertiary referral centre.
Number of participants: 87 participants; 39 females, 48 males; 41 received dexamethasone, 46 received

placebo
Inclusion criteria: clinically diagnosed tuberculous meningitis based on meeting these 3 criteria.
1. Gradual onset of any 2 of fever, progressive headache, or impaired consciousness with at least 1 symp-
tom of 3 weeks duration.
2. At least 1 sign of meningeal irritation for example, neck stiffness, Kernig’s sign, Brudzinski’s sign (ex-
cept in deeply comatose cases).
3. CSF profile characteristic of tuberculous meningitis (containing more than 0.02 × 109 cells per litre
with predominant lymphocytes , protein more than 1 g/Pl, sugar less than two-thirds of simultaneous
blood sugar).
Exclusion criteria

Collaboration.
Informed decisions.

Prasad 2006 (Continued)
1. Alternative diagnosis (including non-tubercular infection, malignancy) made on CSF testing or imag-
ing.
2. Treatment with steroids regularly for more than 10 days used during the current illness.
3. Liver disease or gout.
4. History of gastric or duodenal ulcer, gastrointestinal haemorrhage, malignant hypertension.
5. Pregnant women.
HIV status: not specified.
Interventions 1. ATT plus dexamethasone 0.15 mg per kg body weight (up to a maximum of 4 mg) every 6 hours for 3
weeks then tapered gradually.
2. ATT plus placebo (0.9% saline).
ATT: oral (through nasogastric tube in unconscious participants) administration of isoniazid 10 mg/kg
up to 300 mg, rifampicin 15 mg/kg up to 450 mg, and pyrazinamide 30 mg/kg for participants less than
30 kg and 1500 mg for participants over 30 kg daily, plus pyridoxine 50 mg daily. Total duration was 9
months.
Outcomes Outcomes identified in trial protocol
1. Treatment success, defined as resolution of meningitic symptoms and achievement of good neuro-
logic function and stability of this state for 3 consecutive months.
2. All-cause death in the first 3 months.
3. Secondary treatment failure.
4. Adverse events related to ATT or dexamethasone, for example deranged liver function tests, hyper-
tension, hyperglycaemia, secondary infection, rash, gastrointestinal bleeding.
Outcomes reported in results
1. Death.
2. Non-disabling neurological deficit.
3. Disabling neurological deficit.
4. Bad outcome (death plus disabling neurological deficit).
5. Any deficit (non-disabling neurological deficit plus disabling neurological deficit.
Notes Date: recruitment started February 1996.
Trialists: Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.
We based this trial description and our 'Risk of bias' assessment on the trial protocol and unpublished
outcome data, including baseline characteristics of participants. As the final report was unavailable,
we could not assess variations between the protocol and the trial itself.
There were 6 losses to follow-up at 18 months follow-up, 3 in each group.
Risk of bias
Random sequence genera- Low risk "Eligible consenting subjects will be randomised using block randomisation
tion (selection bias) method. A varying block size of 4 and 6 will be used to avoid possible bias in
selection of subjects if preceding ones had noticeable adverse effects. Patients
will be randomised to either group in 1:1 ratio by statistician in the biostatis-
tics department."
Allocation concealment Low risk "Each patient will be assigned a unique identification number which remained
(selection bias) with him throughout the study and had a drug code incorporated into it. All

Collaboration.
Informed decisions.

Prasad 2006 (Continued)
the care givers, outcome evaluators and patients will be masked to treatment
allocation. Vials containing indistinguishable solutions of either dexametha-
sone or placebo (0.9% NaCl) will be prepared, labelled and distributed by the
pharmacist at AIIMS. Vials will be boxed in sets of thirty (more than one pa-
tient’s requirement) and each vial will have the same code number as the box
and were identically labelled as containing 5mg dexamethasone sodium phos-
phate per ml. Coding will be done by assigning a random set of numbers to the
active drug and a different set to the placebo."
Blinding of participants Low risk "each vial will have the same code number as the box and were identically la-
and personnel (perfor- belled as containing 5mg dexamethasone sodium phosphate per ml".
mance bias)
All outcomes
Blinding of outcome as- Low risk Blinding of outcome assessors was not specified, but this was unlikely to intro-
Blinding of outcome as- Unclear risk Outcome assessors and methods of assessment were not clearly described in
sessment (disabling neu- the protocol.
of follow-up)
Incomplete outcome data Unclear risk The trial profile was not reported, including number of participants eligible,
(attrition bias) and number of participants excluded. Reasons for losses to follow-up were not
All outcomes described.
Selective reporting (re- High risk Outcome measures are re-defined in the reported results. Adverse events and
porting bias) secondary treatment failure were not reported.

Schoeman 1997
Participants Setting: Tygerberg Hospital, Tygerberg, South Africa.
Number of participants: 141 randomized (gender balance not specified); 70 received prednisolone and
71 received no steroid.
Inclusion criteria: children (age limit not specified); diagnosis of tuberculous meningitis based on histo-
ry and "typical CSF changes" with at least 2 of the following: strongly positive (> 15 mm) Mantoux test,
chest x-ray suggesting TB or CT head showing basal enhancement and acute hydrocephalus. Only MRC
Stage II and III included.
Interventions 1. ATT plus prednisolone (given to first 16 participants in a dose of 2 mg/kg/day and to the remaining
54 participants in a dose of 4 mg/kg/day (once in the morning); decision to double the dose after the
first 16 participants).
2. ATT alone.
ATT: isoniazid (20 mg/kg/day), rifampicin (20 mg/kg/day), ethionamide (20 mg/kg/day), and pyrazi-
namide (40 mg/kg/day) for 6 months.
Outcomes 1. Deaths at 6 months.

2. Disability (mild and severe) at 6 months.
3. Serious side effects.
Collaboration.
Informed decisions.

Schoeman 1997 (Continued)
4. Baseline and pulse pressure of lumbar CSF.
5. Changes in ventricular size in CT.
6. Proportion of participants with successful treatment of raised intracranial pressure.
7. Proportion of participants with basal ganglia infarcts, tuberculomas, meningeal enhancement, and
enlarged subarachnoid spaces.
Notes Date: not mentioned.
Trialists: Department of Paediatrics and Child Health, Faculty of Medicine, University of Stellenbosch
and Tygerberg, South Africa, in collaboration with CERSA, Division of Biostatistics, Medical Research
Council, Parow-Valley, South Africa.
The decision to double the prednisolone dose was taken when the authors became aware of a study
that showed that rifampicin decreased the bioavailability of prednisolone by 66% and increased the
plasma clearance of the drug by 45%; trial authors reported the outcome of both the dose groups to-
gether and mentioned that the mortality or morbidity between the 2 prednisolone dosage groups did
not differ significantly.
23/141 CSF culture positive for M. tuberculosis.
Risk of bias
Random sequence genera- Unclear risk "patients whose parents gave informed written consent were randomly allo-
tion (selection bias) cated to a steroid or nonsteroid treatment group".

