- Email: [email protected]
High dose versus low dose steroids in children with tuberculous meningitis
Journal of Clinical Neuroscience 21 (2014) 761–764
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
High dose versus low dose steroids in children with tuberculous meningitis Ira Shah ⇑, Lalit Meshram Pediatric TB Clinic, B.J. Wadia Hospital for Children, Mumbai 400012, Maharashtra, India
a r t i c l e
i n f o
Article history: Received 8 November 2012 Accepted 13 July 2013
Keywords: Children Outcome Steroids Tuberculous meningitis
a b s t r a c t Guidelines for the best steroid dose in children with tuberculous meningitis (TBM) have not been established. We enrolled 63 children with TBM and divided them into three steroid dose groups: Group 1 (prednisolone 2 mg/kg/day over 4 weeks), Group 2 (prednisolone 4 mg/kg/day over 1 week and 2 mg/ kg/day for the next 3 weeks) and Group 3 (prednisolone 4 mg/kg/day over 4 weeks). All patients received standard antituberculous therapy. Optic atrophy, tuberculoma, hydrocephalus, mental retardation, spasticity, hearing impairment, vasculitis and mortality outcomes were compared. Optic atrophy was higher in Group 3 compared to Group 1 (odds ratio [OR] = 2.8) and Group 2 (OR = 2.8), although Group 3 had a high incidence of optic atrophy at diagnosis. Tuberculomas were more frequent in Group 1 (OR = 2.4) and Group 3 (OR = 3.0) as compared to Group 2. Infarcts were more common in Group 3 than in Group 1 (OR = 1.9) and in Group 2 (OR = 3.5). Hearing loss was higher in Group 2 as compared to Group 1 (OR = 2.88) and Group 3 (OR = 4.8). Evolving hydrocephalus was higher in Group 3 as compared to Group 2 (OR = 2.8) and Group 1 (OR = 3.1). Mental retardation was higher in children in Group 3 (OR = 1.6) and in Group 2 (OR = 1.9) as compared to Group 1. Spasticity was higher in Group 3 (OR = 2.0) and in Group 2 (OR = 1.4) as compared to Group 1. There was no difference in mortality between the groups. We conclude that prednisolone at a dose of 4 mg/kg/day for 1 week followed by 2 mg/kg/day for 3 weeks is associated with fewer tuberculomas and infarcts but a higher incidence of hearing loss. A prolonged period of high dose steroids increases the risk of optic atrophy and hydrocephalus. Prednisolone at a dose of 2 mg/kg/day is associated with lower risk of mental retardation and spasticity. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
2. Methods and materials
The incidence of tuberculous meningitis (TBM) varies from 1–4% of total in-patient admissions across India [1,2]. The reported mortality rate in TBM is 15–75% [1,2]. Adverse sequelae occur in 10–85% of patients [3,4]. These include mental retardation, epilepsy, neurological deficit in the form of hemiplegia, quadriplegia, cranial nerve palsy (commonly cranial nerves VII, III and VI), blindness, deafness, behavioural problems, hydrocephalus, and hypothalamic disturbances in the form of precocious puberty and diabetes insipidus [2]. Though the beneficial effects of steroids have been documented in TBM, to our knowledge there is no direct evidence to guide selection of the dose of prednisolone to be used [5–7]. Doses of steroids in studies have varied from 1 mg/kg/day to 4 mg/kg/day for intervals of 3–4 weeks [7–9]. Our study evaluated the efficacy of steroids in various doses and durations in TBM patients.
This randomised study was conducted between 2009–2011 after attaining approval from the Institutional Ethics Committee to evaluate the beneficial effects and side effects of three different dosages of prednisolone in TBM. Patients between the ages of 4 months and 14 years with TBM who were admitted to our hospital from May 2009 to May 2011 were included and randomized into three groups after initial dexamethasone (0.15 mg/kg/ dose 8 hourly for 5 days) by a blinded health care worker randomly picking up chits of Group 1, Group 2 or Group 3. Group 1 received prednisolone of 2 mg/kg/day over 4 weeks which was then tapered over the next 4 weeks. Group 2 received prednisolone of 4 mg/k/ day over 1 week and 2 mg/k/day for the next 3 weeks which was then tapered over the next 4 weeks. Group 3 received prednisolone of 4 mg/k/day over 4 weeks which was then tapered over the next 4 weeks. Diagnosis of TBM was based on the British Medical Research Council for Tuberculosis (TB) criteria [10]. The staging of TBM was based on Doerr’s criteria [11]. Baseline investigations including neurological imaging, ophthalmological examination, chest
⇑ Corresponding author. Tel.: +91 22 3290 5610. E-mail address: [email protected] (I. Shah). 0967-5868/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2013.07.021
I. Shah, L. Meshram / Journal of Clinical Neuroscience 21 (2014) 761–764
