Corticosteroids for managing tuberculous meningitis

 

Characteristics of included studies [ordered by study ID]

Chotmongkol 1996

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Methods	Generation of allocation sequence: unclear, but randomization in blocks of 4 Allocation concealment: unclear Blinding: participants, enrolling physicians, and assessors; using identical appearing placebo Inclusion of all randomized participants in analysis: 100% (no loss to follow up) Length of follow up: 6 months but post-study follow up continued for 16 to 45 months (mean = 30 months)
Participants	Number: 59 randomized Description: age > 15 years; both sexes; clinically diagnosed tuberculous meningitis (characteristic clinical features, typical cerebrospinal fluid profile consisting of lymphocytic meningitis with low glucose level and elevated protein, negative cerebrospinal fluid culture for bacteria and fungus, cerebrospinal fluid negative for bacterial and cryptococcal antigen and malignant cells, negative serologic tests for syphilis and HIV); all stages of severity and all duration of disease (range 1 to 60 days); HIV-negative
Interventions	1. Antituberculous treatment plus prednisolone 2. Antituberculous treatment alone Antituberculous treatment: isoniazid oral (300 mg), rifampicin oral (600 mg, 450 mg for those weighing < 50 kg), pyrazinamide oral (1500 mg), and streptomycin intramuscular (750 mg) for the first 2 months; followed by isoniazid and rifampicin in above dosage for 4 months; prednisolone oral on tapering dosage for 5 weeks (week 1 = 60 mg, week 2 = 45 mg, week 3 = 30 mg; week 4 =20 mg, week 5 = 10 mg)
Outcomes	1. Death at the end of 6 months 2. Residual deficits at the end of 6 months 3. Time until normal body temperature 4. Adverse events recorded were gastrointestinal bleeding and hyperglycaemia Not included in review: 5. Time until disappearance of headache
Notes	Location: Thailand Date: July 1990 to December 1992 Trialists: Department of Medicine, Khon Kaen University, Thailand; no collaborators

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Girgis 1991

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Methods	Generation of allocation sequence: pre-designed chart Allocation concealment: unclear Blinding: none Inclusion of all randomized participants in analysis: unclear Length of follow up: 24 months
Participants	Number: 280 randomized Description: all ages; both sexes; clinically diagnosed tuberculous meningitis based on history/findings (duration of illness > 30 days, consisting of fever, headache, vomiting, altered sensorium, generalized weakness or cranial nerve deficits); comparison of first and second cerebrospinal fluid findings; and a poor response to antibacterial therapy for 48 h; unclear whether either or both the duration of illness criteria and poor response to antibacterial therapy had to be satisfied Exclusion criteria: not mentioned Unclear whether those participants already receiving a corticosteroid were also included
Interventions	1. Antituberculous treatment plus dexamethasone (Group I of the study) 2. Antituberculous treatment alone (Group II of the study) Antituberculous treatment: isoniazid intramuscular (10 mg/kg/day, maximum 600 mg), streptomycin intramuscular (25 mg/kg/day, maximum 1000 mg), and ethambutol oral (25 mg/kg/day, maximum 1200 mg); dexamethasone given intramuscularly (12 mg/day to adults and 8 mg/day to children weighing < 25 kg) for 3 weeks and then tapered during the next 3 weeks)
Outcomes	1. Death during 2-year follow up 2. Residual neurological sequelae 3. Neurological complications developing during therapy 4. Cerebrospinal fluid leucocytes, glucose, and protein on day 15 and day 30 after initiation of treatment Trial authors reported case-fatality rate, which by definition includes all deaths caused by tuberculous meningitis, but not the ones attributed to other causes. Not reported whether any death during the follow-up period was considered to be due to any cause other than tuberculous meningitis
Notes	Location: Egypt Date: 1982 to 1987 Trialists: United States Naval Medical Research Unit No. 3, Cairo, Egypt; no collaborators 160/280 cerebrospinal fluid culture positive for M. tuberculosis

