Background
Tuberculous meningitis is an inflammation of the meninges, which envelope the brain and the spinal cord. It is caused by infection with Mycobacterium tuberculosis, the bacterium responsible for tuberculosis. Tuberculous meningitis is a severe form of tuberculosis and accounts for many deaths (Tandon 1988). In some countries it accounts for 5% to 7% of all admissions to neurology and paediatric wards in specialist hospitals (Tandon 1988). Extrapulmonary involvement (ie tuberculosis occurring outside the lungs) can be seen in more than 50% people who also have HIV/AIDS (Rieder 1990; Shafer 1991). It appears also that the higher risk of tuberculosis in HIV-infected people means that tuberculous meningitis is also more common in this group (Berenguer 1992; Berger 1994).
Tuberculous meningitis usually presents with headache, fever, vomiting, altered sensorium, and sometimes convulsions. It is diagnosed clinically with confirmation by microscopy, culture of cerebral spinal fluid, or the polymerase chain reaction test. Disability in tuberculous meningitis is multifactorial. Some of the important causes of disability are persistent or progressive hydrocephalus, involvement of the optic nerves or optic chiasm in the supracellar region, vasculitis leading to cerebral infarcts and stroke, multiple cranial neuropathies, and arachnoiditis. Disability related to antituberculous treatment most often occurs as ethambutol-induced toxic optic neuritis, which may be irreversible, or isoniazid-related peripheral neuropathy.
Tuberculous meningitis can be classified according to its severity. The British Medical Research Council (MRC) use three stages (MRC 1948): stage I (mild cases) is for those without altered consciousness or focal neurological signs; stage II (moderately advanced cases) is for those with altered consciousness who are not comatose and those with moderate neurological deficits (eg single cranial nerve palsies, paraparesis, and hemiparesis); and stage III (severe cases) is for comatose patients and those with multiple cranial nerve palsies, and hemiplegia or paraplegia, or both.
Treatment options
Without treatment, people with tuberculous meningitis die. Streptomycin, one of the earliest antituberculous drugs to be introduced, reduced the case-fatality rate to 63% (Parsons 1988). Newer antituberculous drugs − isoniazid, rifampicin, pyrazinamide, and ethambutol − are associated with better survival, but mortality remains comparatively high. Recent reports of mortality rates vary from 20% to 32%, and permanent neurological deficits in an additional 5% to 40% of survivors (Ramchandran 1986; Alarcon 1990; Jacobs 1990; Jacobs 1992).
The role of corticosteroids in the treatment of tuberculous meningitis as an adjunct to antituberculous treatment remains controversial despite being in use since early 1950s. Some authors have reported them as being effective (Ramchandran 1986; Alarcon 1990; Chotmongkol 1996), while others have reported that their use is not supported by the evidence (Holdiness 1990; Prasad 1997; Schoeman 1997). Indirect evidence from animal studies provides a biological basis to how the drug could be effective (Feldman 1958) − they may: decrease inflammation, especially in the subarachnoid space; reduce cerebral and spinal cord oedema and intracranial pressure (Feldman 1958; Parsons 1988); and reduce inflammation of small blood vessels and therefore reduce damage from blood flow slowing to the underlying brain tissue. However, corticosteroids can also cause harm by suppressing the immune mechanism − they may: suppress the symptoms of tuberculosis infection but promote an unchecked growth of the bacteria and an increased bacterial load; reduce inflammation of the meninges, which will then reduce the ability of drugs to seep into the subarachnoid space; and cause gastrointestinal haemorrhage, electrolyte imbalance, hyperglycaemia, and infections from fungi or bacteria. Corticosteroids are also known to have certain adverse effects, such as gastrointestinal bleeding, invasive bacterial or fungal infections, hyperglycaemia, and electrolyte disturbances.
Adjunctive corticosteroids are not known to result in disability, especially when used for short durations as is the case in most clinical trials of this intervention. However, there is a concern that although corticosteroids may save lives of some very sick patients, they may not necessarily improve their quality of life as they are often left bed-bound due to sequelae. In other words, if the survival rate is increased with corticosteroids but not disability-free survival, then corticosteroids actually increase the financial and disease burden on the family and society.