(selection bias)
Blinding of participants Unclear risk No blinding, but the impact on mortality is unclear.
mance bias)
All outcomes
Blinding of outcome as- Low risk Blinding of outcome assessors not specified, but unlikely to introduce bias for
sessment (death) all cause mortality.
Blinding of outcome as- Low risk Blinding of assessors. "All these individuals were blinded to the treatment sta-
sessment (disabling neu- tus of the patients at admission."
of follow-up)
Incomplete outcome data Unclear risk Three participants in the steroid group and 4 participants in the nonsteroid
(attrition bias) group were not accounted for in the results section. Losses to follow-up were
All outcomes not reported, so the impact on results is unclear.
Selective reporting (re- Low risk The protocol was unavailable, but all pre-specified outcomes stated in the
porting bias) methods were reported.

Thwaites 2004
Length of follow-up: 9 months (initial report), followed by a 5-year follow-up trial.

Collaboration.
Informed decisions.

Thwaites 2004 (Continued)
Participants Setting: Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease and the Hospital for Tropical
Diseases, Ho Chi Minh City, Vietnam - two tertiary referral centres.
Number of participants: 545 randomized, 331 males, 214 females; 274 received dexamethasone, 271 re-
ceived placebo.
Inclusion criteria: aged over 14 years, clinical meningitis (defined as combination of nuchal rigidity and
CSF abnormalities). Tuberculous meningitis defined as "definite" if acid-fast bacilli were seen in CSF,
"probable" if at least 1 of the following present: suspected active pulmonary TB on chest radiography,
acid-fast bacilli in any specimen other than CSF, clinical evidence of extrapulmonary TB, and "possible"
if at least 4 of the following were present: history of TB, predominance of lymphocytes in CSF, duration
of illness more than 5 days, ratio of CSF to plasma glucose less than 0.5, altered consciousness, yellow
CSF, focal neurological signs.
Exclusion criteria: contraindication to corticosteroids; received more than 1 dose of any corticosteroid,
or more than 30 days of ATT immediately before the trial.
HIV status: 98/545 HIV-positive, 44/274 (16.1%) in dexamethasone group, 54/271 (19.9%) in placebo
group. Three participants in the dexamethasone group, and eight participants in the placebo group
were not tested for HIV.
Interventions 1. ATT plus dexamethasone, dose stratified by disease severity*.

2. ATT plus placebo.
ATT: For previously untreated participants: oral isoniazid (5 mg/kg), rifampicin (10 mg/kg), pyrazi-
namide (25 mg/kg, maximum, 2 g/day), and intramuscular streptomycin (20 mg/kg, maximum 1 g/day)
for 3 months followed by 6 months of isoniazid, rifampicin, and pyrazinamide at the same daily dos-
es; ethambutol (20 mg/kg; maximum 1.2/day) substituted for streptomycin in HIV-positive participants
and was added to the regimen for 3 months for participants previously treated for TB.
*Grade II and III disease: intravenous dexamethasone sodium phosphate given 0.4 mg/kg/day for week
1, 0.3 mg/kg/d for week 2, 0.2 mg/kg/d for week 3, and 0.1 mg/kg/day for week 4, and then oral dexam-
ethasone for 4 weeks decreasing by 1 mg each week.
Grade I disease: intravenous dexamethasone sodium phosphate 0.3 mg/kg/day for week 1 and 0.2 mg/
kg/day for week 2 followed by 4 weeks of oral dexamethasone (0.1 mg/kg/day for week 3 then a total of
3 mg/day, decreasing by 1 mg each week).
Outcomes Assessed at 9 months post-randomization.
1. Death or severe disability.

2. Adverse events: hepatitis; gastrointestinal bleeding, bacterial sepsis, septic shock, brain herniation
syndrome, decreased visual acuity, hyponatraemia, hyperglycaemia, hypertension, vertigo, deafness,
Cushingoid features, pruritis, polyarthralgia, streptomycin reaction, rifampicin flu, rash, and others.
3. Coma clearance time.
4. Fever clearance time.
5. Time to discharge.
6. Time to relapse.
7. Presence of focal neurological deficit (9 months post-randomization).
Assessed during 5-year follow-up study (9 months to 5 years post-randomization).
1. Death.
2. Disability status.
3. TB relapse.
Notes Date: April 2001 to March 2003 (randomization period).
Trialists: Oxford University Clinical Research Unit at the Hospital for Tropical Diseases, Ho Chi Minh
City, Vietnam, and Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City,

Collaboration.
Informed decisions.

Thwaites 2004 (Continued)
Vietnam, in collaboration with Centre for Tropical Medicine, Nuffield, and Department of Clinical Medi-
cine, John Radcliffe Hospital, Oxford, UK.
In this trial, 187/545 participants were acid-fast stain/culture positive for M. tuberculosis in CSF.
Participants were reclassified to "definite" tuberculous meningitis if participant CSF was culture posi-
tive for M. tuberculosis, or to "not TBM" if an alternative diagnosis was made.
Risk of bias
Random sequence genera- Low risk "A computer-generated sequence of random numbers was used to allocate
tion (selection bias) treatment in blocks of 30."
Allocation concealment Low risk "Numbered individual treatment packs containing the study drug were pre-
(selection bias) pared for the duration of treatment and were distributed for sequential use
once a patient fulfilled the entry criteria. Parenteral placebo and dexametha-
sone were identical in appearance, as were oral placebo and dexamethasone."
Blinding of participants Low risk "All participants, enrolling physicians, and investigators remained blinded to
and personnel (perfor- the treatment allocation until the last patient completed follow-up."
mance bias)
All outcomes In five-year follow-up study: no blinding.
Blinding of outcome as- Low risk "All participants, enrolling physicians, and investigators remained blinded to
sessment (death) the treatment allocation until the last patient completed follow-up."
In five-year follow-up study: no blinding, unlikely to introduce risk of bias for

all-cause mortality.
Blinding of outcome as- Low risk "All participants, enrolling physicians, and investigators remained blinded to
sessment (disabling neu- the treatment allocation until the last patient completed follow-up."
of follow-up) In five-year follow-up study: no blinding, risk of bias was unclear for neurologi-
cal disability.
Incomplete outcome data Low risk Lost to follow-up (initial study): 5/274 in dexamethasone arm and 5/271 in
(attrition bias) placebo arm.
All outcomes
Lost to follow-up (5-year follow-up study): 18/274 in dexamethasone arm and
22/271 in placebo arm.
Selective reporting (re- Low risk All pre-specified outcomes reported as per protocol.
porting bias)
Abbreviations: CT: computerized tomography; HIV: human immunodeficiency virus; MRC: Medical Research Council; M. tuberculosis:
Mycobacterium tuberculosis complex; CSF: cerebrospinal fluid; ATT: antituberculous treatment; TBM: tuberculous meningitis; TB:
tuberculosis.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Donald 2004 Perspective article with no original data.