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Kumarvelu 1994

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Methods	Generation of allocation sequence: pre-designed chart Allocation concealment: unclear Blinding: none Inclusion of all randomized participants in analysis: 87.24% (6/47 lost to follow up) Length of follow up: 3 months
Participants	Number: 47 randomized Description: age > 12 years; both sexes; clinically diagnosed tuberculous meningitis (meeting any 3 of the following 4 criteria: (1) fever, headache, neck stiffness for 2 weeks; (2) cerebrospinal fluid profile of > 20 cells/mm3 predominantly lymphocytes, protein > 1 g/L, and sugar < 2/3 of corresponding blood sugar with no malignant cells on cytological examination and bacteria/fungi on culture; (3) head contrast-enhanced CT showing basal exudates or hydrocephalus; and (4) clinical, radiological, or histological evidence of extracranial tuberculosis); all stages of severity and all duration of disease included
Interventions	1. Antituberculous treatment plus dexamethasone 2. Antituberculous treatment alone Antituberculous treatment: rifampicin (450 mg), isoniazid (300 mg), and pyrazinamide (1500 mg) all oral daily; for those weighing < 30 kg 15 mg/kg, 10 mg/kg, and 30 mg/kg respectively Duration of treatment: 1 year Dexamethasone: intravenous 16 mg/day in 4 divided doses for 7 days, then oral tablet 8 mg/day for 21 doses
Outcomes	1. Death at 3 months 2. Major sequelae (totally dependent for activities of daily living) at 3 months 3. Minor sequelae (activities of daily living with no or minimal assistance) at 3 months 4. Adverse effects Not included in review: 5. Time to recover from altered sensorium, from fever, and from headache
Notes	Location: India Date: March 1991 to March 1992 Trialists: Deptartment of Neurology, All India Institute of Medical Sciences, New Delhi, India; no collaborators Number cerebrospinal fluid culture positive for M. tuberculosis not stated

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Lardizabal 1998

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Methods	Generation of allocation sequence: unclear, but randomization in blocks of 8 Allocation concealment: unclear Blinding: none Inclusion of all randomized participants in analysis: 100% Length of follow up: 2 months
Participants	Number: 58 randomized Description: ages 18 years and above; both sexes; probable tuberculous meningitis diagnosed using ASEAN Neurological Association criteria based on: (1) fever, headache, vomiting followed by altered consciousness, cranial nerve palsies, or long tract signs; (2) cerebrospinal fluid profile of lymphocyte predominance, elevated protein and reduced glucose; (3) cerebrospinal fluid negative for cryptococcal antigen plus 1 or more of the following: basilar/meningeal enhancement on contrast CT scanning, active pulmonary disease, positive purified protein derivative (PPD), history of contact with tuberculosis; confirmed tuberculous meningitis based on positive cerebrospinal fluid culture and/or microscopy; only patients with British MRC stages II and III disease included; HIV testing not mentioned
Interventions	1. Antituberculous treatment plus dexamethasone 2. Antituberculous treatment alone Antituberculous treatment: rifampicin (10 to 15 mg/kg/day), isoniazid (5 to 10 mg/kg/day), pyrazinamide (15 to 30 mg/kg/day), and ethambutol (15 to 20 mg/kg/day) for the first 2 months; thereafter, rifampicin and isoniazid only for 10 months; total treatment duration 12 months; route of administration not stated Dexamethasone: 16 mg/day for 3 weeks (first 5 days intravenous thereafter orally or via nasogastric tube); after 3 weeks corticosteroid was tapered by 4 mg decrements every 5 days An H2-antagonist (famotidine or ranitidine) was given during the period of corticosteroid administration
Outcomes	1. Death on days 15, 30, and 60 post-randomization 2. Functional independence assessed by attending doctor on admission and 60 days after randomization: Functional Independence Measure (FIM) used assesses self care, sphincter control, mobility, locomotion, and social cognition on a 7-point scale 3. Potential adverse reactions to corticosteroids including weakness, oedema, hypertension, euphoria, psychosis, epigastric discomfort, cushingoid facies, hirsutism, acne, insomnia, and increased appetite
Notes	Location: Philippines Date: November 1996 to July 1997 Trialists: University of Philippines, College of Medicine; no collaborators We contacted the trial authors to determine the number of deaths in participants with stage II and III disease Number cerebrospinal fluid culture positive for M. tuberculosis not stated