Why it is important to do this review?
Several randomized controlled trials have been conducted on the effect of corticosteroids in managing tuberculous meningitis. The conclusions from these trials, seen individually, appear inconsistent. One trial, Thwaites 2004, showed that dexamethasone increases survival rate, but it also raised two questions − do patients who survive because of dexamethasone therapy tend to be left with severe disability, and are there differential effects among subgroups of patients with different degrees of disease severity? The editorial that accompanied the trial (Quagliarello 2004) and several letters to the editor in response to this trial (Marras 2005; Seligman 2005) have commented that the trial did not have enough statistical power to answer these questions. We have prepared a meta-analysis that synthesizes the results from all the trials to try and provide the necessary power to address these questions.
Objectives
To evaluate the effects of corticosteroids as an adjunct to antituberculous treatment on death and severe disability in people with tuberculous meningitis.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials.
Types of participants
People of any age with clinically diagnosed tuberculous meningitis.
Types of interventions
Intervention
Corticosteroid (hydrocortisone, prednisolone, or dexamethasone) given orally, intramuscularly, or intravenously plus antituberculous treatment.
Control
Antituberculous treatment (same as intervention) with or without placebo.
Types of outcome measures
Primary
- Death.
- Death or disabling residual neurological deficit at the end of follow up.
Adverse events
Adverse events, including upper gastrointestinal bleeding, invasive bacterial or fungal infections, and hyperglycaemia.
Search methods for identification of studies
We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).
Databases
We searched the following databases using the search terms and strategy described in Appendix 1: Cochrane Infectious Diseases Group Specialized Register (September 2007); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2007, Issue 3); MEDLINE (1966 to September 2007); EMBASE (1974 to September 2007); and LILACS (1982 to September 2007). We also searched Current Controlled Trials (www.controlled-trials.com; accessed September 2007) using 'tuberculosis' and 'meningitis' as search terms.
Researchers
We contacted the following organizations and individuals working in the field: delegates at the V
Reference lists
We also drew on existing reviews of this topic (Ramchandran 1986; Jacobs 1990; Geiman 1992), and checked the citations of all the trials identified by the above methods.
Data collection and analysis
Heterogeneity
We assessed heterogeneity by visually inspecting the forest plots to determine closeness of point estimates with each other and overlap of confidence intervals. We used the chi-square test with a P value of 0.10 to indicate statistical significance and the I
Sensitivity analyses
For trials with missing data, we conducted two analyses: an available-case analysis and then a 'worst-case scenario' analysis for trials with missing data. All participants who had dropped out of the corticosteroid group were considered to have an unfavourable outcome whereas those who had dropped out of the control group were considered to have a favourable outcome. We conducted a sensitivity analysis imputing the missing data in this way to determine whether the overall results were sensitive to this assumption.
Assessment of reporting biases
We also conducted visual inspection of the funnel plot of the studies for any obvious asymmetry that could be evidence of publication bias.
Selection of studies
We independently screened the search results and retrieved the full articles of all potentially relevant trials. Each trial report was scrutinized to ensure that multiple publications from the same trial were included only once. Trial investigators were contacted for clarification if a trial's eligibility was unclear. We resolved disagreements through discussion and listed the excluded studies and the reasons for their exclusion.
Data extraction and management
We independently extracted data using a pre-piloted data extraction form. Data extracted included participant characteristics, diagnostic criteria, disease severity, HIV status, antituberculous drug regimen, corticosteroid regimen, and outcome measures. We resolved disagreements through discussion and contacted the corresponding publication author in the case of unclear or missing data. We contacted the authors of Lardizabal 1998 to determine the number of deaths in participants with stage II and III disease.
For dichotomous outcomes, we recorded the number of participants experiencing the event and the number randomized in each treatment group. To allow an available-case analysis, we recorded the numbers of participants analysed in each treatment group and used them in the analyses. However, the number of participants randomized into the treatment arms was also recorded and the discrepancy between the figures used to calculate the loss to follow up. Also, these figures allowed a worst-case scenario analysis to be carried out to investigate the effect of missing data.