Collaboration.
Informed decisions.

Study Reason for exclusion
Escobar 1975 Not a randomized study. The report says that a pair of participants matched for age and neurologi-
cal status was administered differential therapy in a double-blind fashion. However, it is unclear if
this differential administration was random.
Freiman 1970 Case series.
Girgis 1983 Participants allocated to steroid or non-steroid group on alternate basis; unclear why there is a dif-
ference of 4 in the number of participants in the 2 groups (non-steroid 70 and steroid 66).
Heemskerk 2016 RCT comparing standard ATT regimen with an intensified ATT regimen, all participants received
dexamethasone.
Hockaday 1966 Case series.
Kalita 2001 Study with historical controls, not a randomized study.
Kapur 1969 Case series.
Karak 1998 Commentary on an included trial (Schoeman 1997).
Lepper 1963 Allocation was not truly randomized: the first half of the study was an alternate participant design,
whereas in the last half, participants were randomized by using random numbers.
Marras 2005 Letter to the editor with no original data.
Quagliarello 2004 Editorial.
Seligman 2005 Letter to the editor with no original data.
Shah 2014 RCT comparing three different doses of prednisolone; no placebo arm.
Vagenakis 2005 Letter to the editor with no original data.
Voljavec 1960 Comparison cohort with historical controls.
Wasz-Höckert 1963 Control trial using historical controls.
Weiss 1965 Retrospective case series of 102 cases.

DATA AND ANALYSES

Comparison 1. Any corticosteroid versus control
Outcome or subgroup title No. of studies No. of partici- Statistical method Effect size
pants
1 Death 9 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Follow-up at 2 to 24 9 1337 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.65, 0.87]
months

Collaboration.
Informed decisions.

pants
1.2 Follow-up at 2 years 1 545 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.67, 1.01]
2 Disabling neurological 8 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
deficit
2.1 Follow-up 2 to 24 months 8 1314 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.71, 1.20]
3 Death or disabling neuro- 8 1314 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.72, 0.89]
logical deficit
4 Adverse events 4 2620 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.67, 1.17]
4.1 Hyperglycaemia/glyco- 3 627 Risk Ratio (M-H, Fixed, 95% CI) 1.82 [0.40, 8.36]
suria
4.2 Hepatitis 2 642 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.57, 1.09]
4.3 Gastrointestinal bleeding 4 724 Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.61, 3.48]
4.4 Invasive bacterial infec- 3 627 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.36, 1.93]
tion

Analysis 1.1. Comparison 1 Any corticosteroid versus control, Outcome 1 Death.
Study or subgroup Corticosteroid Control Risk Ratio Weight Risk Ratio
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
1.1.1 Follow-up at 2 to 24 months
Chotmongkol 1996 5/29 2/30 0.74% 2.59[0.54,12.29]
Girgis 1991 72/145 79/135 30.71% 0.85[0.68,1.05]
Kumarvelu 1994 5/24 7/23 2.68% 0.68[0.25,1.85]
Lardizabal 1998 4/29 6/29 2.25% 0.67[0.21,2.12]
Malhotra 2009 17/65 13/32 6.54% 0.64[0.36,1.16]
O'Toole 1969 6/11 9/12 3.23% 0.73[0.39,1.37]
Prasad 2006 9/41 19/46 6.72% 0.53[0.27,1.04]
Schoeman 1997 4/70 13/71 4.85% 0.31[0.11,0.91]
Thwaites 2004 87/274 112/271 42.27% 0.77[0.61,0.96]
Subtotal (95% CI) 688 649 100% 0.75[0.65,0.87]
Total events: 209 (Corticosteroid), 260 (Control)
Heterogeneity: Tau2=0; Chi2=7.59, df=8(P=0.47); I2=0%
Test for overall effect: Z=3.9(P<0.0001)

1.1.2 Follow-up at 2 years
Thwaites 2004 99/274 119/271 100% 0.82[0.67,1.01]
Subtotal (95% CI) 274 271 100% 0.82[0.67,1.01]
Favours [corticosteroids] 0.01 0.1 1 10 100 Favours [placebo]

Collaboration.
Informed decisions.


Heterogeneity: Not applicable
Test for overall effect: Z=1.85(P=0.06)

Thwaites 2004 121/274 128/271 100% 0.93[0.78,1.12]
Subtotal (95% CI) 274 271 100% 0.93[0.78,1.12]
Test for subgroup differences: Chi2=3.31, df=1 (P=0.19), I2=39.51%
Favours [corticosteroids] 0.01 0.1 1 10 100 Favours [placebo]

Analysis 1.2. Comparison 1 Any corticosteroid versus control, Outcome 2 Disabling neurological deficit.
1.2.1 Follow-up 2 to 24 months
Kumarvelu 1994 0/24 1/23 1.59% 0.32[0.01,7.48]
Girgis 1991 14/145 27/135 29.14% 0.48[0.26,0.88]
Lardizabal 1998 10/29 14/29 14.59% 0.71[0.38,1.34]
Schoeman 1997 14/70 19/71 19.66% 0.75[0.41,1.37]
Malhotra 2009 11/65 5/32 6.98% 1.08[0.41,2.85]
Thwaites 2004 34/274 22/271 23.05% 1.53[0.92,2.54]
Prasad 2006 5/41 3/46 2.95% 1.87[0.48,7.34]
Chotmongkol 1996 4/29 2/30 2.05% 2.07[0.41,10.44]
Subtotal (95% CI) 677 637 100% 0.92[0.71,1.2]
Heterogeneity: Tau2=0; Chi2=11.85, df=7(P=0.11); I2=40.93%

Thwaites 2004 17/128 18/116 100% 0.86[0.46,1.58]
Subtotal (95% CI) 128 116 100% 0.86[0.46,1.58]
Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%
Test for subgroup differences: Chi2=0.05, df=1 (P=0.83), I2=0%
Favours [corticosteroid] 0.01 0.1 1 10 100 Favours [placebo]

Analysis 1.3. Comparison 1 Any corticosteroid versus control, Outcome 3 Death or disabling neurological deficit.
Chotmongkol 1996 9/29 4/30 1.11% 2.33[0.81,6.73]
Girgis 1991 86/145 106/135 31.08% 0.76[0.64,0.89]
Kumarvelu 1994 5/24 8/23 2.31% 0.6[0.23,1.56]
Lardizabal 1998 14/29 20/29 5.66% 0.7[0.45,1.1]
Favours corticosteroid 0.1 0.2 0.5 1 2 5 10 Favours control

Collaboration.
Informed decisions.