radiograph, Mantoux test using 5 tuberculin units, haemogram, and erythrocyte sedimentation rate were carried out in all patients. Cerebrospinal fluid TB culture was done if affordable. Induration of more than 10 mm was taken as a positive Mantoux test. All patients were screened for human immunodeficiency virus infection using an enzyme-linked immunosorbent assay. A detailed history was taken and all patients underwent a clinical examination. Status of Bacillus Calmette–Guérin vaccination was noted in all patients. Associated pulmonary TB was noted. All patients were treated with four-drug antituberculous therapy (ATT) in the form of isoniazid, rifampicin, pyrazinamide, and streptomycin for the initial 2 months of the study period as per the Indian Academy of Pediatrics 2010 Guidelines, followed by isoniazid and rifampicin for 10 months. Compliance was ensured with pill recall at each visit to the clinic. In patients with drug resistant TB, ATT was given as per the sensitivity report. Patients with hydrocephalus and raised intracranial pressure not responding to medical management underwent a shunt surgery or insertion of a reservoir. Repeat neurological imaging was done after 3 months of therapy to look for new changes, including an increase in the size of a previous tuberculoma or appearance of a new tuberculoma, increase in hydrocephalus, or appearance of a new infarct. All patients also underwent ophthalmological evaluation at the end of 3 months to assess for papilledema, blindness and optic atrophy. A hearing assessment was also carried out at the end of 3 months. Further neurological imaging was done as and when required if there were signs of raised intracranial pressure or to assess the size of tuberculomas in the 26 patients who had them. The follow-up period ranged from 6 months to 18 months. The mean and standard deviation follow-up duration was 10.8 ± 1.6 months in Group 1, 9.6 ± 2.0 months in Group 2 and 11.6 ± 3 months in Group 3. Neurological deficit in the form of decerebrate posturing, spasticity, dystonia, and hemiparesis were noted. Adverse effects of steroids such as hypertension, opportunistic infections, cataracts and cushingoid features were monitored and the steroid dosage was reduced if the child developed steroid toxicity. Shunt complications, in the form of shunt block, infection and the need for revision surgery in each group were assessed. At the end of the ATT treatment period, patients were evaluated for visual impairment and hearing loss as well as comorbid conditions including spasticity, mental retardation and mobility. Mortality was calculated in each group. The clinical features of TBM were noted at the different stages of TBM. Baseline clinical and radiological parameters were assessed in all three groups to remove selection bias. The effect of steroid dose on outcomes such as tuberculoma, infarct, hydrocephalus, hearing impairment and visual impairment was compared using the chi-squared test or Fischer’s exact test and odds ratios (OR) calculated using the Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA) software.
3. Results A total of 63 patients with TBM were included in this study, of which 29 (46%) patients were randomised to be in Group 1, 16 (25%) were in Group 2 and 18 (28%) were in Group 3 (Fig. 1). The baseline clinical, laboratory and radiological features were similar in all three groups (Table 1). The clinical and radiological outcomes of all patients in the three groups are depicted in Table 2. Optic atrophy was higher in Group 3 compared to Group 1 (OR = 2.78) and Group 2 (OR = 2.75). Incidence of new tuberculoma and worsening of existing tuberculomas was higher in Group 1 compared to Group 2 (OR = 2.4), and higher in Group 3 compared to Group 2
60 50 40 Group1
30
Group2
20
Group3
10 0 Tu be rc ul om a Hy dr oc ep ha lu s co St m er pl oid ica o n Op c at ro ph y He ar in gl os s
762
Fig. 1. Outcome of the three groups of paediatric tuberculous meningitis patients, treated with different prednisolone regimens. (This figure is available in colour at www.sciencedirect.com)
Table 1a Baseline clinical, radiological and laboratory profiles in the three groups of paediatric tuberculous meningitis patients, treated with different prednisolone regimens
Male:Female Fever Altered sensorium Convulsion Headache TBM stage I II III Focal neurological deficit Dystonia Decerebrate posturing Optic atrophy Hydrocephalus Tuberculoma Infarct BCG scar Positive Mantoux test Associated pulmonary TB
Group 1
Group 2
Group 3
p value
13:16 25 (86.2%) 17 (58.6%) 20 (68.9%) 8 (27.6%)
8:8 16 (100%) 14 (87.5%) 8 (50%) 5 (31.3%)
7:11 17 (94.4%) 13 (72.2%) 10 (55.5%) 2 (11.1%)
0.8 0.2 0.1 0.4 0.3 0.8
2 (6.9%) 12 (41.4%) 15 (51.7%) 11 (37.9%) 6 (20.7%) 5 (17.2%) 3 (10.3%) 18 (62.1%) 13 (44.8%) 7 (24.1%) 24 (82.7%) 13 (44.8%) 7 (24.1%)
1 (6.2%) 6 (37.5%) 9 (56.3%) 5 (31.2%) 5 (31.2%) 3 (18.7%) 1 (6.2%) 14 (87.5%) 3 (18.7%) 6 (37.5%) 10 (62.5%) 9 (56.2%) 6 (37.5%)
0 7 (38.9%) 11 (61.1%) 9 (50%) 3 (16.7%) 1 (5.5%) 5 (27.8%) 11 (61.1%) 8 (44.4%) 5 (27.8%) 16 (88.9) 14 (77.8%) 6 (33.3%)
0.5 0.5 0.4 0.1 0.1 0.2 0.6 0.1 0.08 0.6
All data are presented as n (%) unless otherwise stated. BCG = Bacillus Calmette-Guérin, TB = tuberculosis, TBM = tuberculous meningitis.
