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 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. 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.
Tuberculous meningitis can be classified according to its severity. The British Medical Research Council MRC staging system categorizes patients into three stages MRC : stage I mild cases for those without altered consciousness or focal neurological signs; stage II moderately advanced cases for those with altered consciousness who are not comatose and those with moderate neurological deficits for example, single cranial nerve palsies, paraparesis, and hemiparesis ; and stage III severe cases for comatose patients and those with multiple cranial nerve palsies, and hemiplegia or paraplegia, or both.
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. 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. 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: do people who survive because of dexamethasone therapy tend to be left with severe disability, and are there differential effects among subgroups of people with different degrees of disease severity? 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.
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 also searched Current Controlled Trials www. 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 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. 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 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. We carried out a sensitivity analysis to explore the impact of the missing data on the summary effect estimate for death. We assessed heterogeneity by visually inspecting the forest plots to determine closeness of point estimates with each other and overlap of confidence intervals CIs. We planned to investigate heterogeneity through the following subgroup analyses: drug resistance susceptible versus resistant M.
We conducted visual inspection of the funnel plot of the trials for any obvious asymmetry that could be evidence of publication bias. There was no significant heterogeneity to indicate investigation of its potential sources. We assumed all participants who had dropped out of the corticosteroid group had an unfavourable outcome whereas those who had dropped out of the control group had a favourable outcome, and compared these results to an available case analysis.
We included nine trials and excluded 18 trials Figure 1 ; Characteristics of included studies ; Characteristics of excluded studies. We have provided a description of the included RCTs in Table 6. The included trials were conducted in different time periods one in the s, one in the s, four in the s, and two between and and in different geographical regions: Thailand Chotmongkol ; Egypt Girgis ; India O'Toole ; Kumarvelu ; Prasad ; Malhotra ; Philippines Lardizabal ; South Africa Schoeman ; and Vietnam Thwaites All participants were enrolled on the basis of clinical diagnosis of probable tuberculous meningitis.
We have described the diagnostic criteria used in each included trial in Table 7. The trials included young children Schoeman or adults Kumarvelu ; Chotmongkol ; Lardizabal ; Thwaites ; Prasad , or both O'Toole ; Girgis , and both sexes. Only Thwaites reported on drug resistance. In this trial, M. Of isolates, 99 Six included trials used the corticosteroid dexamethasone and two trials used prednisolone Chotmongkol ; Schoeman One trial, Malhotra , compared both dexamethasone and methylprednisolone with placebo.
We have described the dose regimens of corticosteroids used in Table 8. Duration of antituberculous treatment varied from six months Chotmongkol ; Schoeman , nine months Thwaites ; Prasad ; Malhotra , 12 months Kumarvelu ; Lardizabal , to 24 months Girgis In one trial, O'Toole , the duration of antituberculous treatment was unclear.
It was unclear in O'Toole and Prasad All but one trial reported on disabling neurological deficit in some way, although there was substantial variation in methods of assessment of this outcome between the trials O'Toole Abbreviations: IQ: intelligence quotient; DQ: development quotient. Five trials mentioned adverse events. The trials reported on a number of other immediate outcome measures we had not considered in this Cochrane review see ' Characteristics of included studies ' section.
We have listed the reasons for excluding 18 studies in the ' Characteristics of excluded studies ' section. See the ' Characteristics of included studies ' section, which includes a 'Risk of bias' table for each included trial. We have summarized the results of the 'Risk of bias' assessments across all included trials in Figure 2 and Figure 3. Five included trials reported adequate methods of randomization using either computer generated sequences of random numbers or random number tables Girgis ; Kumarvelu ; Thwaites ; Prasad ; Malhotra The remaining included trials did not clearly report the method of randomization.
We assessed four trials O'Toole ; Chotmongkol ; Thwaites ; Prasad as having adequate allocation concealment, with participants allocated coded treatment packs. The remaining trials did not clearly describe allocation concealment. Chotmongkol reported an imbalance in the severity of disease between the two groups, with the placebo group having a greater number of cases with Grade I disease and the steroid group having a greater number with Grade III disease.
Both favoured the placebo group. Four included trials had adequate blinding of participants and personnel O'Toole ; Chotmongkol ; Thwaites ; Prasad Participants and personnel were not blinded in the remaining trials. We evaluated the blinding of outcome assessors separately for the two primary outcome measures. For death, we assessed all included trials as at low risk of bias, apart from Girgis We assessed Girgis as having unclear risk of bias because this trial reported death as a case fatality rate, meaning that death was attributed specifically to tuberculous meningitis.
The effect of misclassification of deaths as being due to tuberculous meningitis when they were in fact due to another cause on the overall estimate of mortality is unknown. For disabling neurological deficit, we categorized unblinded outcome assessments as high risk, given the subjectivity of such assessments. Two trials blinded assessors of neurological disability and were assessed as low risk of bias Schoeman ; Thwaites ; and two trials had unblinded outcome assessors and were assessed as high risk of bias Kumarvelu ; Malhotra Kumarvelu included We therefore assessed this trial as high risk of bias.
We assessed these trials as at unclear risk of bias. For two included trials we had access to a trial protocol Thwaites ; Prasad We assessed Thwaites as at low risk of bias as the trial authors reported on all outcomes stated in the protocol in full. We assessed Prasad as at high risk of bias, as the definitions of the main outcomes were altered in the available unpublished data set, and adverse events were not reported.
