This real-world retrospective cohort study consecutively included children <15 years of age treated for TBM at the Department of Child Health of Hasan Sadikin Hospital, a national tertiary teaching hospital in Bandung, Indonesia, during January 2011–December 2020. The study was approved by the Independent Ethics Committee of Hasan Sadikin Hospital (approval no. LB.02.01/X.6.5/91/2021). Because of the retrospective nature of the study design, the Ethics Committee waived the need for written informed consent.

We established TBM diagnosis on the basis of clinical, laboratory, and radiologic findings (17), combining medical history, physical and clinical examinations, tuberculin skin test, chest radiography, cerebrospinal fluid (CSF) analysis, and neuroimaging by using computed tomography (CT) scan. We performed microbiologic examination of CSF and non-CSF samples, including smear microscopy for acid-fast bacilli (AFB), culture for M. tuberculosis, and Xpert MTB/RIF assay, depending on sample availability. We assessed diagnostic certainty of definite, probable, or possible TBM by using uniform case definition criteria for TBM research (18) (Appendix Table 1). We presumed that patients had drug-susceptible TBM unless drug resistance was proven in Xpert MTB/RIF or drug-susceptibility testing. We excluded TBM patients with drug-resistant TB from the study.

We based treatment regimens on the 2010 WHO guidelines in accordance with the Indonesian Paediatric Society guidelines for TBM treatment in children, consisting of daily isoniazid at 10 mg/kg (range 7–15 mg/kg), rifampin at 15 mg/kg (range 10–20 mg/kg), pyrazinamide at 35 mg/kg (range 30–40 mg/kg), and ethambutol at 20 mg/kg (range 15–25 mg/kg) for a 2-month intensive phase, followed by a 10-month continuation phase with isoniazid and rifampin at the same doses (17,19). We administered all anti-TB drugs orally as fixed-dose combination or single-drug formulation tablets, where available. Patients received facility-based directly observed therapy (DOT) during hospitalization. After discharge, patients received home-based DOT under the supervision of parents or other family members. Most patients received adjunctive oral prednisone (2–4 mg/kg/d) for the first 4–8 weeks, tapered according to the national guidelines (17). We treated patients with increased intracranial pressure with hypertonic saline or mannitol 20% (0.5–1 g/kg) every 8 hours. We performed ventriculoperitoneal shunt or extraventricular drain placements in patients with obstructive hydrocephalus, at the discretion of the neurosurgical team.

We collected individual patient data from hospital registry in a predefined form and appropriately deidentified the data before analysis. These data were demographic information (age, sex, parents’ education and income, area of living, and length of hospital admission); medical history (HIV infection, bacillus Calmette-Guérin [BCG] vaccination, and TB contact history); clinical characteristics (symptoms of TBM, vital signs, nutritional status, physical and neurologic examinations, tuberculin skin test, Glasgow coma scale [GCS], and TBM staging); laboratory findings (CSF analysis, AFB microscopy, mycobacterial culture, and Xpert MTB/RIF test); radiographic findings (chest radiograph and neuroimaging); and other supporting data (corticosteroid therapy and in-hospital complications).

We developed operational definitions for all variables (Appendix Table 2). We defined definite TBM as microbiologic confirmation of CSF and probable TBM as a total diagnostic score of >12 when neuroimaging was available or ≥10 when neuroimaging was unavailable. We defined possible TBM as a total score of 6–11 when neuroimaging was available or 6–9 when neuroimaging was unavailable (18). We classified TBM staging according to the modified British Medical Research Council grading system (20), as follows: stage I, GCS 15 without focal neurologic deficit; stage II, GCS 11–14, or 15 with focal neurologic deficit; and stage III, GCS <10. Patients with known BCG vaccination included those who had a documented vaccination history at hospital admission or had a BCG scar in the deltoid region of the upper arm. Motor deficits included hemiparesis, quadriparesis, and diplegia. Other neurologic deficits were signs of upper motor neuron lesion and cranial nerve palsies. We performed motor, hearing, visual, and neurodevelopmental function assessments at treatment completion as indicated by the attending physicians (Appendix).