(OR = 3.0), but was similar in Group 1 and 3 (OR = 0.8). New infarcts were seen more in Group 3 than in Group 1 (OR = 1.9) and Group 2 (OR = 3.5). However, the OR of infarcts was higher in Group 1 compared to Group 2 (OR = 1.82). Hearing loss was higher in Group 2 as compared to Group 1 (OR = 2.88) and as compared to Group 3 (OR = 4.8). Evolving hydrocephalus was higher in Group 3 than in Group 2 (OR = 2.75) and in Group 1 (OR = 3.05). Incidence of mental retardation was higher in children in Group 3 as compared to Group 1 (OR = 1.57) and in children in Group 2 as compared to Group 1 (OR = 1.88). Spasticity was higher in Group 3 as compared to Group 1 (OR = 2) and in Group 2 as compared to Group 1 (OR = 1.4). There was no difference in mortality between the three groups. Six children (9.5%) had drug induced hepatitis during the study period, of which four children received steroids at 2 mg/kg/day, and two received steroids at 4 mg/kg/day (one each in Group 2 and Group 3). All six patients had to be administered ofloxacin, streptomycin, ethambutol while rifampicin, isoniazid and pyrazinamide were stopped until the hepatitis resolved. Five children had multidrug resistant TB and one child had extensively drug resistant TB. Two of these patients were in Group 1, three were in Group 2 and one was in Group 3.
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I. Shah, L. Meshram / Journal of Clinical Neuroscience 21 (2014) 761–764 Table 1b Baseline clinical, radiological and laboratory profiles in the three groups of paediatric tuberculous meningitis patients, treated with different prednisolone regimens
Age (years) Duration of fever (days) ATT duration (months) CSF protein (mg/dl) CSF sugar (mg/dl) CSF polymorphs (%) CSF lymphocytes (%)
Group 1 (mean ± SD)
Group 2 (mean ± SD)
Group 3 (mean ± SD)
p value
3.7 ± 2.8 16.1 ± 14.7 10.8 ± 1.6 94.3 ± 41.1 44.5 ± 23.1 13.9 ± 18.3 87.3 ± 17
3.1 ± 2.9 19.3 ± 17 9.6 ± 2.0 92 ± 34.4 39.8 ± 23.3 18.9 ± 29.9 79.7 ± 29.6
3.3 ± 3 36.4 ± 46.3 11.6 ± 3 96.6 ± 29.6 53.8 ± 43.8 9.4 ± 9.9 76.5 ± 33.7
0.7 0.07 0.03 0.9 0.4 0.4 0.3
ATT = antituberculous therapy, CSF = cerebrospinal fluid, SD = standard deviation.
Table 2 Radiological and clinical outcomes in the three groups of paediatric tuberculous meningitis patients, treated with different prednisolone regimens
Shunt complication Tuberculoma, new/increase Hydrocephalus, new/increase New CNS infarct Follow-up Recovered Disabled Died Steroid complication Optic atrophy Hearing loss Spasticity Mental retardation
Group 1
Group 2
Group 3
p value
1 4 5 6
(3.44%) (13.8%) (17.24%) (21%)
2 1 3 2
(12.5%) (6.25%) (18.8%) (12.5%)
1 3 7 6
0.48 0.64 0.2 0.33 0.635
17 (58.6%) 11 (38%) 1 (3.45%) 4 (13.8%) 9 (31.03%) 5 (17.24%) 7 (24.1%) 7 (24%)
7 8 1 0 5 6 5 6
(43.75%) (50%) (6.25%)
7 (38.9%) 9 (50%) 2 (11.1%) 6 (33.3%) 10 (55.56%) 2 (11.1%) 7 (38.9%) 6 (33%)
4. Discussion Corticosteroids are commonly used in addition to ATT for treating TBM. They reduce swelling and congestion of the meninges and thus decrease intracranial pressure and the attendant risk of death or disabling residual neurological deficit among survivors. A Cochrane analysis of randomised controlled trials found that corticosteroids reduce the risk of death (relative risk = 0.78) or disabling residual neurological deficit (relative risk = 0.82) [12]. Although prednisolone has been used at the dose of 2 mg/kg/ day for 4 weeks there have been reports of prednisone being used at a dose of 4 mg/kg/day for the first 4 weeks of treatment, which was found to significantly decrease the incidence of new tuberculomas, decrease basal enhancement and also reduce mortality in Stage III as per Doerr’s criteria for TBM [8,9]. A study by Shah et al. in seven children with TBM found that patients given prednisolone at 4 mg/kg/day for 1 week had no new tuberculoma on follow-up [13]. In our study, we found that prednisolone at 4 mg/ kg/day for 1 month had no additional benefit in terms of prevention of hydrocephalus or in decreasing the incidence of new tuberculomas, new infarcts, mortality and morbidity over a period of 3 months. In our study we did find that prednisolone