Lardizabal ; Malhotra and Schoeman reported all outcomes stated in the methods section in the results, so we assessed them as having low risk of bias. Chotmongkol ; Girgis ; Kumarvelu and O'Toole did not state the outcome measures in the results, so we assessed them as having unclear risk of reporting bias.
All included trials based the inclusion of participants on a clinical diagnosis of tuberculous meningitis, due to the limitations of microbiological tests to confirm the diagnosis. The direction of bias caused by such inclusions is not likely to favour corticosteroids. See: Table 1. 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.
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. 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. All nine included trials reported on death Figure 4. The two largest trials, Girgis and Thwaites , had more than deaths in each, and the remaining trials were small trials with fewer deaths. Eight trials reported on disabling neurological deficit Figure 5. This summary estimate of effect was deemed to be low quality using the GRADE approach, because half the trials were at high risk of bias due to lack of blinding of outcome assessors and the estimate was imprecise.
Forest plot of comparison: 1 Any corticosteroid versus control, outcome: 1. Comparison 1 Any corticosteroid versus control, Outcome 2 Disabling neurological deficit. Eight trials reported data from which we could derive a combined outcome incorporating death and disabling neurological deficit Chotmongkol ; Girgis ; Kumarvelu ; Lardizabal ; Malhotra ; Prasad ; Schoeman ; Thwaites For this outcome, the overall estimate showed a reduction in the risk of death or disabling residual neurological deficit with corticosteroids RR 0.
This effect mirrors the results of the mortality analysis which is the main contributor of events. Comparison 1 Any corticosteroid versus control, Outcome 3 Death or disabling neurological deficit. Fifty participants 9. Of the six included trials that mentioned adverse events O'Toole ; Kumarvelu ; Chotmongkol ; Schoeman ; Thwaites ; Malhotra , three trials reported on incidence O'Toole ; Thwaites ; Malhotra ; Figure 6.
O'Toole reported four different adverse events gastrointestinal bleeding, glycosuria, infections, and hypothermia , which occurred in both groups Table Thwaites reported on several adverse events, which were divided into "severe" and other events Table Schoeman had "serious side effects" as an outcome measure and reported "no serious side effects of corticosteroid therapy".
Abbreviations; n: number of participants with event. The effect of corticosteroids appeared to be consistent across all stages of the disease although the analysis is relatively underpowered stage I RR 0. Forest plot of comparison: 2 Any corticosteroid versus control: stratified by severity of illness, outcome: 2. Comparison 2 Any corticosteroid versus control: stratified by severity of illness, Outcome 1 Death. Analyses stratifying the outcomes of death and disabling neurological deficit did not detect any large differences, and so showed no apparent effect of HIV status on the effect estimates, but the analysis is underpowered Analysis 3.
Forest plot of comparison: 3 Any corticosteroid versus control: stratified by HIV status, outcome: 3. Under this extreme assumption, there was still a reduction in deaths with corticosteroids RR 0. Six included trials date to the period when registry of clinical trials was not mandatory or routine.
Protocols of the included trials were unavailable except for two trials Prasad ; Thwaites For five trials where the outcomes were not clearly specified in the methods section, we assessed the risk of reporting bias as unclear. We assessed three trials as at low risk of reporting bias as all outcomes specified in the protocol or methods were reported Schoeman ; Thwaites ; Malhotra We assessed one trial as at high risk of bias, as outcome definitions were changed in the reported data unpublished , and adverse events were not reported Prasad Overall, the main analysis is unlikely to have been affected by reporting bias.
We have presented a funnel plot of the included trials in Figure 9. It refers to the outcome death and values below one favour corticosteroids. There is no obvious evidence of publication bias, but the number of included trials was low. Funnel plot of risk ratio RR from the included trials with the log of their standard error SE values. See 'Summary of findings' table 1 Table 1.
Nine trials met the inclusion criteria. There was no difference between groups in the incidence of adverse events, which included gastrointestinal bleeding, invasive bacterial infections, hyperglycaemia and hepatitis, although adverse events were not reported in all studies.
Though the included trials varied in their use of bacteriological confirmation of diagnosis, there is reasonable evidence to suggest that the trial participants had tuberculous meningitis. This is important because the decision to use corticosteroids is usually taken on a purely clinical basis when culture reports are unavailable 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. All included trials were conducted in high TB burden settings, in specialist referral hospitals. We assessed the estimate of effect as being at low risk of bias, as while there are some included trials that did not clearly report on the randomization method or allocation concealment, or both, the two largest included trials had few concerns and showed a consistent effect.
The trials provided evidence of benefit for all age groups. Although only one trial reported on outcomes for people living with HIV, there was no obvious qualitative heterogeneity. We did not find any serious imprecision. We assessed the quality of the estimate of effect for the outcome disabling neurological deficit as low quality.
The lack of blinding of outcome assessors of disabling neurological deficit in four of the eight trials reporting this outcome led us to downgrade the quality of evidence by one for risk of bias. There was imprecision of this estimate relating to the small number of events, which led us to downgrade by one. We have attempted to limit bias in the review process. The Cochrane Infectious Diseases Group Information Specialist conducted the literature search, and it is unlikely that these searches missed any major trials; however, we cannot rule out the possibility that we missed some small unpublished trials.
The funnel plot did not assist with this because there were too few included trials. To limit bias in the trial selection process and data extraction, we independently examined the search results, determined study selection, and extracted data. Questions remain about the mechanism by which corticosteroids improve clinical outcomes, and advances in understanding of these mechanisms have led to a suggestion that some people may benefit from corticosteroids while others do not, and some may even be adversely affected by steroids Thwaites Tobin et al.