Malhotra 2009 28/65 18/32 6.83% 0.77[0.51,1.16]
Prasad 2006 14/41 22/46 5.87% 0.71[0.42,1.2]
Schoeman 1997 18/70 32/71 8.99% 0.57[0.36,0.92]
Thwaites 2004 121/274 134/271 38.14% 0.89[0.75,1.07]

Total (95% CI) 677 637 100% 0.8[0.72,0.89]
Favours corticosteroid 0.1 0.2 0.5 1 2 5 10 Favours control

Analysis 1.4. Comparison 1 Any corticosteroid versus control, Outcome 4 Adverse events.
1.4.1 Hyperglycaemia/glycosuria
Chotmongkol 1996 0/29 0/30 Not estimable
O'Toole 1969 1/11 0/12 0.54% 3.25[0.15,72.36]
Thwaites 2004 3/274 2/271 2.27% 1.48[0.25,8.81]
Subtotal (95% CI) 314 313 2.81% 1.82[0.4,8.36]

1.4.2 Hepatitis
Malhotra 2009 12/65 8/32 12.08% 0.74[0.34,1.62]
Thwaites 2004 45/274 56/271 63.45% 0.79[0.56,1.13]
Subtotal (95% CI) 339 303 75.53% 0.79[0.57,1.09]

1.4.3 Gastrointestinal bleeding
Chotmongkol 1996 0/29 0/30 Not estimable
Malhotra 2009 6/65 1/32 1.51% 2.95[0.37,23.51]
O'Toole 1969 4/11 1/12 1.08% 4.36[0.57,33.32]
Thwaites 2004 4/274 6/271 6.8% 0.66[0.19,2.31]
Subtotal (95% CI) 379 345 9.39% 1.45[0.61,3.48]

1.4.4 Invasive bacterial infection
Chotmongkol 1996 1/29 1/30 1.11% 1.03[0.07,15.77]
O'Toole 1969 3/11 3/12 3.23% 1.09[0.28,4.32]
Thwaites 2004 5/274 7/271 7.93% 0.71[0.23,2.2]
Subtotal (95% CI) 314 313 12.27% 0.84[0.36,1.93]
Favours [Corticosteroid] 0.01 0.1 1 10 100 Favours [Control]

Collaboration.
Informed decisions.



Total (95% CI) 1346 1274 100% 0.88[0.67,1.17]
Favours [Corticosteroid] 0.01 0.1 1 10 100 Favours [Control]

Comparison 2. Any corticosteroid versus control: stratified by severity of illness
pants
1 Death 8 1320 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.57, 0.80]
1.1 Stage I (mild) 6 305 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.29, 0.85]
1.2 Stage II (moderately se- 7 581 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.56, 0.93]
vere)
1.3 Stage III (severe) 8 434 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.54, 0.88]

Analysis 2.1. Comparison 2 Any corticosteroid versus control: stratified by severity of illness, Outcome 1 Death.
2.1.1 Stage I (mild)
Girgis 1991 0/6 2/5 1.27% 0.17[0.01,2.92]
Kumarvelu 1994 0/2 0/6 Not estimable
Malhotra 2009 0/14 1/7 0.92% 0.18[0.01,3.88]
O'Toole 1969 0/1 0/1 Not estimable
Prasad 2006 0/41 0/46 Not estimable
Thwaites 2004 15/90 26/86 12.51% 0.55[0.31,0.97]
Subtotal (95% CI) 154 151 14.69% 0.5[0.29,0.85]

2.1.2 Stage II (moderately severe)
Girgis 1991 10/42 18/45 8.17% 0.6[0.31,1.14]
Kumarvelu 1994 5/19 5/13 2.79% 0.68[0.25,1.9]
Malhotra 2009 11/35 8/18 4.97% 0.71[0.35,1.44]
O'Toole 1969 3/6 5/8 2.02% 0.8[0.31,2.1]
Prasad 2006 2/41 5/46 2.22% 0.45[0.09,2.19]
Schoeman 1997 1/30 1/31 0.46% 1.03[0.07,15.78]
Thwaites 2004 38/122 50/125 23.23% 0.78[0.55,1.09]
Favours steroid 0.01 0.1 1 10 100 Favours control

Collaboration.
Informed decisions.


Subtotal (95% CI) 295 286 43.86% 0.72[0.56,0.93]

2.1.3 Stage III (severe)
Girgis 1991 10/42 18/45 8.17% 0.6[0.31,1.14]
Kumarvelu 1994 0/3 2/4 1.05% 0.25[0.02,3.86]
Lardizabal 1998 4/29 6/29 2.82% 0.67[0.21,2.12]
Malhotra 2009 6/12 4/5 2.66% 0.63[0.31,1.28]
O'Toole 1969 3/4 4/4 2.12% 0.78[0.41,1.48]
Prasad 2006 2/41 4/46 1.77% 0.56[0.11,2.9]
Schoeman 1997 3/24 12/24 5.64% 0.25[0.08,0.78]
Thwaites 2004 34/62 36/60 17.21% 0.91[0.67,1.24]
Subtotal (95% CI) 217 217 41.44% 0.69[0.54,0.88]
Test for overall effect: Z=3.03(P=0)

Total (95% CI) 666 654 100% 0.67[0.57,0.8]
Favours steroid 0.01 0.1 1 10 100 Favours control

Comparison 3. Any corticosteroid versus control: stratified by HIV status
Outcome or subgroup ti- No. of studies No. of partici- Statistical method Effect size
tle pants
1 Death 1 534 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.66, 1.02]
1.1 HIV-positive 1 98 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.67, 1.20]
1.2 HIV-negative 1 436 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.58, 1.06]
2 Disabling neurological 1 534 Risk Ratio (M-H, Fixed, 95% CI) 1.15 [0.73, 1.79]
deficit
3 Death or disabling resid- 1 545 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.76, 1.09]
ual neurological deficit

Collaboration.
Informed decisions.