Outcomes of hospitalization were recovery (with or without disability), nonrecovery (persistent vegetative state and discharge against medical advice), and death. After 12 months of treatment, we reported the following outcomes: treatment completion, death, and lost to follow-up (LTFU; i.e., patients who stopped treatment for >2 consecutive months). “Not evaluated” or “unknown treatment outcome” categories were patients who were transferred back to regional public hospitals or community health clinics for follow-up after discharge. We defined survival as being alive at treatment completion and neurologic sequelae as any motor, hearing, visual, or neurodevelopmental impairment that appeared during the illness and persisted through treatment completion.

We evaluated associations of patient characteristics with poor outcomes. First, we compared patients who died during hospitalization (in-hospital death) with those who had recovered at the time of discharge; this definition excluded persistent vegetative state and discharge against medical advice. Second, we compared patients who died after discharge (postdischarge death) with those who completed treatment, regardless of their sequelae status; this definition excluded LTFU and unknown outcomes. Third, we compared survivors with neurologic sequelae with those without sequelae; this definition excluded death, LTFU, and unknown outcomes.

We used Cox proportional-hazards regression analysis to assess predictors of in-hospital death. We calculated time to death on the basis of length of stay by subtracting day of admission from day of death. Most patients were discharged within 2 months of hospitalization; in this case, we assumed that recovering patients (with or without disability) discharged before 2 months were alive until the end of 2 months, and thus we censored these patients in the Cox regression analysis. Because the time to death after discharge was not recorded, we assessed associated factors with postdischarge death and neurologic sequelae by using logistic regression analysis. We adjusted our multivariate models for age, sex, and TBM staging, and completed the models with variables showing a trend toward association in univariate analysis. We selected these variables by using backward deletion, and the final models retained all additional variables with a p value <0.1. For logistic regression analysis, we evaluated the goodness-of-fit of the final models by using Hosmer-Lemeshow test and performance by the area under the receiver operating characteristic curve. For Cox regression analysis, we checked proportional hazards assumption using Kaplan-Meier curve before fitting the model, and using log-minus-log survival curve after fitting the model. We used adjusted hazard ratios (aHRs) for Cox regression models and adjusted odds ratios (aORs) for logistic regression models, as well as 95% CIs, to estimate the association between explanatory variables and outcomes. We defined statistical significance as p<0.05. We performed all analyses by using IBM SPSS Statistics 26.0 (https://www.ibm.com).

During the study period (2011–2020), 286 children with TBM were treated at Hasan Sadikin Hospital; 3 patients with rifampin-resistant TB were excluded. No patients had concurrent bacterial meningitis. Among 283 included patients, 150 (53.0%) were boys, 153 (54.1%) were <5 years of age, 183 (64.7%) were malnourished, 226 (79.9%) had stage II or III TBM, and 51 (18.0%) had definite TBM. At admission, most patients had history of fever (88.3%), decreased consciousness (74.6%), and seizures (55.0%); the next most common signs and symptoms were weight loss (37.6%), persistent cough (33.7%), muscle weakness (26.3%), and severe headache (21.9%). These signs and symptoms had existed for >5 days before admission in 87.0% of patients (Table 1). We stratified manifestations by disease staging (Appendix Table 3).

In CSF analysis, most patients had pleocytosis (>10 cells/µL, 76.8%), and lymphocytic predominance (>50%, 81.8%), followed by a low CSF-to-plasma glucose ratio (<0.5, 54.8%), elevated protein level (>100 mg/dL, 51.8%), and hypoglycorrhachia (<40 mg/dL, 41.6%). M. tuberculosis susceptible to rifampin was identified by Xpert MTB/RIF assay in 48 (34.3%) of 140 CSF samples and in 76 (33.9%) of 224 non-CSF samples. In neuroimaging, most patients had basal meningeal enhancement (52.4%), followed by hydrocephalus (41.2%), tuberculoma (12.4%), and infarct (10.0%) (Table 2). Among 103 patients with hydrocephalus, 45 (43%) received neurosurgical intervention: 44 (97.8%) ventriculoperitoneal shunt and 1 (2.2%) extraventricular drain.