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O'Toole 1969

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Methods	Generation of allocation sequence: random allocation Allocation concealment: unclear Blinding: double, using placebo injections and tablets Inclusion of all randomized participants in analysis: no mention of losses to follow up Length of follow up: unclear
Participants	Number: 23 randomized Description: all ages; both sexes; eligibility criteria not mentioned, but 16/23 participants had either smear (2) or culture (9), or both smear and culture (5) positive for tubercle bacillus; remaining 7 participants had clinical features consistent with the diagnosis of tuberculous meningitis and cerebrospinal fluid profile consisting of elevated white cell count and protein, decreased glucose, and negative India ink smear for cryptococcus; authors intended to include only moderately advanced (stage II) and severe (stage III) cases, but 1 case of stage I was entered in the treatment group
Interventions	1. Antituberculous treatment plus dexamethasone 2. Antituberculous treatment alone Antituberculous treatment: isoniazid intramuscular or oral (10 mg/kg/day, except in children < 2 years of age who received 20 mg/kg/day) and streptomycin (20 mg/kg/day, maximum 1 g) Dexamethasone: given for up to 4 weeks in an adult dose of 9 mg/day during the first week, 6 mg/day during the second week, 3 mg/day during the third week, and 1.5 mg/day during the fourth week; dose for children was calculated according to their body surface area (no more details available)
Outcomes	1. Death at the end of follow up (duration not clear) 2. Number with elevated cerebrospinal fluid opening pressure on days 1, 4, 7, 14 3. Cerebrospinal fluid sugar, protein, and cell count on days 1, 4, 7, 14, 21, and 28 in decreasing number of participants, depending apparently on the surviving number. Number with residual deficits not given. Surviving participants all been described as "significantly improved" 4. Adverse events recorded: upper gastrointestinal bleed, invasive bacterial infection, hypoglycaemia, and hypothermia Not included in the review: 5. Resolution of cerebrospinal fluid findings
Notes	Location: Calcutta, India Date: February 1966 to March 1967 Trialists: Calcutta School of Tropical Medicine and the Infectious Disease Hospital, Calcutta, India, in collaboration with Johns Hopkins University, Baltimore, USA

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Schoeman 1997

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Methods	Generation of allocation sequence: random allocation Allocation concealment: unclear Blinding: assessors only; blinded disability assessment Inclusion of all randomized participants in analysis: 95.04% (apparently, the losses to follow up were 3/70 in the treatment group and 4/71 in the control group as evident from table 4 of the report) Length of follow up: 6 months
Participants	Number: 141 randomized Description: children; both sexes; clinically diagnosed tuberculous meningitis fulfilling the following criteria of history and cerebrospinal fluid suggestive of tuberculous meningitis with any 2 or more of a strongly positive (> 15 mm) Mantoux test, chest x-ray suggesting tuberculosis or CT of head showing basal enhancement and acute hydrocephalus; only stage II and III included
Interventions	1. Antituberculous treatment plus prednisolone 2. Antituberculous treatment alone Antituberculous treatment: isoniazid (20 mg/kg/day), rifampicin (20 mg/kg/day), ethionamide (20 mg/kg/day), and pyrazinamide (40 mg/kg/day) for 6 months Prednisolone: given to first 16 participants in a dose of 2 mg/kg/day and to the remaining 54 participants in a dose of 4 mg/kg/day (once in the morning); decision to double the dose after the first 16 participants was taken when the authors became aware of a study that showed that rifampicin decreased the bioavailability of prednisolone by 66% and increased the plasma clearance of the drug by 45%; trial authors reported the outcome of both the dose groups together and mentioned that the mortality or morbidity between the 2 prednisolone dosage groups did not differ significantly
Outcomes	1. Deaths at 6 months 2. Disability (mild and severe) at 6 months 3. Serious side effects Not included in review: 4. Baseline and pulse pressure of lumbar cerebrospinal fluid 5. Changes in ventricular size in CT 6. Proportion of participants with successful treatment of raised intracranial pressure 7. Proportion of participants with basal ganglia infarcts, tuberculomas, meningeal enhancement, and enlarged subarachnoid spaces
Notes	Location: South Africa Date: not mentioned Trialists: Department of Paediatrics and Child Health, Faculty of Medicine, University of Stellenbosch and Tygerberg, South Africa, in collaboration with CERSA, Division of Biostatistics, Medical Research Council, Parow-Valley, South Africa 23/141 cerebrospinal fluid culture positive for M. tuberculosis