at a dose of 4 mg/kg/day for 1 week followed by 2 mg/kg/day for the next 3 weeks and then tapering, was associated with a lesser incidence of tuberculomas and new infarcts, though hearing loss was higher in these patients (Group 2). Optic atrophy increased from 10.3% at baseline to 31% in Group 1 during the study period, from 6.2% to 31.3% in Group 2 and from 27.8% to 55.6% in Group 3. Though development of subsequent optic atrophy in all patients was not statistically significantly different between the three patient groups, it was found that that incidence of optic atrophy was higher in patients who received high dose steroids for a longer time (Group 3) as compared to those who received steroids for a shorter time (Group 2) and at the lower dose of 2 mg/kg/day (Group 1). Since visual impairment in TBM is not immunological, prolonged treatment with high dose steroids in TBM patients may not be beneficial. Brainstem auditory evoked
(31.25%) (37.5%) (31.25%) (37%)
(5.5%) (16.7%) (38.9%) (33.3%)
0.027 0.2 0.137 0.56 0.6
response abnormalities have been reported in 56% of children with TBM. The cause of brainstem auditory evoked response abnormalities could be multifactorial. Bilateral and unilateral absent response may be due to involvement of cranial nerve VIII due to basal exudates, toxic effects and vascular involvement. Early institution of dexamethasone has been associated with significant reduction in severe hearing loss [14]. In our study we found that hearing loss was seen less frequently in children who had taken high dose steroids for a longer time (Group 3). Prednisolone in doses of 2 mg/kg/day for 4 weeks (Group 1) was associated with a lower rate of mental retardation and spasticity in our study. This may be related to the lesser degree of immunosuppression that the patient would experience during the intensive phase of ATT. Mortality and morbidity in TBM remains high even with current treatment regimens, and many survivors develop serious neurological sequelae necessitating long-term care. A study by Escobar et al. found that the mortality rate in steroid groups (both a low dose of 1 mg/kg/day and high dose of 10 mg/kg/day over 30 days) was low but there was no difference between the two groups in terms of neurological sequelae [7]. Similarly in South Africa it was seen that high dose steroids (4 mg/kg/day) did not significantly decrease the incidence of permanent motor deficit, raised intracranial pressure, or incidence of basal ganglia infarction, as compared to the lower dose of prednisolone 2 mg/kg/day [8]. Ten patients suffered complications related to steroid treatment in our study, of which six patients (60%) were on high dose steroids for a longer time (Group 1 = four patients, Group 3 = six patients). Common complications seen were hypertension, cushingoid features and infection. Our study limitations include the small number of patients and the lack of a control group of patients not on steroids during therapy. In conclusion, prednisolone at 4 mg/kg/day for 1 month does not offer any benefit in patients with TBM and can in fact be detrimental due to an increased risk of optic disturbances and adverse effects from steroid treatment. However, prednisolone at 4 mg/kg/
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day for 1 week decreases the incidence of new tuberculomas and new infarcts on follow-up at 3 months. This finding needs to be confirmed in further studies. Mortality of patients with TBM does not vary with dose or duration of steroids. Conflicts of interest/disclosure The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Khatua SP. Tuberculous meningitis in children; analysis of 231 cases. J Indian Med Assoc 1961;37:332–7. [2] Benakappa DG, Chandrasekhar SK, Chandrasekhar P, et al. Tuberculous meningitis: review of 50 cases. Indian Pediatr 1975;12:1161–7. [3] Udani PM, Parekh UC, Dastur DK. Neurological and related syndromes in CNS tuberculosis. Clinical features and pathogenesis. J Neurol Sci 1971;14:341–57. [4] Ramachandran RS, Ramanathan K, Indra G. Tuberculous meningitis. A review of 288 cases in children. Indian J Pediatr 1970;37:85–8.
