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 Pakistan – account for greater than 70% of the global burden of the disease. [1]. Twenty-six per cent of these cases live in India. [2]. India accounts for nearly 2.5 million new infections annually leading to over 200,000 deaths. [3]. In 2016, the death toll in India due to TB was estimated at 4.5 lakh population with a total of 28 lakh new cases.

Tuberculous meningitis (TBM) constitutes approximately 1% of all cases of TB. [4]. Globally, the number of TBM cases would be over 100,000 annually. Despite a good clinical exposure in India, diagnosis of TBM remains a challenge as it is a great mimicker of various other diseases with its wide spectrum of manifestations. Due to heterogeneity of the disease, reliance on microbiological confirmation often results in misdiagnosis or a delay in diagnosis and initiation of therapy. India has more than a million “missing” cases every year that are not notified.

TBM has higher morbidity and mortality than any other form of TB with a reported incidence of mortality >20% and neurological sequelae in 78.5% of patients. [5]. Delay in diagnosis and treatment is one of the major factors contributing to morbidity and mortality. [6]. With poor availability of resources for diagnosis and treatment in the rural and suburban population who form the major chunk of cases, mortality due to TBM in India remained high i.e. 1.5/100000. [7]. Fatalities are also caused by disease complications and the inability to detect antimicrobial resistance.

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. Lack of expertise at peripheral health care in dealing with the disease complications and delay in referring cases to a tertiary care centre is leading to significant morbidity. The drug in compliance due to financial constraints is one of the major factors contributing to indolently spreading multidrug resistance amongst Mycobacteria, adding to the complex scenario. This study is an attempt to look into various aspects of the disease that can predict the outcome, to promote a timely referral to an appropriate centre thus lessening the case fatalities.

Subsequent MRI or CT imaging during follow up was done only in subjects suspected to have developed complications like hydrocephalus, paradoxical reaction, optochiasmatic arachnoiditis and vasculitis.

All patients were treated with four-drug regimen of isoniazid 5 mg/kg/day (maximum of 300 mg/day); rifampicin 10mg/kg/day (maximum of 600 mg/day) for 12 months supplemented by pyrazinamide 15-30 mg/kg/day (maximum of 2000 mg/day) and streptomycin 20-40 mg/kg/day or ethambutol 15-25 mg/kg/day for the first 2 months. All patients with stage 2 or 3 MRC received dexamethasone 8 – 16 mg/day for 3 – 6 weeks, tapered over the next 2 – 4 weeks. Patients with hydrocephalus and altered sensorium and/ or neurological deficit underwent ventriculoperitoneal shunting unless CSF protein was more than 1 g/l. In the latter case, a temporary external ventricular drainage using a reservoir was kept.

Poor clinical outcome is defined as death, MRC stage ≥ II and poor functional outcome as mRS score ≥ 2 at the time of discharge. These variables were correlated to clinical profile (presence of seizures, focal limb weakness, cranial nerve palsies, altered sensorium, MRC stage, mRS score and Vellore grade at presentation, occurrence of ventilator-associated pneumonia or pneumonia complicating aspiration and or sepsis during hospital stay), lab parameters (hyponatremia, drug-induced hepatitis), CSF (opening pressure, protein, glucose, total leucocyte count) and radiological findings (presence of basal meningeal enhancement, hydrocephalus and vasculitis).

Statistical methods: MRC stage and mRS score at discharge was considered as primary outcome variables. Various clinical, CSF and imaging features, MRC stage and mRS score at admission were considered as primary explanatory variables. Descriptive analysis was carried out by mean and standard deviation for quantitative variables, frequency and proportion for categorical variables. The association between primary explanatory variables and primary outcome variables were assessed by cross-tabulation and comparison of percentages. The Chi-square test was used to test statistical significance. Variables with a probable association with MRC stage and mRS score at discharge on univariate analysis were included in a multivariable logistic regression model to accurately identify an independent association. P-value < 0.05 was considered statistically significant. IBM SPSS version 22 was used for statistical analysis. [10].

Imaging revealed intracranial meningeal enhancement in 95% (n=95), of which meningeal enhancement across Sylvian fissure is seen in 8 % (n=8), basal exudates were seen in 42% (n=42). Concomitant spinal arachnoiditis was found in 8% (n=8), vasculitic infarcts in 28% (n=28), tuberculoma in 40% (n=40). (Table 3) Twenty patients had hydrocephalus at the time of admission, 32 patients had hydrocephalus during the hospital stay, 11 patients developed hydrocephalus after discharge within the first month of illness. 37% (n=37) patients underwent ventriculoperitoneal shunting and 7% (n=7) underwent reservoir placement with external ventricular drainage. Drug-induced hepatitis occurred in 34% (n=34) of the patients.

Table 3: Brain and spine imaging findings

Functional independence at discharge (as determined by mRS score), on univariate analysis, correlated negatively with focal limb weakness (p=0.004), altered sensorium (p=0.01) at presentation, elevated CSF protein (p=0.009), higher MRC stage (p<0.001), higher mRS score (p<0.001) and higher Vellore hydrocephalus grade (p<0.001). (Table 5) Time to diagnosis correlated neither with poor clinical nor functional outcome.

Table 5: Factors associated with mRS score at discharge (Univariate analysis)

In our series, 78% of patients had subacute presentation i.e they presented in the 3^rd and 4^th 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.

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.

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.