Both of these states led to uncontrolled mycobacterial replication. Thus, hypersusceptibility to mycobacterial infection is associated with both inadequate and excessive inflammatory responses. Genotyping performed on participants from a series of clinical studies in Vietnam demonstrated that people with the TT genotype high LTA4H, hyperinflammatory had the highest mortality amongst participants who did not receive dexamethasone, but the lowest in the dexamethasone group; the people with the CC genotype low LTA4H, hypoinflammatory had the highest mortality in the dexamethasone group Tobin These results suggest that LTA4H genotype may have an important influence on whether or not steroids are effective in tuberculous meningitis, at least in this population.
Further investigation into the relationship between LTA4H expression in people, dexamethasone use, and outcomes in people with TB meningitis is needed to determine whether dexamethasone use is associated with harm in the subset of people with LTA4H deficiency, and whether genotyping people for LTA4H at diagnosis is useful to guide treatment with corticosteroids.
Other drugs that target parts of this inflammatory pathway, such as thalidomide, adulimumab and infliximab, have been used as rescue therapy in people with severe inflammatory complications of TB meningitis, but few clinical trials have been conducted on the use of these agents, and all these potent immunosuppressive drugs have the potential to cause harm as well as benefit Schoeman ; Schoeman ; Schoeman ; Jorge ; Lee ; Molton There is high quality evidence of the benefit of corticosteroids in preventing death in people with tuberculous meningitis.
Corticosteroids may have no effect on rates of disabling neurological deficit in people who survive TB meningitis, but the confidence interval around this estimate includes increased risk of this outcome. However, given the benefit associated with reduced risk of death, this is unlikely to be quantitatively important when considering whether or not to use corticosteroids in patients with TB meningitis.
Corticosteroids may not be associated with increased risk of adverse events, but there is uncertainty related to the limited reporting of adverse events in the included trials. In people that are immunosuppressed, such as people living with HIV, it is unclear whether corticosteroids are of benefit. As corticosteroids could lead to greater risk of harm in these people, further research would be useful to provide clear guidance for treatment.
Another question that remains unanswered is the optimum choice of corticosteroid drug and dosing regimen. Protocol first published: Issue 1, Review first published: Issue 3, The views expressed in this review do not necessarily reflect UK government policy. Comparison 3 Any corticosteroid versus control: stratified by HIV status, Outcome 3 Death or disabling residual neurological deficit.
CSF leucocytes, glucose, and protein on day 15 and day 30 after initiation of treatment. Minor sequelae activities of daily living with no or minimal assistance at 3 months. Insidious onset fever for at least 1 week, headache and vomiting, with or without nuchal rigidity followed by altered consciousness, cranial nerve palsies, or long tract signs. Upper gastrointestinal bleeding, or history of peptic ulcer disease in the previous month.
Potential adverse reactions to corticosteroids including weakness, oedema, hypertension, euphoria, psychosis, epigastric discomfort, Cushingoid facies, hirsutism, acne, insomnia, and increased appetite. 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". Adverse events recorded: upper gastrointestinal bleed, invasive bacterial infection, hypoglycaemia, and hypothermia. Gradual onset of any 2 of fever, progressive headache, or impaired consciousness with at least 1 symptom of 3 weeks duration. CSF profile characteristic of tuberculous meningitis containing more than 0.
Treatment with steroids regularly for more than 10 days used during the current illness. History of gastric or duodenal ulcer, gastrointestinal haemorrhage, malignant hypertension. ATT plus dexamethasone 0. Treatment success, defined as resolution of meningitic symptoms and achievement of good neurologic function and stability of this state for 3 consecutive months. Adverse events related to ATT or dexamethasone, for example deranged liver function tests, hypertension, hyperglycaemia, secondary infection, rash, gastrointestinal bleeding.
Proportion of participants with successful treatment of raised intracranial pressure. Proportion of participants with basal ganglia infarcts, tuberculomas, meningeal enhancement, and enlarged subarachnoid spaces. 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.
During the 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 National Center for Biotechnology Information , U. Cochrane Database Syst Rev. Published online Apr Kameshwar Prasad, Email: moc. Author information Copyright and License information Disclaimer.
Corresponding author. This article is an update of " Corticosteroids for managing tuberculous meningitis. This article has been cited by other articles in PMC. Abstract Background Tuberculous meningitis is a serious form of tuberculosis TB that affects the meninges that cover a person's brain and spinal cord.
Objectives To evaluate the effects of corticosteroids as an adjunct to antituberculous treatment on death and severe disability in people with tuberculous meningitis. 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. Main results Nine trials that included participants with deaths met the inclusion criteria. Authors' conclusions Corticosteroids reduce mortality from tuberculous meningitis, at least in the short term. Plain language summary Corticosteroids for managing people with tuberculous meningitis What is tuberculous meningitis and how might corticosteroids work?
What the evidence shows 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.
Summary of findings. Background Description of the condition Tuberculous meningitis is an inflammation of the meninges, which are membranes that envelope a person's brain and the spinal cord. Why it is important to do this review Several randomized controlled trials RCTs have been conducted on the effect of corticosteroids in managing people with tuberculous meningitis. Types of participants People of any age with clinically diagnosed tuberculous meningitis.
Types of interventions Intervention Corticosteroid hydrocortisone, prednisolone, methylprednisolone, 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 outcomes Death. Adverse events Adverse events as reported by the authors, 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. Reference lists 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.
