Factors associated with poor outcome in tuberculous meningitis; study from a tertiary care referral Centre from South India

Introduction: Tuberculosis (TB) remains a worldwide burden with a large majority of new active cases occurring in underdeveloped and developing countries. This study is an attempt to look into various aspects of the disease that can be associated with the outcome, to promote a timely referral to an appropriate centre. Purpose: To identify various clinical, lab, CSF and radiological variables associated with poor outcome of TBM at the time of discharge. Material & Methods: Demographic data, duration of symptoms before diagnosis, clinical presentation, staging of the disease at the time of admission of all the TBM patients who presented to our centre between December, 2015 and May 2018 were noted. Results of biochemical investigations and brain and spine imaging were retrieved. Outcome at the time of discharge as measured by MRC and mRS grades was correlated to clinical profile, lab, CSF and radiological findings. Results: A total of 100 patients were included. 15 patients died. Subjects with MRC and mRS grades of 2 or more at admission constituted 65% and 93% respectively. At discharge, MRC and mRS grades of 2 or more were found in 29.63% and 39% respectively. Multivariable analysis showed a significant positive association of MRC stage at discharge with MRC stage (p = 0.001) and mRS score (p = 0.001) at admission and Vellore hydrocephalus grade (p < 0.001) when hydrocephalus first identified. Conclusion: Stage of the disease (MRC) and functional status of the patient (mRS) at admission are the two most important independent factors determining the outcome of TBM patients at the time of discharge. The present study highlights the importance of early diagnosis of TBM and prompt initiation of appropriate treatment. In an endemic country like India, any patient presenting with fever and headache for more than 2 weeks is to be suspected of having TBM. Acute presentations with noncontributory CSF and radiology are very much known with TBM. In those patients who present acutely and in those deteriorating while on treatment, daily clinical assessment and repeat radiological evaluation are warranted to come up with the correct diagnosis.


Introduction
Tuberculosis (TB) remains a worldwide health concern with a large majority of new active cases occurring in underdeveloped and developing countries. WHO estimates that five countries -India, China, South Africa, Indonesia and Pakistanaccount for greater than 70% of the global burden of the disease. Additionally, there is a real risk that the increasing incidence of MDR-TB and even XDR-TB can lead to increased disease burden as well as deaths.

Results
A total of 100 patients were included, 5 of them were probable TBM and the remaining were possible TBM. The median age was 29 (range 9 -63 years).
Of them, 41% (n=41) were male. The median duration of symptoms to diagnosis was 20 days (range 4 -40 days). The median time taken for the patients to arrive at our hospital was 6 days for those with MRC stage I, 12 days for those with MRC stage II and 4 days for those with MRC stage III.
Evidence of pulmonary TB is seen in around 50% of cases of TBM. [12,13]. TBM occurs when subpial or subependymal tubercles seeded during dissemination, the so-called Rich foci, rupture into subarachnoid space. [14]. In our series, a total of 100 patients were identified to have TBM. Most of them aged less than 30 years, constituting 56.5%, which is following the previous reports. In our series, 78% of patients had subacute presentation i.e they presented in the 3rd and 4th week of their illness. 22% of our patient population presented to the hospital within the first 2 weeks of the onset of symptoms. Though TBM classically follows a subacute disease course, acute presentations of TBM as high as 46.6% are well known. [17]. Six of our acute TBM patients were initially misdiagnosed as cerebral malaria or viral meningoencephalitis because of paucicellular CSF with normal or mildly elevated protein, normal glucose levels, normal plain and contrast MRI. Two of them were diagnosed as bacterial meningitis as CSF showed neutrophilic leukocytosis, hypoglycorrhachia and convexal meningeal enhancement before the diagnosis of TBM was made. All these cases were identified as TBM when MRI including post gadolinium sections were repeated because of drop-in sensorium after initiation of treatment.
The most common symptoms of TB meningitis are fever, headache, vomiting and altered level of consciousness. [18]. As is expected, the most common symptoms seen in our study population were fever (71%) & headache (71%). Among the various clinical factors assessed, altered sensorium at presentation significantly correlated with MRC stage (P < 0.001) at discharge. This conforms with the previous reports. [4,19,20]. Forty-seven per cent of our patients had an altered level of consciousness on arrival. The altered sensorium in TBM is due to adjacent encephalon involvement, multiple tuberculomas with perilesional edema or single tuberculoma in a strategic location, vasculitis leading to infarction and hydrocephalus. [21].
Other factors associated with poor clinical outcome at discharge on univariate analysis, as defined by MRC stage ≥ II were elevated CSF opening pressure, presence of vasculitic infarcts on MRI, MRC stage, mRS score at admission and Vellore hydrocephalus grade. Cerebral infarction was an important predictor of the outcome at 6 and 12 months in a study conducted by Kalita et al. [19]. Infarction in TBM is a common complication that occurs due to thrombosis and strangulation of the vessels by the exudates. [19].
Vasculitic infarcts in TBM are commonly seen in the head of the caudate nucleus, genu and anterior limb of the internal capsule, and anteromedial thalamus, the so-called TB zone. [22]. Twenty-eight patients in our series had vasculitic infarction.
TBM is a disease with frequent neurological sequelae and fatalities if not treated early. [12,13,23,24,25]. Various case series indicate a mortality rate of 7%-65% in developed countries, and up to 69% in underdeveloped areas [23,24,25]. Our mortality rate was 15%. Major contributors for mortality in our subjects were pneumonia and sepsis owing to prolonged ICU stay, prolonged ventilatory support and surgical intervention.
Vasculitis resulting especially in brainstem infarction also contributed to mortality.
Residual deficits are known to occur in as high as 50% of the survivors. [25]. On univariate analysis, the functional outcome at discharge as determined by mRS score is related to focal limb weakness, altered sensorium at presentation, elevated CSF protein, MRC stage, mRS score at admission and Vellore hydrocephalus grade. Focal limb weakness in TBM is attributed to vasculitic infarction, tuberculoma in strategic location or arachnoiditis.
Thirty of our patients had focal limb weakness at the time of admission.
After multivariable analysis, the best set of predictors for clinical and functional outcome of TBM patients in our series at the time of discharge were MRC stage and mRS score at admission. Our results were similar to few other series published previously i.e., MRC grade at admission is one of the strong independent predictors of clinical outcome. [5,6,8,9,26]. This study addressed the outcome at the time of discharge. The outcome of TBM patients may get altered because of the complications that develop in the first 2 months of illness. Ideally, all these cases are to be followed for at least 2 months before concluding. As most of our complicated cases were discharged after a prolonged hospital stay of one month, we assume that outcome at discharge provides a valuable yardstick to assess treatment response.

Conclusion
Stage of the disease (MRC) and functional status of the patient (mRS) at admission are the two most important independent factors determining the outcome at the time of discharge in TBM. A high index of suspicion, early diagnosis and prompt treatment are highly essential in the management of TBM to reduce morbidity and mortality. What does the study add to the existing knowledge?
The present study highlights the importance of early diagnosis of TBM and prompt initiation of appropriate treatment. In an endemic country like India, any patient presenting with fever and headache for more than 2 weeks is to be suspected of having TBM. Acute presentations with noncontributory CSF and radiology are very much known with TBM. In those patients who present acutely and in those deteriorating while on treatment, daily clinical assessment and repeat radiological evaluation are warranted to come up with the correct diagnosis.

Author's contribution
All the authors participated actively during the whole study. All the authors reached out to each other in many ways like study design, data collection, and manuscript preparation.