Assessment of risk of bias in included studies
We independently assessed methodological quality and reported the results in a table. We classified generation of allocation sequence and allocation concealment as adequate, inadequate, or unclear according to Jüni 2001. We reported who was blinded in each trial. We classified inclusion of all randomized participants as adequate if at least 90% of participants were followed up to the trial's completion; otherwise we classified inclusion as inadequate. We attempted to contact the authors if this information was not specified or if it was unclear. We resolved any disagreements by discussion between review authors.
Data synthesis
We analysed the data using Review Manager 5. A decision to perform meta-analysis was made in view of absence of significant heterogeneity. We used risk ratios (RR) with 95% confidence intervals (CI) and the fixed-effect model. We determined the number needed to treat (NNT) for various control-event rates (CER) by calculating experimental event rate (EER = CER*RR) and taking inverse of the difference between the CER and EER ( Table 1).
We summarized the adverse event data in tables and did not perform a meta-analysis since some events were reported in only one trial and others were rare events in which the same participant could have contributed more than one event. We were unable to calculate rate ratios or summary rate ratios because person-time over which these events were observed was not available.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.
Search results
The Prasad 2000 version of this Cochrane Review included six trials with 595 participants (574 with follow up, 215 deaths). This update includes one new trial with 545 participants (535 with follow up, 199 deaths). All these studies were identified after scanning the search results (titles and abstracts), selecting 23 abstracts for detailed appraisal, and assessing eligibility based on the full articles. The seven trials (with 1140 participants) from eight articles are described in the 'Characteristics of included studies' and summarized below. The reasons for excluding the other 15 studies are given in the 'Characteristics of excluded studies'. We also identified one trial that started in 1996 with a planned 10-year follow-up period and are awaiting the results (see 'Characteristics of ongoing studies').
Geographical location and time period
The trials were conducted in different time periods (two in the 1960s, four in the 1990s, and one in 2004) and in different geographical regions: Thailand (Chotmongkol 1996); Egypt (Girgis 1991); India (O'Toole 1969; Kumarvelu 1994); Philippines (Lardizabal 1998); South Africa (Schoeman 1997); and Vietnam (Thwaites 2004).
Participants
All participants were entered on the basis of clinical diagnosis, which was subsequently proven by cerebrospinal fluid culture or autopsy in varying proportions: 70% (O'Toole 1969); 57% (Girgis 1991); 16% (Schoeman 1997); 10% (Chotmongkol 1996); percentage not mentioned (Kumarvelu 1994); and culture from cerebrospinal fluid or other sites in Thwaites 2004 (31%). In Schoeman 1997, 60% of participants had a chest x-ray suggestive of tuberculosis, 65% had strongly positive Mantoux test, and 24% (besides 16% cerebrospinal fluid positive culture) had a M. tuberculosis positive culture from gastric aspirate. Chotmongkol 1996 and Kumarvelu 1994 excluded non-tuberculosis chronic lymphocytic meningitis by negative fungal and bacterial culture, cytology for malignant cells, and HIV serology. However, only Girgis 1991 reported the outcome in culture-positive cases separately.
The trials included young children (Schoeman 1997) or adults (Kumarvelu 1994; Chotmongkol 1996; Lardizabal 1998; Thwaites 2004), or both (O'Toole 1969, Girgis 1991), and both sexes. All trials used the MRC system (MRC 1948) to assess baseline severity; two trials included only those with stage II and III tuberculous meningitis (Schoeman 1997; Lardizabal 1998), while the other trials included all stages of severity. Thwaites 2004 specifically reported the inclusion of HIV-positive and HIV-negative patients.
Interventions
Five of the trials used the corticosteroid dexamethasone; the other two trials used prednisolone (Chotmongkol 1996; Schoeman 1997). Six of the trials used a three- or four-drug antituberculous regimen. O'Toole 1969, the earliest trial, used a two-drug regimen.
Follow up
The follow-up period was clearly described in six trials: two months (Lardizabal 1998); three months (Kumarvelu 1994); six months (Schoeman 1997); nine months (Thwaites 2004); two years (Girgis 1991); and 16 to 45 months (Chotmongkol 1996). It was unclear in O'Toole 1969.
