Outcome of Hydrocephalus in Tuberculous Meningitis. A Retrospective Study

Purpose To study outcome of Hydrocephalus in Tuberculous Meningitis (TBMH) and factors associated with poor clinical outcome. Methods Clinical data of 143 adult patients diagnosed with TBM over a 6-year period in 2 tertiary hospitals in Malaysia were retrospectively reviewed. Relevant clinical and radiological data was studied. Patients with Hydrocephalus in TBM (TBMH) were further analysed based on their clinical grade and rendered treatment to identify prognostic factors and outcome of this subgroup of patients. The functional outcome of patients was assessed at 12 months from treatment. The patients’ 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.

Tuberculous meningitis (TBM) is a non-suppurative in ammatory disease of the dura mater and spinal cord meninges caused by tubercle bacillus. It is the most lethal form of tuberculosis. High mortality and neurological disability among survivors is often encountered. Hydrocephalus is one of the most common complications of TBM and is almost always present in patients having disease for 4-6 weeks. 2,3 It occurs in approximately 70% patients and is even more common in children. 3,4,5 The varied pattern of clinical features makes the clinical diagnosis of TBM di cult. It is often diagnosed when brain damaged has already occurred. 4,5,6,7 The emergence of drug-resistant strains has increased in many parts of the world and this disease presents a therapeutic challenge. 1,8 When hydrocephalus is the presenting feature, urgent neurosurgical decompression may be required; the underlying TBM should be promptly diagnosed to minimize any delay in the use of speci c antituberculous drugs. The clinical implication of hydrocephalus upon presentation in adult patients with TBM is uncertain. Hydrocephalus in patients with TBM could be either of the communicating or the obstructive type, the former being more common. Lamprecht et al, in their study of 217 cases, had managed BMRC stages II and III TBM with communicating hydrocephalus with medical therapy and reportedly were able to avoid shunt surgery in 70% of these patients. Even in the other 30% who underwent shunt surgery, 41.5% had obstructive hydrocephalus. 2 Although shunting is recommended particularly in obstructive hydrocephalus, surgical relief of hydrocephalus may not alter the neurological status or long-term outcome. 9, 10 Palur et al, reported that those is grade III and IV of TBM had mortality rates of 51.9% and 100% respectively despite CSF diversion procedures. 9 The grade of patients at admission usually determines the management strategy. There are various grading systems for patients of TBM with hydrocephalus (TBMH). One of the commonly used systems is the Vellore grading system proposed by Palur et al. 11 The internal drainage of CSF, in the form of VP shunt, has been accepted as standard of care in patients presenting in good neurological grade (I and II). 9 There is still no consensus on the treatment protocol for patients of TBM with hydrocephalus, presenting in poor neurological grade (III and IV). In general, a trial of EVD is an accepted method of treatment, to decide whether a patient will bene t from shunt surgery. 12 However, it has been shown that improvement after CSF diversion may take many days or even weeks. 11,13 Prolonged EVD is fraught with the risk of infections.
Thus, a retrospective study at two tertiary teaching hospitals in Malaysia over a 6-year period to study the outcome of Hydrocephalus in Tuberculous Meningitis (TBMH) and factors associated with poor clinical outcome was conducted.

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 classi ed as "De nite" and "Probable" TBM based on the standardized clinical case de nition that was mentioned in the 2010 article of Marais was included. 14 The criteria used in classi cation of Marais are as follows: I. Clinical Criteria (maximum category score = 6) II. CSF Criteria Score (maximum category score = 4) III. Cerebral imaging criteria (maximum category score = 6) IV. Evidence of tuberculosis elsewhere (maximum category score = 4) A diagnosis of de nite 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 de ned as a Glasgow coma score (GCS) of 15 without focal neurological signs; Stage II is de ned as a GCS of 15 with neurological de cit, or a GCS of 11-14; and Stage III is de ned as a GCS of ≤ 10. Those with TBMH, were further graded according to the Modi ed Vellore Grade by Mathew et al. 13 : Grade I, GCS 15 with headache, vomiting, fever ± neck stiffness, and no neurological de cit; Grade II, GCS 15 but neurological de cit present; Grade III, GCS 9-14 and neurological de cit may or may not be present; Grade IV, GCS 3-8 and neurological de cit may or may not be present.

Exclusion Criteria
Patients who did not ful ll 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 vedrug 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 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".

Sample Size and Study Power
The sample size was calculated based on speci c 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. 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 rst 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 signi cant.