[5] Kent SJ, Crowe SM, Yung A, et al. Tuberculous meningitis: a 30-year review. Clin Infect Dis 1993;17:987–94. [6] Girgis NI, Farid Z, Kilpatrick ME, et al. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991;10:179–83. [7] Escobar JA, Belsey MA, Dueñas A, et al. Mortality from tuberculous meningitis reduced by steroid therapy. Pediatrics 1975;56:1050–5. [8] Schoeman JF, Van Zyl LE, Laubscher JA, et al. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics 1997;99:226–31. [9] Karak B, Garg RK. Corticosteroids in tuberculous meningitis. Indian Pediatr 1998;35:193–4. [10] Thwaites G, Fisher M, Hemingway C, et al. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect 2009;59:167–87. [11] Doerr CA, Starke JR, Ong LT. Clinical and public health aspects of tuberculous meningitis in children. J Pediatr 1995;127:27–33. [12] Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008;1:CD002244. [13] Shah I. Steroid therapy in children with tuberculous meningitis. Scand J Infect Dis 2009;41:532–4. [14] Malhotra HS, Garg RK, Singh MK, et al. Corticosteroids (dexamethasone versus intravenous methylprednisolone) in patients with tuberculous meningitis. Ann Trop Med Parasitol 2009;103:625–34.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
High dose versus low dose steroids in children with tuberculous meningitis Ira Shah ⇑, Lalit Meshram Pediatric TB Clinic, B.J. Wadia Hospital for Children, Mumbai 400012, Maharashtra, India
a r t i c l e
i n f o
Article history: Received 8 November 2012 Accepted 13 July 2013
Keywords: Children Outcome Steroids Tuberculous meningitis
a b s t r a c t Guidelines for the best steroid dose in children with tuberculous meningitis (TBM) have not been established. We enrolled 63 children with TBM and divided them into three steroid dose groups: Group 1 (prednisolone 2 mg/kg/day over 4 weeks), Group 2 (prednisolone 4 mg/kg/day over 1 week and 2 mg/ kg/day for the next 3 weeks) and Group 3 (prednisolone 4 mg/kg/day over 4 weeks). All patients received standard antituberculous therapy. Optic atrophy, tuberculoma, hydrocephalus, mental retardation, spasticity, hearing impairment, vasculitis and mortality outcomes were compared. Optic atrophy was higher in Group 3 compared to Group 1 (odds ratio [OR] = 2.8) and Group 2 (OR = 2.8), although Group 3 had a high incidence of optic atrophy at diagnosis. Tuberculomas were more frequent in Group 1 (OR = 2.4) and Group 3 (OR = 3.0) as compared to Group 2. Infarcts were more common in Group 3 than in Group 1 (OR = 1.9) and in Group 2 (OR = 3.5). Hearing loss was higher in Group 2 as compared to Group 1 (OR = 2.88) and Group 3 (OR = 4.8). Evolving hydrocephalus was higher in Group 3 as compared to Group 2 (OR = 2.8) and Group 1 (OR = 3.1). Mental retardation was higher in children in Group 3 (OR = 1.6) and in Group 2 (OR = 1.9) as compared to Group 1. Spasticity was higher in Group 3 (OR = 2.0) and in Group 2 (OR = 1.4) as compared to Group 1. There was no difference in mortality between the groups. We conclude that prednisolone at a dose of 4 mg/kg/day for 1 week followed by 2 mg/kg/day for 3 weeks is associated with fewer tuberculomas and infarcts but a higher incidence of hearing loss. A prolonged period of high dose steroids increases the risk of optic atrophy and hydrocephalus. Prednisolone at a dose of 2 mg/kg/day is associated with lower risk of mental retardation and spasticity. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
2. Methods and materials
The incidence of tuberculous meningitis (TBM) varies from 1–4% of total in-patient admissions across India [1,2]. The reported mortality rate in TBM is 15–75% [1,2]. Adverse sequelae occur in 10–85% of patients [3,4]. These include mental retardation, epilepsy, neurological deficit in the form of hemiplegia, quadriplegia, cranial nerve palsy (commonly cranial nerves VII, III and VI), blindness, deafness, behavioural problems, hydrocephalus, and hypothalamic disturbances in the form of precocious puberty and diabetes insipidus [2]. Though the beneficial effects of steroids have been documented in TBM, to our knowledge there is no direct evidence to guide selection of the dose of prednisolone to be used [5–7]. Doses of steroids in studies have varied from 1 mg/kg/day to 4 mg/kg/day for intervals of 3–4 weeks [7–9]. Our study evaluated the efficacy of steroids in various doses and durations in TBM patients.
