Study Design
A retrospective cohort study of patients with TBM.
Patients and Methods
Data obtained from patients (aged ≥ 18 years) admitted and treated in 2 tertiary centers, Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan and Hospital Umum Sarawak, Kuching, Sarawak between January 2012 and December 2017 with a diagnosis of TBM was analyzed retrospectively. The patients’ medical records were reviewed, and the following information was collected: demographic characteristics, underlying diseases, clinical features, laboratory data, bacteriology, image studies, use of steroids, ATT (anti tuberculosis treatment), surgical interventions or drainage, and clinical outcome. Most patients had CSF taken on admission, and the following tests performed: total cell count, glucose, protein, and mycobacterial smears and cultures. Chest radiography and brain computed tomography (CT) scans was performed on all patients upon admission.
Inclusion Criteria
In our study, all patients classified as “Definite” and “Probable” TBM based on the standardized clinical case definition that was mentioned in the 2010 article of Marais was included.14 The criteria used in classification of Marais are as follows:
- Clinical Criteria (maximum category score = 6)
- CSF Criteria Score (maximum category score = 4)
- Cerebral imaging criteria (maximum category score = 6)
- Evidence of tuberculosis elsewhere (maximum category score = 4)
A diagnosis of definite TBM is made when AFB are seen, Mycobacterium tuberculosis is cultured, or is detected by a reliable molecular method from the CSF in someone with symptoms or signs suggestive of the disease. Probable TBM when imaging is available, a diagnostic score of 12 or above is required, and when imaging is not available, a diagnostic score of 10 or above is required. A diagnosis of TBMH is made when there is accompanying radiological evidence of hydrocephalus on the CT brain.
The severity of TBM at the time of admission was assessed using the British Medical Research Council (BMRC) TBM stages.15: Stage I is defined as a Glasgow coma score (GCS) of 15 without focal neurological signs; Stage II is defined as a GCS of 15 with
neurological deficit, or a GCS of 11–14; and Stage III is defined as a GCS of ≤ 10. Those with TBMH, were further graded according to the Modified Vellore Grade by Mathew et al.13: Grade I, GCS 15 with headache, vomiting, fever ± neck stiffness, and no neurological deficit; Grade II, GCS 15 but neurological deficit present; Grade III, GCS 9-14 and neurological deficit may or may not be present; Grade IV, GCS 3-8 and neurological deficit may or may not be present.
Exclusion Criteria
Patients who did not fulfill the diagnostic criteria of TBM, age <18 years old or an alternative diagnosis to TBM (i.e. Cryptococcal Meningitis) was excluded from study.
Treatment and Outcome
The cases were treated with the classical four-drug ATT (combination of isoniazid-INH, rifampicin-RIF, pyrazinamide-PRZ, and ethambutol-EMB) for 12–18 months. Some cases with prior TB received a five-drug therapy including streptomycin. Dexamethasone was given as an adjunct and tapered off over 4 to 6 weeks. Hydrocephalus was treated medically with dehydrating agents, or surgical intervention via an external ventricular drain (EVD), ventriculoperitoneal shunt or a combination of both. The functional outcome of patients was assessed at 12 months from treatment. These outcomes were based on the Glasgow outcome scale (GOS) as shown below:13
Glasgow Outcome scale:
- Death – dead
- Persistent Vegetative State – absent of awareness
- Severe Disability – ADL - Dependent
- Moderate Disability – ADL - Independent
- Good Recovery – Full recovery or mild disabilities not affecting daily life
In our study good recovery and moderate disability were considered a “Good outcome” while severe disability, persistent vegetative state or death was reckoned as “Poor outcome”.
Ethics Approval
The study protocol was approved by the National Medical Research Register (NMRR ID: NMRR-17-174-34329) and the Jawatankuasa Etika Penyelidikan Manusia Universiti Sains Malaysia (USM/JEPeM/17040234) for both hospitals.
Sample Size and Study Power
The sample size was calculated based on specific objective no. III of this study, to compare and analyze outcome of patients with TBMH treated with or without CSF diversion. Based on a dichotomous endpoint, two independent sample group (TBMHM and TBMHS), the sample size was calculated as below.
PS Power and Sample Size Calculations. Version 3.0, January 2009 William D. Dupont and Walton D. Plummer.
- Alpha: 0.05
- Beta: 0.2
- Power: 0.8
- Incidence in Group 1: 70% (Good outcome in TBMHM)
- Incidence in Group 2: 30% (Good outcome in TBMHS)
Data published by Lamprecht et al. on management of TBMH was used as a reference to calculate the sample size.2 A minimum of 23 patients in each arm is required to achieve the above study parameters. Thereby, the calculated sample size is 46 patients. Including a dropout rate of 15% into the sample, a total sample of 54 patients is required.
Statistical Analysis
Statistical analysis was performed using commercially available statistical software (SPSS 22.0; SPSS, Inc.). Data were first explored and screened. Continuous variables were presented in mean and standard deviation or median and interquartile range. Categorical variables were expressed as frequency and percentage. Meanwhile univariate analysis Simple Cox Regression was used to explore the prognostic factors for poor GOS outcome followed by Multiple Cox Regression. Kaplan Meier survival curves was used to compare TBMHM and TBMHS. A p value of < 0.05 was regarded as significant.