|ORIGINAL CONTRIBUTION: THERAPEUTICS IN CHILDREN
|Year : 2014 | Volume
| Issue : 1 | Page : 3-8
Early outcome of intermittent directly observed treatment- short course, for tuberculous meningitis in children: A descriptive analysis
Pooja Dewan1, Tarun Kumar Chadha1, Iqbal R Kaur2, Piyush Gupta1
1 Department of Pediatrics, University College of Medical Sciences and Guru Tegh Bahadur Hospital, Delhi, India
2 Department of Microbiology, University College of Medical Sciences and Guru Tegh Bahadur Hospital, Delhi, India
|Date of Web Publication||3-May-2014|
Assistant Professor, Department of Pediatrics, UCMS & GTB Hospital, Delhi 110 095
Source of Support: None, Conflict of Interest: None
Background: Effectiveness of intermittent short course chemotherapy for tuberculous meningitis (TBM) has not been well studied. This is particularly relevant for pediatric population where it is associated with a higher mortality and morbidity. Pediatricians are therefore reluctant to accept directly observed treatment, short course (DOTS) strategy for TBM. Aim: To evaluate the early outcome of intermittent DOTS for children with TBM registered under the Revised National TB Control Program (RNTCP) program. Materials and Methods: Children less than or 12 years of age admitted with TBM and receiving chemotherapy under the RNTCP program were recruited in this prospective observational study. We included only those children diagnosed at a tertiary care hospital between May 2008 to March 2009. Diagnostic algorithm and treatment schedule were followed as per the RNTCP guidelines. Treatment outcome and followup status were recorded up to 8 weeks from the time of starting chemotherapy. Results: A total of 30 children (10 months to 12 years of age) with TBM were included in the study. After 8 weeks of treatment, 40% (n=12) children died; all these were diagnosed with stage 3 TBM on admission. Out of the 18 survivors, nearly 50% had significant neurological morbidity (hypertonia 2, cranial neuropathy 6, visual deficit 2, optic atrophy 2, monoplegia 2, hemiplegia 5). Conclusion: The RNTCP regimen for treating TBM in children is associated with a high early mortality and significant neurological morbidity after 8 weeks of therapy under program conditions in India. There is a need to compare it with regimes of daily therapy.
Keywords: DOTS, intermittent, meningitis, morbidity, mortality, short course, tuberculosis
|How to cite this article:|
Dewan P, Chadha TK, Kaur IR, Gupta P. Early outcome of intermittent directly observed treatment- short course, for tuberculous meningitis in children: A descriptive analysis. Astrocyte 2014;1:3-8
|How to cite this URL:|
Dewan P, Chadha TK, Kaur IR, Gupta P. Early outcome of intermittent directly observed treatment- short course, for tuberculous meningitis in children: A descriptive analysis. Astrocyte [serial online] 2014 [cited 2023 Dec 1];1:3-8. Available from: http://www.astrocyte.in/text.asp?2014/1/1/3/131852
| Introduction|| |
According to the World Health Organization (WHO), India has the highest tuberculosis (TB) burden in the world. In 2011, the estimated incidence of TB in India was 2.2 million cases out of a global incidence of 8.7 million cases.  In 2011, the prevalence of TB in India was 3.1 million cases. Childhood TB often goes unrecognized because children lack access to health services or because the health workers who care for them are unprepared to recognize the signs and symptoms of TB in children. Childhood TB has been reported to account for 6% of the total cases of TB,  which may actually be an underestimate of the true burden. Among the protean manifestations of tuberculosis, tuberculous meningitis (TBM) is the most dreaded form, more so in children due to its high mortality and severe neurological sequel. TBM accounts for almost 20% of all cases of childhood TB in India.  Prompt diagnosis and treatment are crucial for the successful management of these cases.
The approach to chemotherapy has undergone significant changes in the past two decades. Short course chemotherapeutic regimens have established their place in the treatment of childhood tuberculosis due to improved compliance, high efficacy, low toxicity, and good tolerance. Intermittent chemotherapeutic regimens have also gained wide acceptance for treating tuberculosis. Although the first-line treatment for all forms of neurotuberculosis includes Isoniazid (H), Rifampicin (R), Pyrazinamide (P), and Ethambutol (E), there is no consensus yet on the frequency and duration of treatment with these drugs. Since 2003, all cases of childhood tuberculosis, including neurotuberculosis and disseminated tuberculosis, in India; are being managed according to the guidelines of the Revised National Tuberculosis Program (RNTCP) using intermittent directly observed treatment, short course (DOTS) strategy. 