This randomised study was conducted between 2009–2011 after attaining approval from the Institutional Ethics Committee to evaluate the beneficial effects and side effects of three different dosages of prednisolone in TBM. Patients between the ages of 4 months and 14 years with TBM who were admitted to our hospital from May 2009 to May 2011 were included and randomized into three groups after initial dexamethasone (0.15 mg/kg/ dose 8 hourly for 5 days) by a blinded health care worker randomly picking up chits of Group 1, Group 2 or Group 3. Group 1 received prednisolone of 2 mg/kg/day over 4 weeks which was then tapered over the next 4 weeks. Group 2 received prednisolone of 4 mg/k/ day over 1 week and 2 mg/k/day for the next 3 weeks which was then tapered over the next 4 weeks. Group 3 received prednisolone of 4 mg/k/day over 4 weeks which was then tapered over the next 4 weeks. Diagnosis of TBM was based on the British Medical Research Council for Tuberculosis (TB) criteria [10]. The staging of TBM was based on Doerr’s criteria [11]. Baseline investigations including neurological imaging, ophthalmological examination, chest
⇑ Corresponding author. Tel.: +91 22 3290 5610. E-mail address: [email protected] (I. Shah). 0967-5868/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2013.07.021
I. Shah, L. Meshram / Journal of Clinical Neuroscience 21 (2014) 761–764
radiograph, Mantoux test using 5 tuberculin units, haemogram, and erythrocyte sedimentation rate were carried out in all patients. Cerebrospinal fluid TB culture was done if affordable. Induration of more than 10 mm was taken as a positive Mantoux test. All patients were screened for human immunodeficiency virus infection using an enzyme-linked immunosorbent assay. A detailed history was taken and all patients underwent a clinical examination. Status of Bacillus Calmette–Guérin vaccination was noted in all patients. Associated pulmonary TB was noted. All patients were treated with four-drug antituberculous therapy (ATT) in the form of isoniazid, rifampicin, pyrazinamide, and streptomycin for the initial 2 months of the study period as per the Indian Academy of Pediatrics 2010 Guidelines, followed by isoniazid and rifampicin for 10 months. Compliance was ensured with pill recall at each visit to the clinic. In patients with drug resistant TB, ATT was given as per the sensitivity report. Patients with hydrocephalus and raised intracranial pressure not responding to medical management underwent a shunt surgery or insertion of a reservoir. Repeat neurological imaging was done after 3 months of therapy to look for new changes, including an increase in the size of a previous tuberculoma or appearance of a new tuberculoma, increase in hydrocephalus, or appearance of a new infarct. All patients also underwent ophthalmological evaluation at the end of 3 months to assess for papilledema, blindness and optic atrophy. A hearing assessment was also carried out at the end of 3 months. Further neurological imaging was done as and when required if there were signs of raised intracranial pressure or to assess the size of tuberculomas in the 26 patients who had them. The follow-up period ranged from 6 months to 18 months. The mean and standard deviation follow-up duration was 10.8 ± 1.6 months in Group 1, 9.6 ± 2.0 months in Group 2 and 11.6 ± 3 months in Group 3. Neurological deficit in the form of decerebrate posturing, spasticity, dystonia, and hemiparesis were noted. Adverse effects of steroids such as hypertension, opportunistic infections, cataracts and cushingoid features were monitored and the steroid dosage was reduced if the child developed steroid toxicity. Shunt complications, in the form of shunt block, infection and the need for revision surgery in each group were assessed. At the end of the ATT treatment period, patients were evaluated for visual impairment and hearing loss as well as comorbid conditions including spasticity, mental retardation and mobility. Mortality was calculated in each group. The clinical features of TBM were noted at the different stages of TBM. Baseline clinical and radiological parameters were assessed in all three groups to remove selection bias. The effect of steroid dose on outcomes such as tuberculoma, infarct, hydrocephalus, hearing impairment and visual impairment was compared using the chi-squared test or Fischer’s exact test and odds ratios (OR) calculated using the Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA) software.
3. Results A total of 63 patients with TBM were included in this study, of which 29 (46%) patients were randomised to be in Group 1, 16 (25%) were in Group 2 and 18 (28%) were in Group 3 (Fig. 1). The baseline clinical, laboratory and radiological features were similar in all three groups (Table 1). The clinical and radiological outcomes of all patients in the three groups are depicted in Table 2. Optic atrophy was higher in Group 3 compared to Group 1 (OR = 2.78) and Group 2 (OR = 2.75). Incidence of new tuberculoma and worsening of existing tuberculomas was higher in Group 1 compared to Group 2 (OR = 2.4), and higher in Group 3 compared to Group 2
60 50 40 Group1
30
Group2
20
Group3
10 0 Tu be rc ul om a Hy dr oc ep ha lu s co St m er pl oid ica o n Op c at ro ph y He ar in gl os s
762
Fig. 1. Outcome of the three groups of paediatric tuberculous meningitis patients, treated with different prednisolone regimens. (This figure is available in colour at www.sciencedirect.com)
Table 1a Baseline clinical, radiological and laboratory profiles in the three groups of paediatric tuberculous meningitis patients, treated with different prednisolone regimens
Male:Female Fever Altered sensorium Convulsion Headache TBM stage I II III Focal neurological deficit Dystonia Decerebrate posturing Optic atrophy Hydrocephalus Tuberculoma Infarct BCG scar Positive Mantoux test Associated pulmonary TB
Group 1
Group 2
Group 3
p value
13:16 25 (86.2%) 17 (58.6%) 20 (68.9%) 8 (27.6%)
8:8 16 (100%) 14 (87.5%) 8 (50%) 5 (31.3%)
7:11 17 (94.4%) 13 (72.2%) 10 (55.5%) 2 (11.1%)
0.8 0.2 0.1 0.4 0.3 0.8
2 (6.9%) 12 (41.4%) 15 (51.7%) 11 (37.9%) 6 (20.7%) 5 (17.2%) 3 (10.3%) 18 (62.1%) 13 (44.8%) 7 (24.1%) 24 (82.7%) 13 (44.8%) 7 (24.1%)
1 (6.2%) 6 (37.5%) 9 (56.3%) 5 (31.2%) 5 (31.2%) 3 (18.7%) 1 (6.2%) 14 (87.5%) 3 (18.7%) 6 (37.5%) 10 (62.5%) 9 (56.2%) 6 (37.5%)
0 7 (38.9%) 11 (61.1%) 9 (50%) 3 (16.7%) 1 (5.5%) 5 (27.8%) 11 (61.1%) 8 (44.4%) 5 (27.8%) 16 (88.9) 14 (77.8%) 6 (33.3%)
0.5 0.5 0.4 0.1 0.1 0.2 0.6 0.1 0.08 0.6
All data are presented as n (%) unless otherwise stated. BCG = Bacillus Calmette-Guérin, TB = tuberculosis, TBM = tuberculous meningitis.