Data collection and analysis For selection of studies and data extraction, we independently conducted each step, and examined agreement between the review authors. Assessment of risk of bias in included studies We independently assessed methodological quality using the Cochrane 'Risk of bias' tool and reported the results in a 'Risk of bias' table Higgins Measures of treatment effect We used relative risk as the measure of treatment effect for analysis.
Unit of analysis issues There were no cluster RCTs. Assessment of heterogeneity We assessed heterogeneity by visually inspecting the forest plots to determine closeness of point estimates with each other and overlap of confidence intervals CIs. Assessment of reporting biases We conducted visual inspection of the funnel plot of the trials for any obvious asymmetry that could be evidence of publication bias.
Subgroup analysis and investigation of heterogeneity There was no significant heterogeneity to indicate investigation of its potential sources. Results Description of studies We included nine trials and excluded 18 trials Figure 1 ; Characteristics of included studies ; Characteristics of excluded studies. Open in a separate window. Geographical location and time period The included trials were conducted in different time periods one in the s, one in the s, four in the s, and two between and and in different geographical regions: Thailand Chotmongkol ; Egypt Girgis ; India O'Toole ; Kumarvelu ; Prasad ; Malhotra ; Philippines Lardizabal ; South Africa Schoeman ; and Vietnam Thwaites Participants All participants were enrolled on the basis of clinical diagnosis of probable tuberculous meningitis.
Pyogenic meningitis and malignancy excluded. Interventions Six included trials used the corticosteroid dexamethasone and two trials used prednisolone Chotmongkol ; Schoeman Girgis 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 Dexamethasone 16 mg IV daily for 7 days 8 mg PO daily for 21 days 0.
Outcome measures All nine trials reported death. Not described. Chotmongkol Persisting neurological abnormalities, including decreased vision, spastic paraparesis and hemiparesis. Lardizabal Functional Independence Measure: Score 18 to severely disabled, requiring maximal to total assistance.
Score 37 to moderate to severe disability, requiring moderate to maximal assistance. Functional Independence Measure: Score 55 to minimal to moderate disability, requiring only minimal assistance. Scores of 3, 4 or 5 indicated severe disability.
Good outcome: Rankin score 0 indicating no symptoms. Intermediate outcome: Rankin score 1 or 2. Prasad "Bad outcome: If the patient has neither recovered nor is independent in activities of daily living". He may or may not have got minimal residual neurological deficit". Malhotra Severe disability: Rankin score of 3, 4 or 5. Good outcome: Rankin score 0. Intermediate outcome: Rankin score of 1 to 2. Excluded studies We have listed the reasons for excluding 18 studies in the ' Characteristics of excluded studies ' section.
Risk of bias in included studies See the ' Characteristics of included studies ' section, which includes a 'Risk of bias' table for each included trial. Allocation Five included trials reported adequate methods of randomization using either computer generated sequences of random numbers or random number tables Girgis ; Kumarvelu ; Thwaites ; Prasad ; Malhotra Blinding Four included trials had adequate blinding of participants and personnel O'Toole ; Chotmongkol ; Thwaites ; Prasad Selective reporting For two included trials we had access to a trial protocol Thwaites ; Prasad Other potential sources of bias All included trials based the inclusion of participants on a clinical diagnosis of tuberculous meningitis, due to the limitations of microbiological tests to confirm the diagnosis.
Effects of interventions See: Table 1 Summary of findings for the main comparison Any corticosteroid compared to control for tuberculous meningitis. 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. Very low quality: we are very uncertain about the estimate. Comparison: any corticosteroid versus control Death All nine included trials reported on death Figure 4.
Analysis Comparison 1 Any corticosteroid versus control, Outcome 1 Death. Disabling neurological deficit Eight trials reported on disabling neurological deficit Figure 5. Analysis Comparison 1 Any corticosteroid versus control, Outcome 2 Disabling neurological deficit. Analysis Comparison 1 Any corticosteroid versus control, Outcome 3 Death or disabling neurological deficit. Adverse events Of the six included trials that mentioned adverse events O'Toole ; Kumarvelu ; Chotmongkol ; Schoeman ; Thwaites ; Malhotra , three trials reported on incidence O'Toole ; Thwaites ; Malhotra ; Figure 6.
Analysis Comparison 1 Any corticosteroid versus control, Outcome 4 Adverse events. Analysis Comparison 2 Any corticosteroid versus control: stratified by severity of illness, Outcome 1 Death. Analysis Comparison 4 Sensitivity analysis, Outcome 1 Worst case scenario analysis. Assessment of reporting biases Six included trials date to the period when registry of clinical trials was not mandatory or routine.
Publication bias We have presented a funnel plot of the included trials in Figure 9. Discussion Summary of main results See 'Summary of findings' table 1 Table 1. Potential biases in the review process We have attempted to limit bias in the review process. Authors' conclusions Implications for practice. Implications for research. What's new Date Event Description 13 April New citation required but conclusions have not changed We included nine trials in total, and the review's conclusions remain unchanged.
We rewrote the Results and Discussion sections, and revised the plain language summary. History Protocol first published: Issue 1, Review first published: Issue 3, Date Event Description 14 November New citation required but conclusions have not changed , Issue 1: we added one new trial, Thwaites We updated the review text and title.
Appendices Appendix 1. Notes Unchanged. Data and analyses Comparison 1 Any corticosteroid versus control. Outcome or subgroup title No. Comparison 2 Any corticosteroid versus control: stratified by severity of illness. Comparison 3 Any corticosteroid versus control: stratified by HIV status.