Analysis 3.1. Comparison 3 Any corticosteroid versus control: stratified by HIV status, Outcome 1 Death.
3.1.1 HIV-positive
Thwaites 2004 27/44 37/54 32.26% 0.9[0.67,1.2]
Subtotal (95% CI) 44 54 32.26% 0.9[0.67,1.2]

3.1.2 HIV-negative
Thwaites 2004 57/227 67/209 67.74% 0.78[0.58,1.06]
Subtotal (95% CI) 227 209 67.74% 0.78[0.58,1.06]

Total (95% CI) 271 263 100% 0.82[0.66,1.02]
Favours steroid 0.1 0.2 0.5 1 2 5 10 Favours control

Analysis 3.2. Comparison 3 Any corticosteroid versus control:
stratified by HIV status, Outcome 2 Disabling neurological deficit.
3.2.1 HIV-positive
Thwaites 2004 1/44 1/54 2.89% 1.23[0.08,19.07]
Subtotal (95% CI) 44 54 2.89% 1.23[0.08,19.07]

3.2.2 HIV-negative
Thwaites 2004 36/227 29/209 97.11% 1.14[0.73,1.8]
Subtotal (95% CI) 227 209 97.11% 1.14[0.73,1.8]

Total (95% CI) 271 263 100% 1.15[0.73,1.79]
Heterogeneity: Tau2=0; Chi2=0, df=1(P=0.96); I2=0%
Test for subgroup differences: Chi2=0, df=1 (P=0.96), I2=0%

Collaboration.
Informed decisions.


Analysis 3.3. Comparison 3 Any corticosteroid versus control: stratified
by HIV status, Outcome 3 Death or disabling residual neurological deficit.
3.3.1 HIV-positive
Thwaites 2004 28/44 38/54 25.67% 0.9[0.68,1.2]
Subtotal (95% CI) 44 54 25.67% 0.9[0.68,1.2]

3.3.2 HIV-negative
Thwaites 2004 93/230 96/217 74.33% 0.91[0.74,1.14]
Subtotal (95% CI) 230 217 74.33% 0.91[0.74,1.14]
Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%

Total (95% CI) 274 271 100% 0.91[0.76,1.09]
Heterogeneity: Tau2=0; Chi2=0, df=1(P=0.95); I2=0%
Test for subgroup differences: Chi2=0, df=1 (P=0.95), I2=0%
Favours steroid 0.1 0.2 0.5 1 2 5 10 Favours control

Comparison 4. Sensitivity analysis
pants
1 Worst case scenario analysis 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Worst case: death 6 911 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.66, 0.96]
1.2 Available case: death 6 882 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.59, 0.86]

Analysis 4.1. Comparison 4 Sensitivity analysis, Outcome 1 Worst case scenario analysis.
4.1.1 Worst case: death
Kumarvelu 1994 9/24 7/23 4.34% 1.23[0.55,2.76]
Lardizabal 1998 4/29 6/29 3.64% 0.67[0.21,2.12]
Malhotra 2009 21/65 13/32 10.58% 0.8[0.46,1.37]
O'Toole 1969 6/11 9/12 5.23% 0.73[0.39,1.37]
Schoeman 1997 7/70 13/71 7.84% 0.55[0.23,1.29]
Thwaites 2004 92/274 112/271 68.37% 0.81[0.65,1.01]

Collaboration.
Informed decisions.


Subtotal (95% CI) 473 438 100% 0.8[0.66,0.96]

4.1.2 Available case: death
Kumarvelu 1994 5/20 7/21 4.15% 0.75[0.28,1.98]
Lardizabal 1998 4/29 6/29 3.65% 0.67[0.21,2.12]
Malhotra 2009 17/61 13/30 10.6% 0.64[0.36,1.14]
O'Toole 1969 6/11 9/12 5.23% 0.73[0.39,1.37]
Schoeman 1997 4/67 13/67 7.9% 0.31[0.11,0.9]
Thwaites 2004 87/269 112/266 68.47% 0.77[0.61,0.96]
Subtotal (95% CI) 457 425 100% 0.71[0.59,0.86]
Test for overall effect: Z=3.51(P=0)

Collaboration.
Collaboration.
ADDITIONAL TABLES
Table 1. Summary of characteristics of included trials
Trial ID Country Year Setting Age TB HIV status TB treat- Steroid Route Starting dose Dura-
Library
Cochrane
menin- reported ment reg- tion
gitis imenb
MRC
Gradea
O'Toole India 1966 to Tertiary All II and III No HS (dura- Dexametha- IM/IV Adults: 9 mg/day 4 weeks
Better health.
Informed decisions.
Trusted evidence.
1969 1967 tion not sone
specified) Children: unclear
Girgis 1991 Egypt 1982 to Research All All No 24HE1.5S Dexametha- IM Adults: 12 mg/day 6 weeks
1987 sone
Children: 8 mg/day
Kumarvelu India 1991 to Tertiary > 12 All No 12HRZ Dexametha- IV 16 mg/day 4 weeks
1994 1992 years sone
Chot- Thailand 1990 to Tertiary > 15 All Yes, HIV- 2HRZS Pred- Oral 60 mg/day 5 weeks
mongkol 1992 years positive par- +4HR nisolone
1996 ticipants ex-
cluded
Schoeman South Unclear Tertiary Children II and III No 6HRZE Pred- Oral 2 to 4 mg/kg/day 4 weeks
1997 Africa nisolone
Lardizabal Phillip- 1996 to Tertiary > 18 II and III No 2HRZE Dexametha- IV/oral 16 mg/day 7 weeks
1998 ines 1997 years +10HR sone
Thwaites Vietnam 2001 to Tertiary > 14 All Yes, HIV par- 3HRZE(or Dexametha- IV Grade II & III: 0.4 mg/kg/ 8 weeks
2004 2003 years ticipants in- S)+6HRZ sone day
cluded Grade I: 0.3 mg/kg/day