Under the RNTCP, neurotuberculosis is categorized among the extrapulmonary seriously ill group, that is, Category I, recommending 2H 3 R 3 Z 3 E 3 /4H 3 R with extension of continuation phase for 3 more months (total 9 months). Although these short course intermittent treatment regimens have been validated and found to be effective against pulmonary tuberculosis (PTB) and other nonserious forms in children, ,,,,, no prospective studies are available to assess their efficacy in children with severe forms of tuberculosis, such as meningitis and miliary and disseminated tuberculosis, which may be associated with a high bacillary load.  We conducted this study to evaluate the early outcome of intermittent DOTS for TBM in children.
| Materials and Methods|| |
This prospective observational study was conducted in the Department of Pediatrics at the University College of Medical Sciences and Guru Tegh Bahadur Hospital, a tertiary hospital in Delhi. All consecutive children less than or 12 years of age admitted with a diagnosis of TBM between May 2008 and March 2009, were enrolled. Children having pre-existing neurological deficit, seizure disorder, mental retardation, cerebral palsy, chronic liver or renal disease, or co-existing HIV infection were excluded.
Diagnosis of TBM was in accordance with the Indian Academy of Pediatrics consensus statement on the diagnosis of childhood tuberculosis.  All children were subjected to a detailed clinical history and a complete physical examination. TBM was suspected based on clinical history (fever without localization for more than 2 weeks and/or altered behavior or personality, headache, vomiting, seizures), clinical examination (nuchal rigidity or positive Kernig's or Brudzinski signs, focal neurological deficit, cranial nerve palsy, dystonia, choreoathetosis, hypertonia, or hypotonia), and a history of tuberculous contact. Cerebrospinal fluid (CSF) was examined in all children suspected with TBM with respect to its gross appearance, cytology, biochemistry, and acid-fast bacilli (AFB) staining. Pleocytosis ≥ 10 cells/mm 3 , with predominance of lymphocytes, protein content ≥ 50 mg/dL, and sugar content < 40 mg/dL or less than two-thirds of the simultaneous blood sugar level were considered highly suggestive of TBM. In case of inconclusive results, the lumbar puncture was repeated after 48-72 h of antibiotic therapy. If the patient did not show any improvement in clinical condition or improved CSF picture, then it was considered in favor of a diagnosis of TBM. Presence of a reactive Mantoux test (induration ≥10 mm after 72 h) and a suggestive chest radiograph were regarded as supportive of tuberculous etiology.
Other laboratory investigations included complete hemogram, serum chemistry, namely, sugar, urea, electrolytes, serum bilirubin, serum proteins, serum glutamic-oxaloacetic transaminase, serum glutamic pyruvic transaminase, chest radiograph, and Mantoux test. Neuroimaging was done soon after admission, wherever feasible. A triad of basal exudates, thalamic infarcts, and hydrocephalus was regarded as diagnostic of TBM; presence of any tuberculomas and calcifications was also noted. An attempt was made to demonstrate mycobacteria by microscopic examination of the gastric aspirate for acid-fast bacillus or histopathological examination of enlarged lymph nodes if present. Each patient was screened for human immunodeficiency virus (HIV) infection using enzyme-linked immunosorbent assay (ELISA) test. Pre-test and Post-test counseling was offered to the parents.
The severity of disease was classified as per the Medical Research Council Guidelines.  Stage 1 (early) included children who were conscious with no neurological signs and nonspecific symptoms. Stage 2 (intermediate) included children with signs of meningeal irritation, slight or no clouding of sensorium, and with or without minor neurological deficit (cranial nerve palsy or limb paresis). Stage 3 (advanced) included children with severe impairment of consciousness, convulsions, focal neurological deficit, and/or involuntary movements. The child's level of consciousness was assessed by the Glasgow Coma Scale (GCS).