Outcome measures
Death was reported in all seven trials and residual neurological deficit in all but two (O'Toole 1969; Lardizabal 1998); Lardizabal 1998 assessed "functional independence". We accepted the definition of disability as presented by the trial authors, and, for the purpose of analysis, classified residual deficits into disabling or non-disabling as shown in Table 2. Only three of trials quantified disability and each used a different scale or method:
- Kumarvelu 1994 described "major sequelae" (totally dependent for activities of daily living) at three months and "minor sequelae" (activities of daily living with no or minimal assistance) at three months.
- Schoeman 1997 classified this as "healthy" (IQ(DQ) > 90 and no motor or sensory deficit); "mild disability" (= 1 of IQ(DQ) 75 to 90, hemiparesis, and decreased vision or hearing); or "severe disability" (= 1 of IQ(DQ) < 75, quadriaparesis, and blindness or deafness).
- Thwaites 2004 quantified disability into "severe disability", "intermediate outcome", and "good outcome" using the Rankin scale and a "simple questions" score.
Four trials mentioned adverse events. The trials reported on a number of other immediate outcome measures not considered in the review (see 'Characteristics of included studies').
Drug resistance
Only Thwaites 2004 reported on drug resistance. In this study, M. tuberculosis was cultured from the cerebrospinal fluid or another site in 170 participants (31.2%), 85 from each group. M. tuberculosis isolates were tested for susceptibility to isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin. Of 170 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%) were resistant to streptomycin, isoniazid, or both (29 in the placebo group and 31 in the dexamethasone group), one was monoresistant to rifampicin (in the dexamethasone group), and 10 (5.9%) were resistant to at least isoniazid and rifampicin (3 in the placebo group and 7 in the dexamethasone group).
Risk of bias in included studies
See Table 3 for a summary and 'Characteristics of included studies' for details of methods.
Thwaites 2004 was the only trial that we assessed as adequate for the generation of allocation sequence and allocation concealment. This trial used a computer-generated sequence of random numbers to generate the allocation sequence and numbered individual treatment packs containing the study drug to conceal allocation. The methods used in the other trials were unclear.
Chotmongkol 1996 and Thwaites 2004 used blinding for the participants, enrolling physicians, and assessors or investigators, O'Toole 1969 used blinding for the participants and enrolling physicians, and Schoeman 1997 used blinding only for the assessors. The other three trials did not use blinding.
Four trials included 90% or more of the randomized participants in the analysis (Chotmongkol 1996; Lardizabal 1998; Schoeman 1997; Thwaites 2004); Chotmongkol 1996 and Lardizabal 1998 had no losses to follow up. Kumarvelu 1994 included 87.24% of the participants after six participants were lost to follow up (4/24 in the corticosteroid group and 2/23 in the control group), which we considered inadequate. The number of participants lost to follow up was unclear for O'Toole 1969 and Girgis 1991.
Effects of interventions
Death
All seven trials reported on death. The two larger trials, Girgis 1991 and Thwaites 2004, had more than 150 deaths in each, but the rest were small trials with fewer deaths. Overall, the direction of effect in each of the trials favoured a benefit for corticosteroids except for Chotmongkol 1996, which had a prognostic imbalance at baseline that favoured the control group. Overall the pooled results showed statistically significant fewer deaths with corticosteroids (RR 0.78, 95% CI 0.67 to 0.91; 1140 participants, 7 trials, Analysis 1.1). This translates to a 22% risk ratio reduction for death, and, with about 40% case-fatality without corticosteroids, a 10% absolute risk reduction and NNT of 10. The benefit of corticosteroids seems to be independent of the length of follow up ( Table 4).
Death or disabling residual neurological deficit
The disabling sequelae could be extracted separately from only three trials. With respect to death or disabling residual neurological deficit, the overall estimate showed a significant reduction in the risk of death or disabling residual neurological deficit with corticosteroids (RR 0.82, 95% CI 0.70 to 0.97; 720 participants, 3 trials, Analysis 1.2). This refers to a risk ratio reduction of 17%, which translates to an absolute risk reduction of 10% and NNT of 10, taking 50% event rate without corticosteroid use.