Prasad India 1996 on- Tertiary > 16 All No 9RHZ Dexametha- IV 0.6 to 12 mg/day 3 weeks
2006 wards years sone then ta-
pered
Malhotra India 2006 to Tertiary > 14 All Yes, HIV- 2HRZE(or Dexametha- IV 0.4 mg/kg/day 8 weeks
2009 2007 years positive par- S)+7HR sone
ticipants ex-
cluded Methylpred- IV 20 mg/kg/day 5 days
nisolone
46

Collaboration.
aTB meningitis MRC Grade: I = mild cases with no altered consciousness or focal neurological signs; II = moderately advanced cases with reduced conscious level but not comatose
or with moderate neurological deficits, or both (for example, single cranial nerve palsies, paraparesis, and hemiparesis); III = severe cases including comatose participants, or
participants with multiple cranial nerve palsies, hemiplegia or paraplegia, or both.
Library
Cochrane
bTB treatment regimen: H = isoniazid; R = rifampicin; Z = pyrazinamide; S = streptomycin; E = Ethambutol; the number = number of months of treatment.
Abbreviations: TB: tuberculosis; IM: intramuscular; IV: intravenous

Better health.
Informed decisions.
Trusted evidence.
47

Informed decisions.


Table 2. Diagnostic criteria used in the included trials
Trial ID Number of participants with microbio- Other diagnostic criteria
logically-confirmed tuberculous menin-
gitisa (percentage)
Steroid group Control group
O'Toole 1969 8/11 (72.7) 6/12 (50) Not described.
Girgis 1991 75/145 (51.7) 85/135 (63.0) Characteristic clinical features and CSF findings, plus poor re-
sponse to broad spectrum antibiotics.
Kumarvelu 1994 Not reported Not reported Characteristic clinical, CSF and CT findings. Pyogenic meningi-
tis and malignancy excluded.
Chotmongkol 1996 4/29 (13.8) 1/30 (3.3) Characteristic clinical and CSF findings, negative latex agglu-
tination tests on CSF for bacterial and cryptococcal antigens,
negative CSF cytology for malignant cells, negative serology for
syphilis and HIV.
Schoeman 1997 56/141 (39.7) had culture-positive gastric Characteristic clinical and CSF findings, plus two or more of:
aspirate positive Mantoux test, chest X-ray suggestive of TB, CT brain
with acute hydrocephalus and basal enhancement.
23/141 (16.3) had culture-positive CSF
Lardizabal 1998 Not reported Not reported "Probable TBM" if characteristic clinical and CSF findings, neg-
ative latex agglutination test on CSF for cryptococcal antigen
plus one or more of meningeal/basilar enhancement on con-
trast CT brain, positive PPD, history of contact with TB partici-
pant, evidence of active pulmonary TB.
"Confirmed TBM" if CSF microscopy positive for AFBs on Ziehl-

Nielsen staining, or culture positive for MTB, or both.
Thwaites 2004 98/274 (35.8) 89/271 (32.8) “Probable” TBM if one or more of chest X-ray suggestive of TB,
AFB in non-CSF specimen, clinical evidence of other EPTB.
“Possible” TBM if 4 of history of TB, lymphocytic CSF, ill for

more than 5 days, CSF:plasma glucose ratio less than 0.5, al-
tered consciousness, yellow CSF, focal neurological signs.
Prasad 2006 Not reported Not reported Characteristic clinical and CSF findings. Pyogenic meningitis
and malignancy excluded.
Malhotra 2009 4/30 (13.3) 15/61 (24.6) “Probable” TBM if one or more of chest X-ray suggestive of TB,
AFB in non-CSF specimen, clinical evidence of other EPTB.
“Possible” TBM if 4 of history of TB, lymphocytic CSF, ill for

more than 5 days, CSF:plasma glucose ratio less than 0.5, al-
tered consciousness, yellow CSF, focal neurological signs.
aReferring to positive microbiological test on CSF, including microscopy for acid-fast bacilli, mycobacterial culture and PCR-based methods.
Abbreviations: TBM: tuberculous meningitis; CSF: cerebrospinal fluid; CT: computer tomography; HIV: human immunodeficiency virus;
EPTB: extrapulmonary tuberculosis; AFB: MTB.


Collaboration.
Informed decisions.

Table 3. Corticosteroid dose regimens used in the included trials

Trial Steroid Dose regimen
Adults Children
O'Toole 1969 Dexamethasone IV 9 mg daily for 7 days Derived from a

standard table
6 mg daily for 7days based on surface
area.
3 mg daily for 7 days
1.5 mg daily for 7 days
Girgis 1991 Dexamethasone IM 12 mg daily for 21 days, then tapered over 21 days 8 mg daily if weight
less than 25 kg,
then tapered over
21 days
Kumarvelu 1994 Dexamethasone 16 mg IV daily for 7 days 0.6 mg per kg daily

for 7 days
8 mg PO daily for 21 days
0.3 mg per kg daily
for 21 days
Chotmongkol 1996 Prednisolone 60 mg daily for 7 days --
Schoeman 1997 Prednisolone n/a 2 mg/kg daily (first

16 participants)
4 mg/kg daily (re-

maining 54 partici-
pants)
Lardizabal 1998 Dexamethasone 16 mg daily for 21 days (IV for first 5 days, PO/NG thereafter) --
Thwaites 2004 Dexamethasone Grade II and III disease: --
IV therapy
0.4 mg per kg daily for 7 days
Then oral therapy starting at 4 mg per day and decreasing by 1

mg every 7 days

Collaboration.
Informed decisions.

Table 3. Corticosteroid dose regimens used in the included trials (Continued)

Grade I disease:
IV therapy
Then oral therapy
3 mg per day decreasing by 1 mg every 7 days
Prasad 2006 Dexamethasone 0.15 mg per kg (up to a maximum of 4mg) every 6 hours for 21 --
days then tapered gradually
Malhotra 2009 Dexamethasone IV 0.4 mg per kg daily for 7 days --
Methylprednisolone 1 g per day for 5 days (if weight over 50 kg) 20 mg/kg
IV
(if weight under 50
kg)
Abbreviations: IV: intravenous; IM: intramuscular; n/a: not applicable.