Children were treated using Revised National Tuberculosis Control Program protocol.  Children with TBM were categorized as either World Health Organization (WHO) Category I or II. Children categorized as WHO Category I received 2H 3 R 3 Z 3 E 3 + 7H 3 R 3 , whereas those categorized as WHO Category II received 2S 3 H 3 R 3 Z 3 E 3 + 1H 3 R 3 Z 3 E 3 + 5H 3 R 3 E 3 . Antituberculous therapy was provided as combination packs according to various weight bands made available through DOTS centers. All children received parenteral dexamethasone in a dose of 0.15 mg/kg every 6 h for the initial 1-2 weeks and changed to oral prednisolone, 1-2 mg/kg/day, to complete 6 weeks of steroid therapy. Supportive therapy in the form of mannitol, acetazolamide, and antiepileptic drugs (phenytoin or carbamazepine) was administered as needed. Nutritional supplementation, physiotherapy, and nursing care were provided to all children. Neurosurgical intervention was done in children with hydrocephalus and uncontrolled raised intracranial tension (ICT) despite decongestive therapy, cerebral abscess, tuberculomas with mass effect, and tuberculous spinal arachnoiditis.
Monitoring and Followup
All children were actively monitored for at least 8 weeks, of which the first 3 weeks were preferably in the hospital setting. Clinical monitoring (vital parameters, neurological status, fundus evaluation) was done on days 0, 3, 7, 14, 21, and 56. Liver and renal function tests were done at admission, 3 weeks, and 8 weeks. CSF examination was repeated after 1 week and 3 weeks of therapy. Antituberculous drugs were dispensed by the nursing staff in the hospital. On discharge, chemotherapy was provided for 1 week from the hospital pharmacy and subsequently by the nearest DOTS center. Compliance was ascertained by evaluation of DOTS records and patient diary.
Primary outcome: mortality within 8 weeks of starting antituberculous therapy. Secondary outcomes: (a) neurological morbidity (consciousness on GCS, seizures, rigidity, neurological deficit, auditory deficit), behavioral changes, raised ICT, hydrocephalus on neuroimaging, need for shunt surgery), (2) general improvement (fever clearance time, vomiting, day to start feeding, days to full feeding, duration of hospitalization), and (c) adverse effects.
An informed written consent was obtained from the parents of all the subjects. Institutional ethics clearance was also obtained prior to the study.
A standardized data entry form was used to document demographic data, clinical symptoms and signs, laboratory findings, Mantoux test result, CSF findings, and radiological investigations. Subsequently, all data were systematically entered in a master sheet and analyzed using SPSS version 17. P < 0.05 was considered as statistically significant.
| Results|| |
A total of 30 children (males 15, 50%), aged 53.8 months (SD, range, 42.5, 7-144 months) with TBM presented to our hospital between May 2008 and March 2009 and all were included. Nearly two-thirds of the study population (n=19) were younger than 5 years; of these 5 were infants. Fourteen children belonged to the upper lower socioeconomic class and 16 belonged to the lower middle socioeconomic class in accordance with the modified Kuppuswamy scale.  Sixty percent (n=18) of the study population hailed from urban slums, whereas the remaining belonged to rural areas; 87% (n=26) of the children were malnourished as defined by World Health Organization  (severe stunting 12, severe wasting 6, wasting 8). Half of the patients had a history of contact with a person suffering from tuberculosis in the past 3 years and in all cases the contact was a family member. Fourteen children had a Bacillus-Calmette-Guérin (BCG) scar.
In 30% children (n=9), Mantoux test was strongly positive (≥10 mm), whereas in 43% children (n=13) Mantoux test results were indeterminate (6-9 mm). Gastric aspirate for acid-fast bacilli was negative in all children, tested on 3 consecutive days. CSF obtained by lumbar puncture was found abnormal in all the study subjects. The total cell count (leukocytes) varied from 90 to 200 cells/mm 3 with a mean (±SD) value of 136 (±28) cells/mm 3 . Lymphocyte predominance was seen in all. Protein values ranged from 114 to 274 mg% [mean(±SD), 174 (±45)]. CSF culture was sterile in all the cases. Chest radiograph was abnormal in 22 cases (73%). Of these 3 had military mottling of the lung fields, 8 had tuberculous bronchopneumonia, and 11 had hilar adenopathy. All children were nonreactive for HIV. Neuroimaging was performed in all children on admission and hydrocephalus was the most common finding (n=24, 80%) followed by the presence of basal exudates (n=17, 57%).