(OR = 3.0), but was similar in Group 1 and 3 (OR = 0.8). New infarcts were seen more in Group 3 than in Group 1 (OR = 1.9) and Group 2 (OR = 3.5). However, the OR of infarcts was higher in Group 1 compared to Group 2 (OR = 1.82). Hearing loss was higher in Group 2 as compared to Group 1 (OR = 2.88) and as compared to Group 3 (OR = 4.8). Evolving hydrocephalus was higher in Group 3 than in Group 2 (OR = 2.75) and in Group 1 (OR = 3.05). Incidence of mental retardation was higher in children in Group 3 as compared to Group 1 (OR = 1.57) and in children in Group 2 as compared to Group 1 (OR = 1.88). Spasticity was higher in Group 3 as compared to Group 1 (OR = 2) and in Group 2 as compared to Group 1 (OR = 1.4). There was no difference in mortality between the three groups. Six children (9.5%) had drug induced hepatitis during the study period, of which four children received steroids at 2 mg/kg/day, and two received steroids at 4 mg/kg/day (one each in Group 2 and Group 3). All six patients had to be administered ofloxacin, streptomycin, ethambutol while rifampicin, isoniazid and pyrazinamide were stopped until the hepatitis resolved. Five children had multidrug resistant TB and one child had extensively drug resistant TB. Two of these patients were in Group 1, three were in Group 2 and one was in Group 3.
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Age (years) Duration of fever (days) ATT duration (months) CSF protein (mg/dl) CSF sugar (mg/dl) CSF polymorphs (%) CSF lymphocytes (%)
Group 1 (mean ± SD)
Group 2 (mean ± SD)
Group 3 (mean ± SD)
p value
3.7 ± 2.8 16.1 ± 14.7 10.8 ± 1.6 94.3 ± 41.1 44.5 ± 23.1 13.9 ± 18.3 87.3 ± 17
3.1 ± 2.9 19.3 ± 17 9.6 ± 2.0 92 ± 34.4 39.8 ± 23.3 18.9 ± 29.9 79.7 ± 29.6
3.3 ± 3 36.4 ± 46.3 11.6 ± 3 96.6 ± 29.6 53.8 ± 43.8 9.4 ± 9.9 76.5 ± 33.7
0.7 0.07 0.03 0.9 0.4 0.4 0.3
ATT = antituberculous therapy, CSF = cerebrospinal fluid, SD = standard deviation.
Table 2 Radiological and clinical outcomes in the three groups of paediatric tuberculous meningitis patients, treated with different prednisolone regimens
Shunt complication Tuberculoma, new/increase Hydrocephalus, new/increase New CNS infarct Follow-up Recovered Disabled Died Steroid complication Optic atrophy Hearing loss Spasticity Mental retardation
Group 1
Group 2
Group 3
p value
1 4 5 6
(3.44%) (13.8%) (17.24%) (21%)
2 1 3 2
(12.5%) (6.25%) (18.8%) (12.5%)
1 3 7 6
0.48 0.64 0.2 0.33 0.635
17 (58.6%) 11 (38%) 1 (3.45%) 4 (13.8%) 9 (31.03%) 5 (17.24%) 7 (24.1%) 7 (24%)
7 8 1 0 5 6 5 6
(43.75%) (50%) (6.25%)
7 (38.9%) 9 (50%) 2 (11.1%) 6 (33.3%) 10 (55.56%) 2 (11.1%) 7 (38.9%) 6 (33%)
4. Discussion Corticosteroids are commonly used in addition to ATT for treating TBM. They reduce swelling and congestion of the meninges and thus decrease intracranial pressure and the attendant risk of death or disabling residual neurological deficit among survivors. A Cochrane analysis of randomised controlled trials found that corticosteroids reduce the risk of death (relative risk = 0.78) or disabling residual neurological deficit (relative risk = 0.82) [12]. Although prednisolone has been used at the dose of 2 mg/kg/ day for 4 weeks there have been reports of prednisone being used at a dose of 4 mg/kg/day for the first 4 weeks of treatment, which was found to significantly decrease the incidence of new tuberculomas, decrease basal enhancement and also reduce mortality in Stage III as per Doerr’s criteria for TBM [8,9]. A study by Shah et al. in seven children with TBM found that patients given prednisolone at 4 mg/kg/day for 1 week had no new tuberculoma on follow-up [13]. In our study, we found that prednisolone at 4 mg/ kg/day for 1 month had no additional benefit in terms of prevention of hydrocephalus or in decreasing the incidence of new tuberculomas, new infarcts, mortality and morbidity over a period of 3 months. In our study we did find that prednisolone at a dose of 4 mg/kg/day for 1 week followed by 2 mg/kg/day for the next 3 weeks and then tapering, was associated with a lesser incidence of tuberculomas and new infarcts, though hearing loss was higher in these patients (Group 2). Optic atrophy increased from 10.3% at baseline to 31% in Group 1 during the study period, from 6.2% to 31.3% in Group 2 and from 27.8% to 55.6% in Group 3. Though development of subsequent optic atrophy in all patients was not statistically significantly different between the three patient groups, it was found that that incidence of optic atrophy was higher in patients who received high dose steroids for a longer time (Group 3) as compared to those who received steroids for a shorter time (Group 2) and at the lower dose of 2 mg/kg/day (Group 1). Since visual impairment in TBM is not immunological, prolonged treatment with high dose steroids in TBM patients may not be beneficial. Brainstem auditory evoked