Adverse events
Of the five trials that mentioned adverse events (O'Toole 1969; Kumarvelu 1994; Chotmongkol 1996; Schoeman 1997; Thwaites 2004), two reported on incidence (O'Toole 1969; Thwaites 2004). O'Toole 1969 reported four different adverse events (gastrointestinal bleeding, glycosuria, infections, and hypothermia), which occurred in both groups ( Table 5). Thwaites 2004 reported on several adverse events, which were divided into "severe" and other events ( Table 5). Schoeman 1997 had "serious side effects" as an outcome measure and reported "no serious side effects of corticosteroid therapy".
Exploring subgroup effects
Drug resistance
No data were available for this subgroup analysis.
Severity of illness
We stratified the results on death by the severity of illness (MRC stages I, II, and III) in Analysis 2.1. Corticosteroids statistically significantly reduced the risk of death across all stages of the disease: stage I (RR 0.52, 95% CI 0.30 to 0.89; 197 participants, 4 trials); stage II (RR 0.73, 95% CI 0.56 to 0.97; 441 participants, 5 trials); and stage III (RR 0.70, 95% CI 0.54 to 0.90; 330 participants, 3 trials). As the trials did not stratify randomization for severity stage, these results should be interpreted with caution.
HIV status
Thwaites 2004 specifically mentioned that 98 of the included participants were HIV-positive. We stratified the results for death ( Analysis 3.1) and death or disabling residual neurological deficit by HIV status (Analysis 03.02). The results for each group and the overall results did not reach statistical significance. However, as this trial did not stratify randomization for HIV status, these results should be interpreted with caution.
Sensitivity analysis
As three trials had losses to follow up (Kumarvelu 1994; Schoeman 1997; Thwaites 2004), we performed sensitivity analysis using the worst-case scenario, that is, assuming that all those lost to follow up in the corticosteroid group had unfavourable outcomes while those in the control group had favourable outcomes. The point estimates of the results remained in favour of corticosteroids for death (RR 0.80, 95% CI 0.65 to 0.98) and also death or disabling residual neurological deficit (RR 0.88, 95% CI 0.75 to 1.04), but only the result for death remained statistically significant.
Assessment of reporting biases
The funnel plot of the included trials is shown in Figure 1. It refers to mortality and values below one favour corticosteroids. The plot does not show a definite inference with regard to publication bias.
 | Figure 1. Funnel plot of risk ratio (RR) from the included trials with the log of their standard error (SE) |
Discussion
Summary of main results
Overall, the results of this review favour routine use of corticosteroids in tuberculous meningitis for reducing death and death or disabling residual neurological deficit. In comparison to the benefits, adverse effects were poorly reported, but those recorded in the trials were infrequent and often mild and treatable. There is no direct evidence to guide selection of the specific corticosteroid to be used in tuberculous meningitis; most trials used dexamethasone or prednisolone, and we therefore favour either of these two drugs in clinical practice or for future studies.
Quality of evidence
This review because included only randomized controlled trials. One trial, Thwaites 2004, had adequate concealment of randomization, good follow up, and blinded outcome assessment. While the other trials did not provide clear information about the generation of the allocation sequence or allocation concealment, they have reasonable internal validity for the outcome of death because the lack of blinding is unlikely to influence the measurement of death.
Overall completeness and applicability of evidence
The trials included male and female children and adults, most of whom were HIV negative. Thwaites 2004 reported that 98 HIV-positive participants were included, but they did not stratify the randomization for this subgroup; the results for this subgroup therefore should be interpreted with caution. The effect of corticosteroids was not significantly different between HIV-positive and HIV-negative participants, but due to the small number of HIV-positive participants the trial lacked the power to detect such a difference even if one did exist.
Though the trials varied in their use of bacteriological confirmation of diagnosis, there is reasonable evidence to suggest that the trial participants had tuberculous meningitis. Moreover, the intention-to-treat analysis in clinically diagnosed participants provides assurance that use of corticosteroids on the basis of clinical diagnosis does more good than harm. This is important because the decision to use corticosteroids is often taken on a purely clinical basis when culture reports are not available and it is the balance of benefit and risk of such a decision that needs to be determined to set a clinical policy. The proportion of confirmed cases is mentioned only to provide confidence in the clinical diagnosis made by the investigators. Separate analysis of culture-positive cases is probably less relevant for clinical decision making and was reported by the trial authors of only one included trial.