All children presented with fever and altered sensorium. Convulsions and symptoms of raised ICT (vomiting, headache) were seen in 83% and 77% children, respectively. A 27% (n=8) and 10% (n=3) children also had the presence of abnormal auscultatory chest findings and hepatomegaly, respectively. The mean duration of fever, altered sensorium, convulsions, and symptoms of raised intracranial pressure were 24.4 (±11.0) days, 5.2 (±2.6) days, 1.17 (±0.4) days, and 1.2 (±0.4) days, respectively. On clinical examination, out of 10 children with open anterior fontanel, 8 had bulging anterior fontanel. Evaluation using GCS revealed moderate or severe brain injury in 9 and 21 children, respectively. Posture was decerebrate, decorticate, or stiff in 15, 4, and 11 children, respectively. All children exhibited meningeal signs and hypertonia on clinical examination. Fifteen children had significant motor deficit; of these 2 had monoplegia, 9 had hemiplegia, and 4 had quadriplegia. Cranial neuropathy was seen in 15 children; 3 had optic neuropathy. Seventy percent of the patients had stage 3 TBM (n=21), whereas the rest were categorized as having stage 2 TBM (n=9). [Table 1] depicts the comparative baseline characteristics of children with stage 2 and stage 3 TBM. Children with stage 3 TBM were significantly younger and had a higher incidence of headache, vomiting, and convulsions at admission. They also had significantly lesser weight for age, height for age, and weight for height and a lesser calorie intake. However, the CSF picture was comparable in the two groups.
|Table 1: Comparative Baseline Characteristics of Children with TBM Stage 2 and TBM Stage 3|
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All the children were started on antituberculous therapy and followed for at least 8 weeks. The overall mortality was 40% (12/30) during the study period. By the 14th day, 21st day, and 35th day, a total of 4, 10, and 12 children died, respectively. All children who died had stage 3 TBM at admission. The overall in-hospital mortality among children with stage 2 TBM was nil, whereas it was 57% (12/21) among children with stage 3 TBM. There was a significant correlation between lack of immunization with BCG vaccine and death in children with TBM (r = 0.6, P < 0.001). Younger age (r = −0.387, P = 0.03), low weight for age (r = -0.596, P = 0.001), low length for age (r = −0.443, P = 0.014), low weight for height (r = 0.508, P = 0.004), and TBM stage 3 (r = 0.535, P = 0.001) correlated significantly with death.
By the 8th week, 18 (60%) survived. Of these, 9 (50%) had significant neurological morbidity. All these 9 survivors had TBM stage 3. Two patients had hypertonia, 7 had significant motor deficit of whom 2 were monoplegic and 5 were hemiplegic, 6 had cranial neuropathy, and 2 patients had visual handicap due to optic atrophy. Four children required ventriculoperitoneal shunting in view of gross hydrocephalus; only 2 of them survived. [Table 2] shows the results of neurological evaluation in all children.
|Table 2: Repeated Neurological Examination of Children Receiving Antitubercular Therapy|
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The overall mean (SD, range) duration of hospital stay was 15 (6.2, 5-15) days. The time to clearance of fever, reduction in vomiting and headache, initiation of feeding, and establishment of full enteral feeds was 19.7 (5.1, 12-30) days, 1.6 (0.5, 1-2) days, 6.5 (2.1, 3-10) days, and 9.5 (2.8, 5-14) days, respectively. The overall mean (SD, range) duration of hospital stay was 15 (6.2, 5-15) days. Survivors (n=18) were found to differ significantly with respect to those who succumbed in terms of having lesser duration of fever (P = 0.03), lesser duration of convulsions (P = 0.008), better premorbid calorie (P = 0.002) and protein intake (P = 0.005), higher weight for age (P < 0.001), more length for age (P = 0.004), and increased weight for height (P = 0.018). However, they did not differ significantly in terms of their age, duration of hospital stay, and biochemical profile of CSF.
| Discussion|| |
Treatment of tuberculosis has undergone considerable changes in the recent past. The DOTS strategy was developed to improve the compliance and intermittent short course therapy was met with favor to improve adherence to treatment and cure rates. Short course intermittent therapy has been recommended in the Revised National Tuberculosis Control Program in India for treating all forms of tuberculosis in children, including those with severe forms of TB, such as TBM, despite the lack of any definite evidence.