(31.25%) (37.5%) (31.25%) (37%)
(5.5%) (16.7%) (38.9%) (33.3%)
0.027 0.2 0.137 0.56 0.6
response abnormalities have been reported in 56% of children with TBM. The cause of brainstem auditory evoked response abnormalities could be multifactorial. Bilateral and unilateral absent response may be due to involvement of cranial nerve VIII due to basal exudates, toxic effects and vascular involvement. Early institution of dexamethasone has been associated with significant reduction in severe hearing loss [14]. In our study we found that hearing loss was seen less frequently in children who had taken high dose steroids for a longer time (Group 3). Prednisolone in doses of 2 mg/kg/day for 4 weeks (Group 1) was associated with a lower rate of mental retardation and spasticity in our study. This may be related to the lesser degree of immunosuppression that the patient would experience during the intensive phase of ATT. Mortality and morbidity in TBM remains high even with current treatment regimens, and many survivors develop serious neurological sequelae necessitating long-term care. A study by Escobar et al. found that the mortality rate in steroid groups (both a low dose of 1 mg/kg/day and high dose of 10 mg/kg/day over 30 days) was low but there was no difference between the two groups in terms of neurological sequelae [7]. Similarly in South Africa it was seen that high dose steroids (4 mg/kg/day) did not significantly decrease the incidence of permanent motor deficit, raised intracranial pressure, or incidence of basal ganglia infarction, as compared to the lower dose of prednisolone 2 mg/kg/day [8]. Ten patients suffered complications related to steroid treatment in our study, of which six patients (60%) were on high dose steroids for a longer time (Group 1 = four patients, Group 3 = six patients). Common complications seen were hypertension, cushingoid features and infection. Our study limitations include the small number of patients and the lack of a control group of patients not on steroids during therapy. In conclusion, prednisolone at 4 mg/kg/day for 1 month does not offer any benefit in patients with TBM and can in fact be detrimental due to an increased risk of optic disturbances and adverse effects from steroid treatment. However, prednisolone at 4 mg/kg/
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day for 1 week decreases the incidence of new tuberculomas and new infarcts on follow-up at 3 months. This finding needs to be confirmed in further studies. Mortality of patients with TBM does not vary with dose or duration of steroids. Conflicts of interest/disclosure The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Khatua SP. Tuberculous meningitis in children; analysis of 231 cases. J Indian Med Assoc 1961;37:332–7. [2] Benakappa DG, Chandrasekhar SK, Chandrasekhar P, et al. Tuberculous meningitis: review of 50 cases. Indian Pediatr 1975;12:1161–7. [3] Udani PM, Parekh UC, Dastur DK. Neurological and related syndromes in CNS tuberculosis. Clinical features and pathogenesis. J Neurol Sci 1971;14:341–57. [4] Ramachandran RS, Ramanathan K, Indra G. Tuberculous meningitis. A review of 288 cases in children. Indian J Pediatr 1970;37:85–8.
[5] Kent SJ, Crowe SM, Yung A, et al. Tuberculous meningitis: a 30-year review. Clin Infect Dis 1993;17:987–94. [6] Girgis NI, Farid Z, Kilpatrick ME, et al. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991;10:179–83. [7] Escobar JA, Belsey MA, Dueñas A, et al. Mortality from tuberculous meningitis reduced by steroid therapy. Pediatrics 1975;56:1050–5. [8] Schoeman JF, Van Zyl LE, Laubscher JA, et al. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics 1997;99:226–31. [9] Karak B, Garg RK. Corticosteroids in tuberculous meningitis. Indian Pediatr 1998;35:193–4. [10] Thwaites G, Fisher M, Hemingway C, et al. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect 2009;59:167–87. [11] Doerr CA, Starke JR, Ong LT. Clinical and public health aspects of tuberculous meningitis in children. J Pediatr 1995;127:27–33. [12] Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008;1:CD002244. [13] Shah I. Steroid therapy in children with tuberculous meningitis. Scand J Infect Dis 2009;41:532–4. [14] Malhotra HS, Garg RK, Singh MK, et al. Corticosteroids (dexamethasone versus intravenous methylprednisolone) in patients with tuberculous meningitis. Ann Trop Med Parasitol 2009;103:625–34.