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Thwaites 2004

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Methods	Generation of allocation sequence: computer-generated sequence of random numbers used to allocate treatment in blocks of 30 Allocation concealment: numbered individual treatment packs containing the study drug prepared for duration of treatment and distributed for sequential use once a patient fulfilled the entry criteria Blinding: using matching placebo; blinded disability assessment; participants, enrolling physicians, and investigators Inclusion of all randomized participants in analysis: 98.17% (5/271 lost to follow up) Length of follow up: 9 months; post-randomization follow up of 28 to 442 days (median 274 days)
Participants	Number: 545 randomized Description: age > 14 years; both sexes; clinically diagnosed meningitis (defined as combination of nuchal rigidity and cerebrospinal fluid abnormalities); tuberculous meningitis defined as "definite" if acid-fast bacilli were seen in cerebrospinal fluid, "probable" if >/-1 of following present: suspected active pulmonary tuberculosis on chest radiography, acid-fast bacilli in any specimen other than cerebrospinal fluid, clinical evidence of extrapulmonary tuberculosis, and "possible" if at least 4 of the following were present: history of tuberculosis, predominance of lymphocytes in cerebrospinal fluid, duration of illness > 5 days, radio of cerebrospinal fluid to plasma glucose < 0.5, altered consciousness, yellow cerebrospinal fluid, or focal neurological signs Exclusion criteria: contraindication to corticosteroids; received > 1 dose of any corticosteroid or > 30 days of antituberculous chemotherapy immediately before study
Interventions	1. Antituberculous treatment plus dexamethasone 2. Antituberculous treatment plus placebo Antituberculous treatment: 1. For previously untreated patients: oral isoniazid (5 mg/kg), rifampicin (10 mg/kg), pyrazinamide (25 mg/kg, maximum, 2 g/day), and intramuscular streptomycin (20 mg/kg, maximum 1 g/day) for 3 months followed by 6 months of isoniazid, rifampicin, and pyrazinamide at the same daily doses; ethambutol (20 mg/kg; maximum 1.2/day) substituted for streptomycin in HIV-positive participants and was added to the regimen for 3 months for participants previously treated for tuberculosis 2. Grade II and III disease: intravenous dexamethasone sodium phosphate given 0.4 mg/kg/day for week 1, 0.3 mg/kg/d for week 2, 0.2 mg/kg/d for week 3, and 0.1 mg/kg/day for week 4, and then oral dexamethasone for 4 weeks decreasing by 1 mg each week 3. Grade I disease: intravenous dexamethasone sodium phosphate 0.3 mg/kg/day for week 1 and 0.2 mg/kg/day for week 2 followed by 4 weeks of oral dexamethasone (0.1 mg/kg/day for week 3 then a total of 3 mg/day, decreasing by 1 mg each week)
Outcomes	Assessed at 9 months post-randomization 1. Death or severe disability 2. Adverse events: hepatitis; gastrointestinal bleeding, bacterial sepsis, septic shock, brain herniation, syndrome, decreased visual acuity, hyponatraemia, hyperglycaemia, hypertension, vertigo, deafness, cushingoid features, pruritis, polyarthralgia, streptomycin, reaction, rifampicin flu, rash, and others Not included in review: 3. Coma clearance time 4. Fever clearance time 5. Time to discharge 6. Time to relapse 7. Presence of focal neurological deficit (9 months post-randomization)
Notes	Location: Vietnam Date: April 2001 to March 2003 Trialists: Oxford University Clinical Research Unit at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, and Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam, in collaboration with Centre for Tropical Medicine, Nuffield, and Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK 187/545 acid-fast stain/culture positive for M. tuberculosis