Analysis Comparison 3 Any corticosteroid versus control: stratified by HIV status, Outcome 3 Death or disabling residual neurological deficit. Comparison 4 Sensitivity analysis. Characteristics of studies Characteristics of included studies [ordered by study ID] Chotmongkol Methods Randomized parallel group study.
Number of participants: 59 participants; 27 females, 32 males; 29 received prednisolone, 30 received no steroid. ATT alone. Outcomes Death at the end of 6 months. Residual neurological deficits at the end of 6 months. Time until resolution of fever. Time until disappearance of headache. Adverse events recorded were gastrointestinal bleeding and hyperglycaemia.
Notes Date: July to December Risk of bias Bias Authors' judgement Support for judgement Random sequence generation selection bias Unclear risk Block randomization by a block size of 4, but insufficient information on sequence generation. Allocation concealment selection bias Low risk "Patients were randomised to receive prednisolone or placebo by a block size of four using coded treatment A and B.
Selective reporting reporting bias Unclear risk The protocol was unavailable, and outcomes were not clearly specified in the methods. Girgis Number of participants: participants; males, females; received dexamethasone, received no steroid. Severe hepatitis developed in eight patients in the placebo group versus none in the dexamethasone group.
The lysis of bacteria with the release of bacterial cell-wall components in the subarachnoid space induces meningeal inflammation by stimulating the production of inflammatory cytokines. The presence of inflammatory cytokines in the subarachnoid space leads to several pathophysiologic consequences. Inflammatory cytokines recruit polymorphonuclear leukocytes from the bloodstream that cause vasculitis-induced stroke.
Inflammatory cytokines also increase the permeability of the blood-brain barrier, allowing leakage of serum proteins and formation of an inflammatory exudate and obstructive hydrocephalus. Dexamethasone exerts its beneficial effect by inhibiting synthesis of the inflammatory cytokines and by decreasing CSF outflow resistance and stabilizing the blood-brain barrier.
The goal of adjunctive therapy with dexamethasone in bacterial and mycobacterial meningitis is to attenuate the inflammatory response. The recommended dose of dexamethasone for adults with bacterial meningitis is 0. No cases of severe hepatitis developed in the dexamethasone-treated group in this study.
Thus, as the authors speculate, dexamethasone may also improve outcomes by reducing the need to change the antituberculosis drug regimen. Previous practice had been to use corticosteroid therapy only in patients with tuberculous meningitis who developed hydrocephalus or presented in coma.
These findings suggest a benefit to using corticosteroids before these complications occur. Thwaites GE et al.
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Pseudomonas strains and reagents were kindly provided by Prof. You can also search for this author in PubMed Google Scholar. Correspondence to Jan Rybniker. Journal peer review information: Nature Communications thanks Randall J. Basaraba and the other anonymous reviewer for their contribution to the peer review of this work.
Reprints and Permissions. Corticosteroids inhibit Mycobacterium tuberculosis -induced necrotic host cell death by abrogating mitochondrial membrane permeability transition. Nat Commun 10, Download citation. Received : 07 May Accepted : 09 January Published : 08 February Infection Scientific Reports Nature Communications By submitting a comment you agree to abide by our Terms and Community Guidelines.
If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Advanced search. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. Download PDF. Subjects Bacterial host response Immune cell death Immune evasion Infection. Abstract Corticosteroids are host-directed drugs with proven beneficial effect on survival of tuberculosis TB patients, but their precise mechanisms of action in this disease remain largely unknown.
Introduction M ycobacterium tuberculosis Mtb , the causative agent of tuberculosis TB , is the major killer among infectious agents which led to 1. Results Corticosteroids potently inhibit Mtb -induced cell death Co-incubation and infection of phagocytes with Mtb inevitably leads to host cell death which is primarily mediated by the mycobacterial ESX-1 type VII secretion system, an essential virulence factor Full size image.
Drugs used in this study Rifampicin was purchased from AppliChem. Culture conditions of bacteria The mycobacterial strain Erdman provided by S. Survival assays For the survival assays, compounds were preplated into well plates at different concentrations.
CFU determination J TMRM staining J Reporting Summary Further information on experimental design is available in the Nature Research Reporting Summary linked to this article. Data availability The authors declare that all data supporting the findings of this study are available within the paper and its supplementary information files. References 1. Article Google Scholar 7. Article Google Scholar PubMed Google Scholar Article Google Scholar Download references. Acknowledgements We thank Prof.
View author publications. Ethics declarations Competing interests The authors declare no competing interests. Supplementary information. Supplementary Information. Reporting Summary. About this article. Sanson , A. Vu Hong , E. Massourides , N. Bourg , L. Suel , F. Amor , G. Corre , P. Blot , A. Bigot , C. Pinset , P. Rustin , L. Servais , T. Voit , I. Beckwith , Marianne S. Beckwith , Sindre Ullmann , Ragnhild S. Comments By submitting a comment you agree to abide by our Terms and Community Guidelines.
Publish with us For authors For Reviewers Submit manuscript. Search Search articles by subject, keyword or author. Show results from All journals This journal. Close banner Close. The recommended dose of dexamethasone for adults with bacterial meningitis is 0. No cases of severe hepatitis developed in the dexamethasone-treated group in this study.
Thus, as the authors speculate, dexamethasone may also improve outcomes by reducing the need to change the antituberculosis drug regimen. Previous practice had been to use corticosteroid therapy only in patients with tuberculous meningitis who developed hydrocephalus or presented in coma. These findings suggest a benefit to using corticosteroids before these complications occur.
