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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.
To evaluate the effects of corticosteroids as an adjunct to antituberculous treatment on death and severe disability in people with tuberculous meningitis.
We also contacted researchers and organizations working in the field, and checked reference lists. 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. We independently assessed search results and methodological quality, and extracted data from the included trials.
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. Nine trials that included participants with deaths met the inclusion criteria. At follow-up from three to 18 months, steroids reduce deaths by almost one quarter RR 0. Disabling neurological deficit is not common in survivors, and steroids may have little or no effect on this outcome RR 0. There was no difference between 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. 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.
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. 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. We examined the evidence published up to 18 March and included nine trials with 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. There are few uncertainties regarding allocation concealment or sequence generation in one of the two largest studies, but the largest trial was high quality and effects between these two trials were consistent.
If making recommendations for HIV-positive participants only, a guidelines panel may wish to downgrade on indirectness. The effect is clinically important. 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.
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.
There were few events, and the confidence interval ranges from substantive harms to substantive benefits. Tuberculous meningitis is an inflammation of the meninges, which are membranes that envelope a person's brain and the spinal cord. It is caused by infection with one of several mycobacterial species that belong to the Mycobacterium tuberculosis complex, which are responsible for tuberculosis TB disease.
Tuberculous meningitis is a severe form of TB and accounts for many deaths Tandon It is a form of extrapulmonary TB that is, TB that occurs outside the lungs. There is an association between extrapulmonary TB and human immunodeficiency virus HIV infection, particularly in people with low CD4 cell counts Naing It appears that the higher risk of TB infection in HIV-positive people means that tuberculous meningitis is also more common in this group Berenguer ; Berger People with tuberculous meningitis usually present with headache, fever, vomiting, altered conscious level, and sometimes convulsions.
It is diagnosed clinically, with confirmation by microscopy and culture of cerebral spinal fluid CSF or a polymerase chain reaction PCR test. The low sensitivity of the diagnostic tests currently available presents a particular challenge for clinicians, especially when treating children and HIV-positive people. Early diagnosis and prompt treatment are the main determinants of a good outcome in people with tuberculous meningitis Thwaites The causes of death and disability in tuberculous meningitis are multifactorial.
The main pathological mechanisms are persistent or progressive raised intracranial pressure with or without hydrocephalus, involvement of the optic nerves or optic chiasm leading to visual deficit, cranial neuropathies, arachnoiditis, and vasculitis of the cerebral blood vessels leading to stroke. Neurological disability related to antituberculous treatment may occur due to optic neuritis related to ethambutol or isoniazid, which sometimes causes permanent loss of vision, or isoniazid-related peripheral neuropathy.
Tuberculous meningitis can be classified according to its severity. Without anti-tuberculous treatment, people with tuberculous meningitis die Tandon ; Thwaites Indirect evidence from animal studies provides a biological basis for how corticosteroids could be effective Feldman They may decrease inflammation, especially in the subarachnoid space; reduce cerebral and spinal cord oedema, and intracranial pressure Feldman ; Parsons ; and reduce inflammation of small blood vessels, and damage due to blood flow slowing to the underlying brain tissue.
However, corticosteroids could also cause harm by suppressing the person's immune system. They may suppress the symptoms of TB infection but promote an unchecked growth of the bacteria and an increased bacterial load, and reduce inflammation of the meninges, which will then reduce the ability of drugs to cross the blood-brain barrier and enter the subarachnoid space. Other adverse effects of corticosteroids include gastrointestinal haemorrhage, electrolyte imbalance, hyperglycaemia, hypertension, and increased risk of infections from other pathogens D'Arcy-Hart The use of adjunctive corticosteroids is not known to result in disability in tuberculous meningitis, especially when used for short periods of time as is the case in most clinical trials of this intervention.
However, there is concern that although corticosteroids may save the lives of some people who have severe tuberculous meningitis, they may not necessarily improve their quality of life, as some people may survive but be left with a severe disability, rendering them bed-bound and highly dependent.
In other words, if corticosteroids increase the survival rate but not disability-free survival, then corticosteroids might actually increase a person's suffering. Several randomized controlled trials RCTs have been conducted on the effect of corticosteroids in managing people with tuberculous meningitis. The conclusions from these trials, seen individually, appear inconsistent. One trial, Thwaites , showed that dexamethasone increases survival rate.
However, it also raised two questions: The editorial that accompanied the trial, Quagliarello , and several letters to the editor in response to this trial Marras ; Seligman commented that the trial did not have sufficient statistical power to answer these questions.
We have prepared a meta-analysis that synthesizes the results from all available RCTs to try and provide the necessary power to address these questions. People of any age with clinically diagnosed tuberculous meningitis. Corticosteroid hydrocortisone, prednisolone, methylprednisolone, or dexamethasone given orally, intramuscularly, or intravenously plus antituberculous treatment. Antituberculous treatment same as intervention with or without placebo.
Adverse events as reported by the authors, including upper gastrointestinal bleeding, invasive bacterial or fungal infections, and hyperglycaemia. We attempted to identify all relevant trials regardless of language or publication status published, unpublished, in press, and in progress.
We searched the following databases using the search terms and strategy described in Appendix 1: We also searched Current Controlled Trials www. We contacted the following organizations and individuals working in the field: We also drew on existing reviews of this topic Ramchandran ; Jacobs ; Geiman , and checked the reference lists of all the trials identified by the above methods. For selection of studies and data extraction, we independently conducted each step, and examined agreement between the review authors.
We resolved any disagreements through discussion. We independently screened the search results and retrieved the full-text articles of all potentially relevant trials.
We examined each trial report to ensure that we included multiple publications from the same trial only once. We contacted trial authors for clarification if a trial's eligibility was unclear. We resolved any disagreements through discussion and listed the excluded studies and the reasons for their exclusion. One of the review authors, KP, conducted one of the included trials Prasad , which was started at the same time as Prasad the first edition of this Cochrane Review.
As of March , this trial had not been published, but the unpublished data is included in this review.
KP is also a co-author on Kumarvelu We independently extracted data on participant characteristics, diagnostic criteria, disease severity, HIV status, antituberculous drug regimen, corticosteroid regimen, and outcome measures using a pre-piloted data extraction form.
We resolved disagreements through discussion and contacted the corresponding trial author in the case of unclear or missing data. For dichotomous outcomes, we recorded the number of participants that experienced the event and the number of participants randomized to each treatment group, and used them in the analysis. We also recorded number of participants analysed in each treatment arm, and used the discrepancy between the figures to calculate the number of participants lost to follow-up.
These figures allowed us to perform a worst-case scenario analysis to investigate the effect of missing data. We independently assessed methodological quality using the Cochrane 'Risk of bias' tool and reported the results in a 'Risk of bias' table Higgins We reported who was blinded in each trial, and assessed the risk of bias associated with blinding separately for the two primary outcomes.
We attempted to contact the trial authors if this information was not specified or if it was unclear. We resolved any disagreements by discussion between the review authors. We used relative risk as the measure of treatment effect for analysis.
The primary analysis is an intention-to-treat analysis where all participants randomized to treatment are included in the denominator.