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 CT: computerized tomography; HIV: human immunodeficiency virus; MRC: Medical Research Council; M. tuberculosis: Mycobacterium tuberculosis.

 

Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Donald 2004	Perspective article with no original data
Escobar 1975	Not a randomized study. The report says that a pair of participants matched for age and neurological status was administered differential therapy in a double-blind fashion. However, it is unclear if this differential administration was random
Freiman 1970	Case series
Girgis 1983	Patients allocated to steroid or non-steroid group on alternate basis; unclear why there is a difference of 4 in the number of participants in the 2 groups (non-steroid 70 and steroid 66)
Hockaday 1966	Case series
Kalita 2001	Study with historical controls, not a randomized study
Kapur 1969	Case series
Karak 1998	Commentary on an included trial (Schoeman 1997)
Lepper 1963	Not truly randomized: the first half of the study was an alternate patient design, whereas in the last half, patients were randomized by using random numbers
Marras 2005	Letter to editor with no original data
Quagliarello 2004	Editorial
Seligman 2005	Letter to the editor with no original data
Vagenakis 2005	Letter to the editor with no original data
Voljavec 1960	Comparison cohort with historical controls
Wasz-Hockert 1963	Control trial using historical controls
Weiss 1965	Retrospective case series of 102 cases

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Characteristics of ongoing studies [ordered by study ID]

Prasad 2006

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Trial name or title	A randomized controlled trial to study the effectiveness of dexamethasone as an adjunct to standard antituberculous treatment in patients with clinically presumed tuberculous meningitis: 10-year follow-up study
Methods	Randomized controlled trial
Participants	Adults, both sexes, clinically presumed tubercular meningitis based on validated criteria
Interventions	1. Antituberculous treatment plus dexamethasone 2. Antituberculous treatment plus placebo Antituberculous treatment (for previously untreated patients): oral isoniazid (5 mg/kg bodyweight), rifampicin (10 mg/kg bodyweight), pyrazinamide (25 mg/kg bodyweight, maximum, 1.5 g/day), and ethambutol (20 mg/kg; maximum 1 g/day) for 12 months
Outcomes	Treatment success defined as resolution of meningitic symptoms and category 1 or 2 of modified Glasgow Outcome Scale
Starting date	February 1996
Contact information	Prof K Prasad Room 704, Neurosciences Centre AIIMS, New Delhi-110029
Notes	—

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Comparison 1. Any corticosteroid vs control

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death	7	1140	Risk Ratio (M-H, Fixed, 95% CI)	0.78 [0.67, 0.91]
2 Death or disabling residual neurological deficit	3	720	Risk Ratio (M-H, Fixed, 95% CI)	0.82 [0.70, 0.97]

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Comparison 2. Any corticosteroid vs control: stratified by severity

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 Death

6

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

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1.1 Stage I (mild)

4

197

Risk Ratio (M-H, Fixed, 95% CI)

0.52 [0.30, 0.89]

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1.2 Stage II (moderately severe)

5

441

Risk Ratio (M-H, Fixed, 95% CI)

0.73 [0.56, 0.97]

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1.3 Stage III (severe)

6

330

Risk Ratio (M-H, Fixed, 95% CI)

0.70 [0.54, 0.90]

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Comparison 3. Any corticosteroid vs control: stratified by HIV status

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 Death

1

534

Risk Ratio (M-H, Fixed, 95% CI)

0.82 [0.66, 1.02]

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1.1 HIV positive

1

98

Risk Ratio (M-H, Fixed, 95% CI)

0.90 [0.67, 1.20]