Thwaites GE et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med Oct 21; N Engl J Med Oct 21 To investigate whether adjunctive therapy with dexamethasone reduces the risk for death or severe disability from tuberculous meningitis in patients with and without HIV infection,. Comment The lysis of bacteria with the release of bacterial cell-wall components in the subarachnoid space induces meningeal inflammation by stimulating the production of inflammatory cytokines.
Citation s : Thwaites GE et al. By continuing to use our site, you accept the use of these cookies. To learn more, please visit our Cookie Information page.
Improved understanding of immunopathogenesis in TBM has led to discovery of target sites for immunotherapies. The cytokine TNF alpha has been a target in both animal and human studies. In a safety and tolerability study using thalidomide at escalating doses, thalidomide was safe and well tolerated as an adjunctive therapy to treat children with stage 2 TBM [ 61 ]. Clinical and radiological data also suggested improved outcome. The results of this study supported a phase 3 randomised controlled trial in paediatric TBM to test thalidomide against placebo in stage 2 and 3 disease.
Forty-seven children were enrolled, of which 30 received thalidomide. This study was terminated early as all adverse events and deaths occurred in the thalidomide arm. Debate around the influence of the high dose and late stage of disease on the adverse outcomes remains [ 62 ]. No further studies have taken place to investigate what was once a promising treatment option in paediatric TBM; however, recent data suggests thalidomide and TNF-alpha blockade may still have a role in tuberculous mass lesions where treatment with corticosteroids has failed [ 63 ].
Early within 2—4 weeks of commencing anti-tubercular therapy antiretroviral ART therapy of HIVassociated tuberculosis is associated with survival benefit in patients with low CD4 counts [ 64 — 66 ]. A meta-analysis including 8 randomised controlled trials in PTB compared survival in patients in whom antiretroviral therapy was started within 1—4 vs 8—12 weeks.
In the aforementioned meta-analysis, there was a twofold increase in TB-associated IRIS in patients treated early with antiretroviral therapy. To our knowledge, no research has addressed the question as to whether the incidence or natural history of HIV-associated TBM is changing or has changed in light of more effective anti-HIV therapies of modern times; however, we feel this would be an important topic for future research.
Other than corticosteroids, thalidomide and antiretroviral therapies, there is little clinical trial data to support efficacy of other host-directed therapies in TBM. Aspirin has a possible anti-inflammatory as well as anti-thrombotic role in TBM which is discussed later in this review. Infliximab is a TNF-alpha inhibitor which is FDA approved for use in inflammatory bowel disease, rheumatoid arthritis and some seronegative arthropathies.
Although most reports of infliximab in TB relate to the reactivation of latent tuberculosis, there are some case reports where corticosteroid has failed to control inflammation yet subsequent reintroduction of infliximab has led to a near complete resolution of symptoms [ 70 , 71 ]. Other therapies to consider include interleukin receptor 1 inhibitors anakinra IL-1 alpha and beta and canakinumab IL-1 beta only. This observation provides support for a dominant role of the innate immune response in TBM inflammation and suggests novel targets for immunotherapies.
Rich and McCordock were the first to describe the pathogenic mechanisms which lead to central nervous system tuberculosis [ 73 ]. Research since then has enabled better understanding of the natural history including the neurological sequelae such as hydrocephalus, vasculitis leading the cerebral infarction and metabolic abnormalities especially hyponatremia.
Early recognition and management of these phenomena remains integral to the treatment of patients with TBM. The inflammatory infiltrate within the subarachnoid space or the ventricular pathways may lead to disruption of CSF flow resulting in hydrocephalus. Hydrocephalus can be communicating caused by abnormal flow through the basal cisterns or non-communicating usually a later complication due to obstruction at the level of the fourth ventricle.
Communicating hydrocephalus is more common and can be managed medically however may require intervention if progressing. Non-communicating hydrocephalus required rapid intervention. CSF diversion techniques such as ventriculoperitoneal shunts VPS and endoscopic third ventriculostomy are the mainstay of surgical treatment for hydrocephalus [ 74 ].
Evidence as to which technique is most effective is lacking. A systematic review of adults and children with TBM and hydrocephalus demonstrated good outcome, defined as Glasgow Outcome Scale 4 or 5 Table 2 in Good outcomes were observed in more patients with less severe disease specifically those found to be Grade I Patients were followed up at two time points, discharge short term and 3 months after VP shunt insertion long term. Although short-term outcomes were only marginally better in the HIV-negative group, long-term outcomes differed significantly with It remains unclear as to whether this is due to the secondary compressive effect on brain parenchyma or whether these inflammatory mediators are involved in the pathogenesis of hydrocephalus.
Further research is required to establish best evidence-based practice for the treatment of this common complication in TBM in particular for HIV-associated disease. In TBM, meningeal pathology may extend into the parenchyma and lead to encephalitis, whilst obliterative vasculitis within the vessels leads to infarction.
These processes may result in cytotoxic and vasogenic oedema. The presence of parenchymal pathology may lead to failure of cerebral vascular autoregulation. Metabolic abnormalities such as hyponatraemia, hyperthermia and hypercapnia can cause further dysregulation. Thus, clinical management should be directed at the frequent monitoring and correction of abnormalities in gas exchange and tissue oxygenation, through mechanical ventilation if necessary , meticulous fluid and electrolyte management, monitoring and intervention to treat raised intracranial pressure where appropriate as well as adequate temperature control.
When there is no surgical intervention indicated, yet ICP remains high, hyperosmolar agents most commonly mannitol may be effective yet a randomised control trial to examine this theory is required [ 80 , 81 ]. Several mechanisms exist. Cerebral salt wasting CSW is characterised by natriuresis, hyponatremia and volume contraction in response to brain injury [ 83 ].