Results
Clinical descriptive data A total of 143 patients with mean age of 35.6 ± 12.4 years were included in this study. Majority of them were male (67.1%). Only 10.5% of patients were diagnosed with de nite TBM, the rest were probable TBM based on Marais criteria. The most common presenting symptoms in TBM according to order were; fever (86.7%), neck stiffness (63.6%), constitutional symptom (33.6%), altered consciousness (30.1%), raised intracranial pressure symptoms (28.7%), hemiplegia (23.8%), cranial nerve palsies (10.5%), and seizure (9.1%). Mantoux test results was positive in 58.7% of patients. Abnormal chest x-ray ndings suggestive of TB were seen in 51% of patients. Positive CT Brain ndings were cerebral edema (56.6%), hydrocephalus (44.1%), basal enhancement (32.2%), tuberculoma (14.7%), and infarcts (11.9%). A negative CT nding was seen in 9.1% of patient. All patients received ATT, and 85.3% had steroids as an adjunct. Forty four percent had TBMH, of which 42.9% had surgical intervention for the management of hydrocephalus. Table 1 summarizes the clinical and laboratory ndings in our patients. Descriptive analysis was used to study the treatment rendered in the good and poor Modi ed Vellore Grade, as the numbers were small in this subgroup of patients. All patient in the good grade had a good outcome, of which only 4 had CSF diversion procedures, the remaining was managed medically (Table 2). In the poor grade, only 2 patients bene tted from surgery, the other 21 patients despite CSF diversion procedures had poor outcome (Table 3).  grouped into good outcome (moderate disability and good recovery) and poor outcome (death, persistent vegetative state and severe disability). Event was de ned as poor outcome and censored for good outcome. Figure 1 shows the median survival time for patients with TBMH was 432 days. The median survival time for TBM without hydrocephalus was not calculated as the smallest survival function did not reach 0.5 or below. Figure 2   Log-minus = log plot, hazard function plot and partial residuals were applied to check the model assumption and found ful lled anti-TB drugs in the second half of the 20th century, TBM was a fatal disease for everyone. However, its mortality can still reach 60% today particularly in developing countries. Sequelae can be seen in 25% of survivors despite ve major and numerous minor drug options available. 16,17 As advanced disease stage and delay in therapy are considered poor prognostic factors, early diagnosis and treatment is important.
The de nitive bacteriological diagnosis of TBM depends on demonstration of Mycobacterium tuberculosis by smear or culture in CSF, meninges or brain tissue. Con rmatory CSF culture isolation and PCR for TBM are known to have low yield and sensitivity, this by itself presents another challenge to an already constrained setting. 18,19 Positive culture has been found in 12-74% of patients. 8,20,21,22 In our study, the rate of bacteriological diagnosis was lower than most other large studies, 10.5%. This was via direct smear for AFB, as cost was a limiting factor for TB-polymerase chain reaction (PCR) or GeneXpert then. Mantoux test results were positive in 58.7% of patients, however this result alone is not speci c for the diagnosis if TBM, as it has been reported in various literatures ranging from 39-85% in TBM con rmed patients. 19,21 Abnormal CXR ndings were seen in 51% of our patients, which was within the reported incidence of its occurrence ( 44-71%). 19 Previous studies indicate a correlation between the severity of TBM and poor outcome, 19,21,23 and this was also seen in our study.
There have been many studies on poor prognostic factors in TBM, some of which were advanced age, low GCS on admission, hydrocephalus, concomitant TB at other sites, and BMRC stage III on admission. 8,28,31,32 (Table 3). In the good Modi ed Vellore Grade, 76.5%(n = 13) was managed medically with a combination of ATT, steroids and osmotic agents. Four patients had surgery early in the disease as they did not respond to medical therapy and reported a good outcome subsequently (Table 2). Figure 2 showed that patients with TBMHM (medical management) had better survival compared to TBMHS (surgical management). This was partly due to the poor pre-operative grades of the patients undergoing CSF diversion procedures, which was 85.2% (n = 23) (Table 4). Rajashekar et al in his review article, reported a high mortality in excess of 80% in those with poor grade. 29

Conclusion
In conclusion, patients receiving medical therapy had better survival than those requiring CSF diversion procedures for TBMH. In our study cohort, majority of the patients were males. Fever and neck stiffness were the most common presenting symptom. Hydrocephalus was seen in 44% in this study. GCS score, seizure and high CSF cell count were factors associated with a poor prognosis in TBMH. In the subgroup descriptive analysis (Table 2), the good Modi ed Vellore Grade had good outcomes regardless of the method of treatment. However, further study to determine its signi cance needs to be conducted prospectively. Patients with TBMHM had better survival function compared to those with TBMHS. Finally, this retrospective study emphasizes that TBMH is still a serious illness, as 47.6% of these patients had poor outcome despite adequate treatment.

Study Limitations
There were a few noticeable limitations in this study, rstly being the management and timeliness of the referral to the neurosurgical unit for the management of hydrocephalus. Not all patients with TBMH was referred to the neurosurgical unit upon diagnosis. Majority of them were referred in the later stages of the disease or following neurological deterioration due to hydrocephalus. This could be the reason why the patients in TBMHS had a worse off outcome compared to TBMHM. Secondly, not all patients had an MRI done during hospitalization as cost was a limiting factor. This is an important modality to rule out other causes of reduced consciousness such as brainstem infarcts in a patient with confounding TBMH. Due to the retrospective nature of this study, the interrater variability was not calculated. The diagnosis of TBM was based on the clinico-radiological diagnosis by the treating physician and radiologist. As the treating physician/radiologist are not constant, the author does agree that there would be a certain degree of interrater variability in the diagnosis and management of TBM or TBMH in this study. Lastly, being a retrospective study, the advantages of a prospective randomized study for direct comparison was not possible. Hence, a future prospective study comparing this management dilemma will be of great signi cance. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing Interest
The authors declare that they have no competing interests.

Not applicable
Authors Contributions DK conceptualise, designed and was the principal investigator for the study. RK was involved in study design, data interpretation and manuscript drafting. AWSH was involved in study design and data interpretations. JT conceptualise and designed the study along with principal investigator. LCJ performed the statistical analysis and data interpretations. JMA was a major contributor in data interpretation, manuscript drafting and review. All authors read and approved the nal manuscript.