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1.2 HIV negative

1

436

Risk Ratio (M-H, Fixed, 95% CI)

0.78 [0.58, 1.06]

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 2 Death or disabling residual neurological deficit

1

545

Risk Ratio (M-H, Fixed, 95% CI)

0.91 [0.76, 1.09]

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2.1 HIV positive

1

98

Risk Ratio (M-H, Fixed, 95% CI)

0.90 [0.68, 1.20]

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2.2 HIV negative

1

447

Risk Ratio (M-H, Fixed, 95% CI)

0.91 [0.74, 1.14]

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Table 1. Effect of different control group experimental event rates on the number needed to treat

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Control event rate	Risk ratio	Experimental event rates	Number needed to treat
20%	0.8	16%	25
30%	0.8	24%	17
40%	0.8	32%	13
50%	0.8	40%	10
60%	0.8	48%	9
80%	0.8	64%	7

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Table 2. Classification of residual neurological deficits

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Trial	Disabling	Non-disabling
Kumarvelu 1994	Major sequelae	Minor sequelae
Schoeman 1997	Severe disability	Healthy and mild disability
Thwaites 2004	Severe disability	Intermediate and good outcome

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Table 3. Risk of bias assessment

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Trial	Allocation sequence generation	Allocation concealment	Blinding	Inclusion^a
Chotmongkol 1996	Unclear	Unclear	Participants, enrolling physicians, and assessors	Adequate
Girgis 1991	Unclear	Unclear	None	Unclear
Kumarvelu 1994	Unclear	Unclear	None	Inadequate
Lardizabal 1998	Unclear	Unclear	None	Adequate
O'Toole 1969	Unclear	Unclear	Participants and enrolling physicians	Unclear
Schoeman 1997	Unclear	Unclear	Assessors	Adequate
Thwaites 2004	Adequate	Adequate	Participants, enrolling physicians, and investigators	Adequate

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 ^aInclusion of all randomized participants in the analysis.

 

Table 4. Length of follow up vs number of deaths

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Trial	Follow up (months)	Corticosteroids: n/N	Corticosteroids: %	Control: n/N	Control: %	Overall: %
Chotmongkol 1996	16 to 45	5/29	17%	2/30	7%	12%
Girgis 1991	24	72/145	50%	79/135	59%	54%
Kumarvelu 1994	3	5/20	25%	7/21	33%	29%
Lardizabal 1998	2	4/29	14%	6/29	21%	17%
O'Toole 1969	—	6/11	55%	9/12	75%	65%
Schoeman 1997	6	4/67	6%	13/67	19%	13%
Thwaites 2004	9	87/274	32%	112/271	41%	36%

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 n/N: number of deaths/number of participants.

 

Table 5. Adverse events reported in O'Toole 1969 and Thwaites 2004

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Trial	Event	Corticosteroid: n/N^a	Control: n/N^b
O'Toole 1969	Gastrointestinal bleeding	5	5
—	Glycosuria	1	0
—	Infections	2	5
—	Hypothermia	5	1
Thwaites 2004: "severe"	Hepatitis (severe)	0	8
—	Gastrointestinal bleeding (severe)	2	3
—	Bacterial sepsis (severe)	3	4
—	Hyperglycaemia (severe)	0	0
Thwaites 2004: other	Subclinical hepatitis	0	0
—	Septic shock	3	0
—	Brain herniation syndrome	1	4
—	Decrease in visual acuity	6	8
—	Hyponatraemia	1	6
—	Hypertension	0	0
—	Vertigo	0	0
—	Deafness	3	3
—	Cushing's features	0	0
—	Pruritis	0	0
—	Polyarthralgia	0	0
—	Streptomycin reaction	0	0
—	Rifampicin flu	0	0
—	Rash	1	0

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 ^aO'Toole 1969: episodes/11 participants in arm; Thwaites 2004: no. with event/274 participants in study.
^bO'Toole 1969: no. with event/274 participants in study arm; Thwaites 2004: no. with event/271 participants in study arm.