The syndrome of inappropriate anti-diuretic hormone SIADH is also associated with brain injury and occurs due to excessive release of antidiuretic hormone from the posterior pituitary gland resulting in inappropriate, continued secretion or action of the antidiuretic hormone arginine vasopressin AVP despite normal or increased plasma volume leading to hyponatraemia [ 84 ].
In a prospective hospital-based study conducted in India, of 76 patients with TBM, 34 By convention, SIADH is managed by fluid restriction and cerebral salt wasting by fluid administration. Some suggest that both conditions can be treated with hypertonic saline [ 83 ], whereas others state that fluid restriction, the traditional treatment for SIADH, has had little benefit in meningitis and might result in worsening hypovolaemia and harm [ 84 ].
This complex and often overlooked complication in TBM should be further investigated to define optimal investigation and management. Tuberculomas can occur together with or independently of TBM. Clinical presentation depends on site and includes seizures, focal neurological weakness or symptoms of raised intracranial pressure due to hydrocephalus or mass effect. There was no effect of dexamethasone on incidence of tuberculoma formation or on resolution of tuberculomas [ 85 ]. The mainstay of treatment remains anti-tuberculous therapy, the duration of which is debated.
There is lack of evidence in this area but consensus suggests four anti-tuberculous drugs for 18 months or until the tuberculoma resolves [ 7 ]. In some cases, where there is diagnostic doubt or where the size and anatomical location of the tuberculoma is causing clinical worsening, surgical excision may be required. Stereotactic craniotomy and excision of superficial small tuberculomas and microsurgery are procedures now used.
In cases where there is no response to dexamethasone, alternative anti-inflammatory agents have been tried, particularly when the tuberculoma involves the optic chiasm and threatens vision. Some case series suggest that thalidomide could help to alleviate these problems [ 86 — 88 ]. The macroscopic pathological appearance in the brain vasculature is that of gelatinous fibrocellular leptomeningeal infiltrates initially enveloping the vessels including the carotid arteries, middle cerebral arteries and their branches.
Vasculitis within the affected vessels may occur with intimal proliferation. This process with or without superadded thrombosis leads to cerebral infarction [ 89 ]. There is no established prevention or treatment for stroke in TBM. Corticosteroids do not prevent stroke [ 56 ]. Aspirin has antiplatelet, anti-aggregant, anti-inflammatory and antioxidant properties [ 94 , 95 ].
In a study of zebrafish, models with the hyperinflammatory LTA4H phenotype treated with aspirin showed reduced expression of pro-inflammatory eicosanoids and TNF alpha with subsequent modulation of inflammatory response [ 96 ]. In a placebo-controlled trial of aspirin in adult patients with TBM in India, mg OD aspirin was associated with a significantly lower 3-month mortality and a lower incidence of stroke that was not significant [ 97 ].
These findings suggest the effect of aspirin may be as much anti-inflammatory as anti-thrombotic. In this trial, there was no significant effect of aspirin on mortality; however, there was a significant effect on incidence of new hemiplegia in those receiving high-dose aspirin [ 98 ]. Although more effective therapies are now available for acute treatment and secondary prevention of ischaemic stroke associated with non-infectious vascular risk factors, aspirin an inexpensive well-tolerated drug remains the most commonly used treatment worldwide.
Further large-scale randomized controlled trials are required to explore its role in reducing inflammation and vascular complications in TBM. Computerised tomography CT of the head with evidence of probable perforator territory infarction on the left in an HIVinfected patient with tuberculous meningitis. The neurological presentations of tuberculosis are the most lethal and under-researched manifestations of TB which remains a major global health problem.
Further research is required to investigate the safety and efficacy of intensified therapy regimens and newer anti-tuberculous agents to treat CNS tuberculosis. Corticosteroids have proven mortality benefit except in HIV-associated TBM where as yet no sufficiently powered study has been able to prove benefit or lack thereof. More research is required to develop and evaluate novel host-directed therapies. Immune response phenotypes and genetic polymorphisms may direct individualized immune therapies and mediators of the innate immune response may provide targets for the development novel therapies.
Stroke is a major cause of morbidity and mortality in TBM. Recent studies have shown a potential benefit of aspirin in the prevention of stroke as well as in the modulation of the host immune response in TBM. This requires further investigation in large phase 3 clinical trials.
A large randomized clinical trial is required to investigate outcomes comparing available CSF diversion techniques in this particularly vulnerable subgroup of patients. A treatment algorithm provided in this paper gives a practical holistic approach to the management of patients with tuberculous meningitis Fig.
He also receives support from Wellcome , The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. This article does not contain any studies with human or animal subjects performed by any of the authors. National Center for Biotechnology Information , U. Current Treatment Options in Neurology. Curr Treat Options Neurol. Published online Feb Robert J. Author information Copyright and License information Disclaimer.
Angharad Davis, Email: moc. Corresponding author. This article has been cited by other articles in PMC. Recent findings Current antimicrobial regimes do not factor the differing ability of drugs to cross the blood-brain barrier. Summary Further clinical trial data is required to improve treatment outcomes in TBM in particularly in regard to the value of high-dose rifampicin, newer antimicrobials with improved central nervous system penetration and host-directed therapies.
Keywords: Tuberculous meningitis, Immunotherapies, Anti-tuberculous therapies, Hydrocephalus, Tuberculoma, Human immunodeficiency virus. Introduction Tuberculosis remains a major global health problem. Table 1 Anti-tuberculous drugs in tuberculous meningitis and drug-resistant tuberculosis. IV or IM.