Potential biases in the review process
We have attempted to limit bias in the review process. The literature search was conducted by the Cochrane Infectious Diseases Group Information Specialist, and it is unlikely that any major trials were missed; however, we cannot rule out the possibility that missing some small unpublished trials were missed. The funnel plot did not assist with this because there were too few trials. To limit bias in the trial selection process and data extraction, we independently examined the search results and determined study selection, and extracted data.
Agreements and disagreements with other studies or reviews
A question with regard to use of corticosteroids in tuberculous meningitis, which has been repeatedly raised, is whether corticosteroids save patients' lives only to leave them disabled. Apparently, it emerged from statistically non-significant reduction of combined outcome of death or disability within individual studies with inadequate power to address the question. This is apparent from the fact that two of the three trials reporting this outcome showed a trend of risk reduction for this outcome but could not reach statistical significance. When all the three trials are combined, there is statistically significant as well as clinically important reduction in the combined endpoint of death or disabling residual neurological deficit, which means corticosteroids in tuberculous meningitis save lives without increasing the number of individuals with disabling residual neurological deficit. The worst-case scenario analysis for losses to follow up is somewhat unsettling, but it is known that this scenario is a rather stringent test unlikely to be true. The overall interpretation of evidence remains in favour of corticosteroids.
Authors' conclusions
Implications for practice Corticosteroids should be routinely used in HIV-negative people with tuberculous meningitis to reduce death and disabling residual neurological deficit amongst survivors. The drug and dose as used in most trials may be dexamethasone (for adults 12 to 16 mg/day for three weeks, tapered over the next three weeks; for children 0.3 to 0.4 mg/kg/day for one to two weeks and tapered over the next two weeks; given intravenously until the patient starts accepting orally when tablets can be used) or prednisolone (for adults 60 mg/day for three weeks and tapered over the next three weeks; for children 2 mg/kg/day for three weeks and tapered over the next three weeks), and either of the two may be used in clinical practice. However, there is not enough evidence to support or refute a similar conclusion for those who are HIV positive. |
Implications for research New randomized controlled trials should address the following research questions.
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Acknowledgements
We acknowledge the help provided by All India Institute of Medical Sciences, New Delhi, India. Prasad 2000 version: We gratefully acknowledge the contribution of J Volmink and GR Menon as co-authors. The authors are grateful to Shell Petroleum Ltd, UK and the European Commission (Directorate General XII), Belgium for providing support for this review version. The editorial base for the Cochrane Infectious Diseases Group is funded by the UK Department for International Development (DFID) for the benefit of developing countries.
Data and analyses
- Top of page
- Background
- Objectives
- Methods
- Results
- Discussion
- Authors' conclusions
- Acknowledgements
- Data and analyses
- Appendices
- What's new
- History
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
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Appendices
Appendix 1. Search methods: detailed search strategies for databases
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What's new
Last assessed as up-to-date: 13 November 2007.
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History
Protocol first published: Issue 1, 1998
Review first published: Issue 3, 2000
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Contributions of authors
K Prasad conceptualized and developed the first review. During this update he 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 Review Manager. She added some parts to the review text and participated in data interpretation.
Declarations of interest
K Prasad is involved in one ongoing study (Prasad 2006) and is a co-author of one of the included trials (Kumarvelu 1994).
Sources of support
Internal sources
- All India Institute of Medical Sciences, India.
External sources
- No sources of support supplied
Index terms
Medical Subject Headings (MeSH)
Antitubercular Agents [*therapeutic use]; Chemotherapy, Adjuvant; Dexamethasone [therapeutic use]; Glucocorticoids [*therapeutic use]; Hydrocortisone [therapeutic use]; Prednisolone [therapeutic use]; Randomized Controlled Trials as Topic; Tuberculosis, Meningeal [*drug therapy; mortality]
MeSH check words
Adult; Child; Humans
* Indicates the major publication for the study