Table 4. Disabling/non-disabling terms used in this review: mapped onto terms in primary trials
Trial "Disabling" as defined in this Cochrane Review "Non-disabling" as defined in this
Cochrane Review
Girgis 1991 Permanent residual neurological sequelae, including hy- Not described.
drocephalus, hemiparesis and fundus abnormalities.
Kumarvelu 1994 Major sequelae: persistent vegetative state, blind, symp- Minor sequelae: mild intellectual impairment,
tomatic hydrocephalus, moderate-severe intellectual mild to moderate functional disability (ac-
impairment, severe functional disability (totally depen- tivities of daily living with no/minimal assis-
dent). tance) or no sequelae.
Chotmongkol 1996 Persisting neurological abnormalities, including de- Not described.

creased vision, spastic paraparesis and hemiparesis.
Schoeman 1997 Severe disability: “One or more of the following present: Healthy: “IQ (DQ) greater than 90; no motor or
IQ (DQ) less than 75, quadriparesis, and blindness or sensory deficit”.
deafness”.
Mild disability: “One or more of the following
present: IQ (DQ) 75 to 90, hemiparesis, and
decreased vision or hearing”.
Lardizabal 1998 Functional Independence Measure: Functional Independence Measure:
Score 18 to 36: severely disabled, requiring maximal to Score 55 to 90: minimal to moderate disabil-
total assistance. The subject can carry out less than 25% ity, requiring only minimal assistance. The
of the activities for self-care, sphincter control, mobility, subject can carry out more than 50% of the
locomotion, communication and cognition. activities of self-care, sphincter control, mo-
Collaboration.
Informed decisions.

Table 4. Disabling/non-disabling terms used in this review: mapped onto terms in primary trials (Continued)
Score 37 to 54: moderate to severe disability, requiring bility, locomotion, communication and cogni-
moderate to maximal assistance. The subject can carry tion.
out more than 25 to 50 % of the activities for self-care,
sphincter control, mobility, locomotion, communication Score 91-126: minimal disability to functional-
and cognition. ly independent. The subject requires no assis-
tance in self-care, sphincter control, mobility,
Iocomotion, communication, cognition.
Thwaites 2004 Severe disability: “Severe disability: assessed on Rankin Good outcome: Rankin score 0 indicating no
scale (assessor reported outcome) AND “simple ques- symptoms. ‘No’ to all simple questions.
tions” (patient reported outcome).
Intermediate outcome: Rankin score 1 or 2.
Rankin scale – “3 indicated symptoms that restricted “1 indicated minor symptoms not interfer-
lifestyle and prevented independent living; 4 indicated ing with lifestyle; 2 indicated symptoms that
symptoms that prevented independent living, although might restrict lifestyle, but patients could
constant care and attention were not required; and 5 in- look after themselves”.
dicated total dependence on others, requiring help day
and night”. ‘No’ to simple questions, but ‘yes’ to fol-
low-up question asking about “any other
Scores of 3, 4 or 5 indicated severe disability. problems”.
“simple questions” – 2 simple questions on recovery

(question 1: do you feel that you have made a complete
recovery?) and dependency (question 2: do you require
help from another person for everyday activities?) “yes”
to either indicates severe disability.
Prasad 2006 "Bad outcome: If the patient has neither recovered nor is "Functionally independent: If the patient is
independent in activities of daily living". independent in activities of daily living. He
may or may not have got minimal residual
neurological deficit".
Malhotra 2009 Severe disability: Good outcome:
Rankin score of 3, 4 or 5. Rankin score 0. “A score of 0 indicates that

there are no symptoms at all”.
“A subject with moderate disability (requiring some help,
but able to walk without assistance) is scored 3, one with Intermediate outcome:
moderately severe disability (unable to walk without as-
sistance and unable to attend to own bodily needs with- Rankin score of 1 to 2. “A score of 1 indicates
out assistance) is scored 4, while a patient who is bedrid- no significant disability despite the presence
den, incontinent and requiring constant nursing care of symptoms (with the subject able to carry
and attention is scored 5”. out all their usual duties and activities) and a
score of 2 indicates slight disability (with the
subject unable to carry out all their previous
activities, but able to look after their own af-
fairs without assistance)".
Abbreviations: IQ: intelligence quotient; DQ: development quotient

Table 5. Adverse events
Trial Severity Event Corticosteroid Control
n out of total in n out of total in

group group
O'Toole 1969 a — Gastrointestinal bleeding 5 5

Collaboration.
Informed decisions.

Table 5. Adverse events (Continued)

Glycosuria 1 0
Infections 2 5
Hypothermia 5 1
Schoeman 1997 — "Serious side effects" 0 0

b
Thwaites 2004 c Severe Hepatitis (severe) 0 8
Gastrointestinal bleeding (severe) 2 3
Bacterial sepsis (severe) 3 4
Hyperglycaemia (severe) 0 0
Other Subclinical hepatitis 0 0
Septic shock 3 0
Brain herniation syndrome 1 4
Decrease in visual acuity 6 8
Hyponatraemia 1 6
Hypertension 0 0
Vertigo 0 0
Deafness 3 3
Cushing's features 0 0
Pruritis 0 0
Polyarthralgia 0 0
Streptomycin reaction 0 0
Rifampicin 'flu' 0 0
Rash 1 0
Malhotra 2009 d — Hepatitis 12 8
Anti-epileptic toxicity 4 3
Gastrointestinal bleeding 6 1
Paradoxical tuberculoma 3 5
Abbreviations; n: number of participants with event.

a O'Toole 1969: n/11 participants in corticosteroid arm; n/12 participants in control arm.
b Schoeman 1997: n/67 participants in corticosteroid arm; n/67 participants in control arm.

Collaboration.
Informed decisions.

c Thwaites 2004: n/274 participants in corticosteroid arm; n/271 participants in control arm.
d Malhotra 2009: n/61 participants in corticosteroid arm; n/30 participants in control arm.

APPENDICES
Appendix 1. Search methods: detailed search strategies for databases

Search set CIDG SRa CENTRAL MEDLINEb EMBASEb LILACSb
1 tuberculosis tuberculosis tuberculosis TUBERCU- tuberculosis

LOSIS-MENINGITIS
2 TB steroid* tuberculosis tuberculosis TB
3 steroids corticosteroid* TB TB 1 or 2
4 corticosteroids glucocorticoid* 1 or 2 or 3 1 or 2 or 3 steroid*
5 dexamethasone hydrocortisone steroid* steroid$ hydrocorti-

sone
6 hydrocortisone prednisolone STEROIDS STEROIDS dexametha-

sone
7 prednisolone dexamethasone corticosteroid* corticosteroid$ prednisolone
8 1 or 2 2 or 3 or 4 or 5 or 6 glucocorticoid* glucocorticoid$ 4 or 5 or 6 or 7
or 7
9 3 or 4 or 5 or 6 or 1 and 8 hydrocortisone hydrocortisone 3 and 8

7
10 8 and 9 — dexamethasone dexamethasone —
11 — — prednisolone prednisolone —
12 — — prednisone methylprednisone —
13 — — methylprednisone 5-12/or —
14 — — 5-13/or 4 and 13 —
15 — — 4 and 14 Limit 14 to human —
16 — — Limit 15 to human — —

aCochrane Infectious Diseases Group Specialized Register.
bSearch terms used in combination with the search strategy for retrieving trials developed by Cochrane (Lefebvre 2011); upper case: MeSH
or EMTREE heading; lower case: free text term.
WHAT'S NEW


Collaboration.
Informed decisions.