Limited availability. Probably very low but data from one patient only Delamanid Not determined New drug. No data. Open in a separate window. Host-directed therapies In TB, there has been much recent interest in adjunctive host-directed immune interventions to either enhance protective immunity or regulate pathological tissue-damaging immunity [ 47 ].
Supportive therapies Rich and McCordock were the first to describe the pathogenic mechanisms which lead to central nervous system tuberculosis [ 73 ]. Hydrocephalus and raised intracranial pressure The inflammatory infiltrate within the subarachnoid space or the ventricular pathways may lead to disruption of CSF flow resulting in hydrocephalus.
Table 2 Clinical rating scores in TBM. Tuberculomas Tuberculomas can occur together with or independently of TBM. Conclusions and research priorities The neurological presentations of tuberculosis are the most lethal and under-researched manifestations of TB which remains a major global health problem. Compliance with Ethical Standards Conflict of Interest The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. References and Recommended Reading. World Health Organization. Global tuberculosis report 20th edition. World Health Organization, Geneva; Streptomycin in tuberculosis trials committee, Medical Research Council. Streptomycin treatment of tuberculous meningitis. Lancet — Treatment of pulmonary tuberculosis with isoniazid; an interim report to the Medical Research Council by their Tuberculosis Chemotherapy Trials Committee.
Br Med J — Nitti V. Results and tolerance of prolonged rifampicin treatment in recent and chronic forms of pulmonary tuberculosis. Chiang SS, et al. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis. Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting. Plos ONE. Treatment of tuberculosis guidelines.
World Health Organisation. Geneva, Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev. Donald PR. Cerebrospinal fluid concentrations of antituberculosis agents in adults and children. Tuberculosis Edinb ; 90 — Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis. Am Rev Resp Dis. Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis.
Int J Tuberc Lung Dis. Heemskerk AD, et al. Intensified antituberculosis therapy in adults with tuberculous meningitis. N Engl J Med. Van Toorn R, et al. Short intensified treatment in children with drug-susceptible tuberculous meningitis.
Pediatr Infect Dis J. Ruslami R, et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Am Rev. Respir Dis. Why do we use mg of rifampicin in tuberculosis treatment? Clin Infect Dis.
Boeree M. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis. Early bactericidal activity of ethambutol, pyrazinamide and the fixed combination of isoniazid, rifampicin and pyrazinamide Rifater in patients with pulmonary tuberculosis. S Afr Med J. World Health Organization treatment guidelines for drug-resistant tuberculosis, update.
The European Respiratory Journal. Therapeutic effect of a new antibacterial substance ofloxacin DL on pulmonary tuberculosis. Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis.
Antimicrobial Agents and Chemotherapy. The effectiveness and safety of fluoroquinolone-containing regimen as a first-line treatment for drug-sensitive pulmonary tuberculosis: a systematic review and meta-analysis. De Socio GV. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Eng J Med. Te Brake L, et al. Int J of Antimicr Agents. The discovery of linezolid, the first oxazolidinone antibacterial agent.
Curr Drug Targets Infect Dis. Linezolid ZYVOX , the first member of a completely new class of antibacterial agents for treatment of serious Gram- positive infections. J Med Chem. Linezolid for the treatment of multidrug-resistant tuberculosis. J Antimicrob Chemother. J Infect. Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis. Eur Respir J. Linezolid in the treatment of multidrug-resistant tuberculosis.
A retrospective TBNET assessment of linezolid safety, tolerability and efficacy in multidrug-resistant tuberculosis. Linezolid use for the treatment of multi-drug resistant and extensively drug resistant tuberculosis, New York City, Linezolid for treatment of chronic extensively drug-resistant tuberculosis.
Linezolid: an effective, safe and cheap drug for patients failing multidrug-resistant tuberculosis treatment in India. 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.
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. Abstract Background: Tuberculous meningitis is a serious form of tuberculosis TB that affects the meninges that cover a person's brain and spinal cord.
Corticosteroids have proven mortality benefit polymorphisms may direct individualized immune therapies and mediators of the well as in the modulation of new hemiplegia in those. Inflammasome activation underlies central nervous in patients with tuberculous meningitis. A large randomized clinical trial is required to investigate outcomes the most lethal and under-researched remains a major global health. Corticosteroids may have no effect on the number of people outcomes in TBM in particularly stroke associated with non-infectious vascular risk factors, aspirin an inexpensive with improved central nervous system commonly used treatment worldwide. Linezolid ZYVOXthe first HIV infection influence intracerebral inflammation with newly diagnosed pulmonary tuberculosis:. Human and Animal Rights and The inflammatory infiltrate within the the prevention of stroke as study has been able to of CSF flow resulting in. Optimal timing of antiretroviral therapy investigate the safety and efficacy clinical outcome in young children. Stroke is a major cause system deterioration in HIV-associated tuberculosis. Computerised tomography CT of the groups steroid tb meningitis mechanism the incidence of drug resistant tuberculosis, New York to central nervous system tuberculosis and liver dysfunction. Table 2 Clinical rating scores of Thailand.The causes of death and disability in tuberculous meningitis are multifactorial. The main pathological mechanisms are persistent or. The first 16 patients in the steroid group were given prednisone in a dose of 2 mg/kg/day, while the remaining 54 subjects in the group received it in a dose of. Steroids for treating tubercular meningitis It is possible that steroids may harm TBM patients by suppressing the immune mechanism.