For in-hospital complications, 106 (37.5%) of the 283 patients had motor disorders, 37 (13.1%) had neurodevelopmental delay, 19 (6.7%) had epileptic seizures, 17 (6.0%) had visual impairment, 12 (4.2%) had hearing impairment, and 27 (9.5%) had anti-TB drug-induced hepatotoxicity. Adjunctive oral corticosteroid was administered to 262 (92.6%) of patients. In addition, 1 of the patients (a 6-month-old boy with stage II TBM) had severe acute respiratory syndrome coronavirus 2 coinfection (Appendix).

Upon discharge, 231 (81.6%) of 283 patients had recovered (with or without disability), 3 (1.1%) had a persistent vegetative state, and 5 (1.8%) were discharged against medical advice. The remaining 44 (15.5%) died; median time to death was 7 days (interquartile range 3–13 days) after admission (Table 3).

We performed univariate (Appendix Table 4) and multivariate (Table 4) analyses of risk for in-hospital death. In multivariate analysis, factors associated with increased risk were stage III TBM (aHR 5.96 [95% CI 1.39–25.58]), hydrocephalus (aHR 2.32 [95% CI 1.13–4.79]), male sex (aHR 2.10 [95% CI 1.09–4.05]), low-income parents (aHR 2.59 [95% CI 1.06–6.31]), seizures on admission (aHR 1.96 [95% CI 1.01–3.82]), and unknown BCG vaccination (aHR 1.97 [95% CI 1.03–3.76]). Among children <5 years of age, known history of TB contact was associated with an increased risk for in-hospital death (aHR 2.42 [95% CI 1.06–5.50]), adjusted for age, sex, and TBM staging. We charted Kaplan-Meier curves for several risk groups for in-hospital death (Figure).

After the 12-month follow-up, 272 (96.1%) of 283 patients were evaluated for treatment outcomes, and 11 (3.9%) in ongoing treatment who started taking anti-TB drugs in late 2020 were excluded from further analysis. Among the 272 patients, 91 (33.5%) completed treatment, 1 (0.4%) was LTFU, and 62 (22.8%) died, including 18 (6.6%) who died after discharge; 118 (43.4%) had unknown outcomes (Table 3).

We performed univariate (Appendix Table 5) and multivariate (Table 5) analyses of odds for postdischarge death. Multivariate analysis identified that patients with unknown BCG vaccination status (aOR 5.38 [95% CI 1.07–27.07]) and those with clinical findings during hospitalization such as hydrocephalus (aOR 18.97 [95% CI 2.68–134.38]) and tuberculoma (aOR 8.78 [95% CI 1.10–70.39]) had increased odds of postdischarge death. Among patients with hydrocephalus, the absence of neurosurgical intervention was associated with increased odds of postdischarge death (aOR 11.06 [95% CI 1.61–76.12]), adjusted for age, sex, and TBM staging.

Among 91 survivors who completed treatment, 58 (63.7%) had good recovery without neurologic sequelae and 33 (36.3%) had severe neurologic sequelae (Table 3). Of patients with severe neurologic sequelae, 22 (66.7%) had motor disorders, 9 (27.3%) had epileptic seizures, 7 (21.2%) had neurodevelopmental delay, 3 (9.1%) had visual impairment, and 3 (9.1%) had hearing impairment. Neurologic sequelae were observed in 23% of patients diagnosed with TBM at stage I, 31% at stage II, and 58% at stage III.

We performed univariate (Appendix Table 6) and multivariate (Table 6) analyses of odds for neurologic sequelae. In multivariate analysis, factors associated with higher odds of severe neurologic sequelae were baseline temperature >38°C (aOR 6.68 [95% CI 1.55–28.85]), stage III TBM (aOR 5.65 [95% CI 1.21–26.43]), and motor deficits at baseline (aOR 3.64 [95% CI 1.19–11.16]).