We evaluated the early outcome of the intermittent antituberculous therapy in this prospective study. After 8 weeks of thrice weekly therapy, we found a very high mortality of 40%; most (83%) of these deaths had occurred within the initial 3 weeks of starting treatment. Among the survivors, we found that more than half of them had significant morbidity. Only 23.3% of children with TBM had complete clinical recovery. We could not find any randomized clinical trials or case-control studies comparing thrice weekly antituberculous regimens with daily regimens in children with TB. Only 4 studies compared daily with twice weekly antituberculous regimens in children, but none evaluated children with TBM. ,,, A single retrospective chart review comparing in-hospital mortality of intermittent (n=55) versus daily (n=43) antituberculous regimen in 98 adults with TBM reported same rates of 27% in both groups (P = 0.148).  We also could not find any study reporting the outcome of children with meningeal TB treated with intermittent DOTS. Indumathi et al.,  in a prospective study in children with 14 children with central nervous system TB (7 with TBM), reported complete recovery in 86% children and no mortality using intermittent short course chemotherapy (SCC). The superior results reported by Indumathi et al.  using intermittent SCC need to be interpreted with caution as they had a very small sample of only 7 out of 14 children with TBM and their patients received daily therapy during the first 2 weeks of therapy. Venugopal et al. evaluated the outcome of 29 adults with neurotuberculosis who received DOTS for 9 months and reported a mortality of 14% following completion of therapy of 9 months duration, thereby suggesting that RNTCP guidelines were efficient for treating neurotuberculosis in adults.
We could find 9 studies ,,,,,,,, reporting the outcome of children with TBM receiving daily antitubercular therapy for durations ranging from 6 to 12 months. Ramachandran et al., in two separate studies involving 117  and 180  children with TBM, reported an average mortality of 14.5% and 27%, respectively, following 12 months of daily therapy. They reported a morbidity of 53% and 63% among the cases, respectively. Donald et al.  reported a mortality of only 16% after 6 months of daily therapy, 6 (HRZE) 7 in 95 children. Jacobs et al.  reported an overall mortality of 20.8% (11 of 53) with sequelae rate of 35.7% (15 of 42) in children receiving daily SCC, 2HRZS/4HR. In another study by Jacobs et al.,  in 325 children with TBM receiving any of the three regimens (12HES, 9HRS, and 6HRSZ), the overall mortality was only 20% following completion of therapy, and shorter duration of therapy was not associated with an inferior outcome. In another study in 51 Thai children with TBM,  following 12 months of daily anti-tuberculous therapy, there was only 6% mortality and only 25% of children had neurological sequel. In contrast to these results, where the mortality following completion of therapy ranged from 14.5% to 32% and 38% to 63% morbidity among survivors, we found a much higher mortality and morbidity even after 8 weeks of therapy.
Absence of vaccination with BCG had a significant association with mortality in children with TBM, suggesting a need for improved immunization coverage with BCG to improve survival in children with TBM. Previously, immunization with BCG has been reported with better outcome in children with TBM. , Although the NFHS-3 data show an improved coverage with BCG of 78% in 12-23 months old children from the 72% coverage in NFHS-2, there is a scope for improvement to curtail child mortality due to TBM. 
On the basis of our results, however, we cannot recommend the efficacy of intermittent short course tuberculous therapy in children with TBM. The main limitation of our study was the lack of a control group receiving daily antituberculous therapy for comparison. However, it was not possible to conduct such a study prospectively in our institution due to the currently adopted national policy on treatment of childhood TB whereby thrice weekly therapy is mandatory. In addition, we did not follow up all our patients beyond the initial 2 months of treatment; therefore, we do not have any data on the final outcome of these children in terms of mortality, morbidity, relapse, or failure. We recommend larger controlled studies to compare the outcome of daily versus intermittent therapy in children with TBM.
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[Table 1], [Table 2]