Date Event Description
13 April 2016 New citation required but conclusions We included nine trials in total, and the review's conclusions re-
have not changed main unchanged.
13 April 2016 New search has been performed Hannah Ryan joined the review author team. We included two
new trials (one published and one unpublished), added pub-
lished follow-up data from Thwaites 2004, and constructed 'Risk
of bias' tables and a 'Summary of findings' table. We presented
outcomes for disabling neurological deficit separately following
feedback, reviewed all included studies, and re-extracted data.
We rewrote the Results and Discussion sections, and revised the
plain language summary.

HISTORY
Protocol first published: Issue 1, 1998
Review first published: Issue 3, 2000

Date Event Description
14 November 2007 New citation required but conclusions 2008, Issue 1: we added one new trial, Thwaites 2004. We updat-
have not changed ed the review text and title. MB Singh joined the author team,
and J Volmink and GR Menon stepped down from the author
team.

CONTRIBUTIONS OF AUTHORS
Kameshwar Prasad (KP) developed the first published version of this Cochrane Review (Prasad 2000). During the 2008 update, KP screened
the search results, assessed methodological quality, extracted and analysed data, interpreted the results, and rewrote several sections of
the review. MB Singh also screened the search results, assessed methodological quality, extracted data, and entered data into RevMan
(RevMan 2014). For the 2015 update, Hannah Ryan (HR) re-extracted and analysed the data, revised the 'Risk of bias' assessment,
constructed a 'Summary of findings' table with GRADE assessment, and revised the Background, Results, and Discussion sections.
DECLARATIONS OF INTEREST
KP is a co-author of two of the included trials (Kumarvelu 1994; Prasad 2006). HR independently conducted 'Risk of bias' assessments and
data entry and interpretation with the CIDG Co-ordinating Editor, Paul Garner.
SOURCES OF SUPPORT
Internal sources
• All India Institute of Medical Sciences, India.
• Liverpool School of Tropical Medicine, UK.
External sources
• Department for International Development, UK.
Grant number: 5242
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
None.

Collaboration.
Informed decisions.

INDEX TERMS
Medical Subject Headings (MeSH)

Antitubercular Agents [*therapeutic use]; Chemotherapy, Adjuvant; Dexamethasone [therapeutic use]; Glucocorticoids [*therapeutic
use]; Hydrocortisone [therapeutic use]; Intention to Treat Analysis; Prednisolone [therapeutic use]; Randomized Controlled Trials as
Topic; Tuberculosis, Meningeal [*drug therapy] [mortality]
MeSH check words

Adult; Child; Humans

Collaboration.

STEROID II

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Prasad K, Singh MB, Ryan H

Prasad K, Singh MB, Ryan H.

Corticosteroids for managing tuberculous meningitis (Review) i

Corticosteroids for managing tuberculous meningitis

Kameshwar Prasad1, Mamta B Singh1, Hannah Ryan2

Editorial group: Cochrane Infectious Diseases Group.

Data collection and analysis

Corticosteroids for managing tuberculous meningitis (Review) 1

All studies incorporated from most recent search

Corticosteroids for managing people with tuberculous meningitis

What is tuberculous meningitis and how might corticosteroids work?

What the evidence shows

Corticosteroids for managing tuberculous meningitis (Review) 2

Death 41 per 100 31 per 100 RR 0.75 1337 ⊕⊕⊕⊕

Disabling neurolog- 8 per 100 7 per 100 RR 0.92 1314 ⊕⊕⊝⊝6,7,8

Death 47 per 100 44 per 100 RR 0.93 545 participants ⊕⊕⊕⊝9,10

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence.

Cochrane Database of Systematic Reviews

BACKGROUND additional 5% to 40% of people who survive tuberculous meningitis

Corticosteroids for managing tuberculous meningitis (Review) 5

Types of participants Data collection and analysis

Corticosteroids for managing tuberculous meningitis (Review) 6

Measures of treatment effect Data synthesis

Corticosteroids for managing tuberculous meningitis (Review) 7

Figure 1. Study flow diagram.

Corticosteroids for managing tuberculous meningitis (Review) 8

Interventions Outcome measures

Corticosteroids for managing tuberculous meningitis (Review) 9

Corticosteroids for managing tuberculous meningitis (Review) 10

Allocation Incomplete outcome data

Corticosteroids for managing tuberculous meningitis (Review) 11

Corticosteroids for managing tuberculous meningitis (Review) 12

Corticosteroids for managing tuberculous meningitis (Review) 13

Corticosteroids for managing tuberculous meningitis (Review) 14

Corticosteroids for managing tuberculous meningitis (Review) 15

Corticosteroids for managing tuberculous meningitis (Review) 16

Corticosteroids for managing tuberculous meningitis (Review) 18

In people that are immunosuppressed, such as people living ACKNOWLEDGEMENTS

Corticosteroids for managing tuberculous meningitis (Review) 19

Corticosteroids for managing tuberculous meningitis (Review) 20

Lepper 1963 {published data only} BSI 2009

Corticosteroids for managing tuberculous meningitis (Review) 21

steroids in steroid-refractory tuberculous meningitis. Journal of Schoeman 2010

Corticosteroids for managing tuberculous meningitis (Review) 22

References to other published versions of this review Prasad 2008

Characteristics of included studies [ordered by study ID]

Number of participants: 59 participants; 27 females, 32 males; 29 received prednisolone, 30 received no

HIV status: HIV-positive participants excluded.

Outcomes 1. Death at the end of 6 months.

Adverse events recorded were gastrointestinal bleeding and hyperglycaemia.

Notes Date: July 1990 to December 1992.

Trialists: Department of Medicine, Khon Kaen University, Thailand; no collaborators.

Corticosteroids for managing tuberculous meningitis (Review) 23

Bias Authors' judgement Support for judgement

Blinding of participants Low risk Blinding with use of placebo.

Length of follow-up: 24 months.