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Infectious Diseases in Clinical Practice:
doi: 10.1097/IPC.0b013e31817e5c16
Original Articles

Clinical Profile of Tuberculous Meningitis in Kashmir Valley-The Indian Subcontinent

Wani, Abdul Majid MD, MRCPI*; Hussain, Waleed Mohd MD*; Fatani, Mohd MD*; Shakour, Bothaina Abdul MD*; Akhtar, Mubeena MBBS*; Ibrahim, Fathaia MBBS*; Tawakul, Abdullah MBBS*; Khojah, Amer M. MBBS†

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Author Information

*Hera General Hospital and †Umul-Qurah University, Makkah, Saudi Arabia.

Address correspondence and reprint requests to Abdul Majid Wani, MD, MRCPI, Hera General Hospital, Makkah-10513, Saudi Arabia. E-mail: dr_wani_majid@yahoo.co.in.

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Abstract

Background: Tuberculosis is a global issue and 2 billion people are infected out of which 1.3 billion come from developing world and tuberculous meningitis (TBM) complicates 1 of every 300 untreated primary tuberculosis infections. Diagnosis is still difficult especially in developing and resource poor countries. We conducted the study to see the clinical profile and the use of available diagnostic tools in the early diagnosis of TBM in our part of the world.

Methods: Sixty-eight patients were enrolled and only 38 followed for a period of 3 years from hospitalization to completion of treatment and for sequelae in a tertiary care hospital of Kashmir valley India. Clinical presentation, use of available diagnostic tools, treatment, outcome, and sequelae were studied with the aim to find helpful available tools in early diagnosis and management of TBM.

Results: Only 38 patients completed the follow-up and important results were that 29 patients (76.31%) belonged to rural areas, 21 (55.26) were in the age group 20 to 39 years, 60% were females. Relation between stage at presentation, early treatment and outcome, useful laboratory investigations, cerebrospinal fluid (CSF) analysis, computed tomography scan findings, usefulness of serum and CSF enzyme-linked immunoabsorbent assay, most effective treatment regimen, sequelae and mortality were some of the important results obtained.

Conclusions: Tuberculous meningitis was found to be more common in female rural population of the valley. Erythrocyte sedimentation rate, CSF analysis, serum and CSF enzyme-linked immunoabsorbent assay, computed tomography scan were the most useful diagnostic tools to support clinical suspicion. Combination 4 drug antitubercular regimen for 12 months was the most effective and steroids improved the outcome in stages II and III of the disease. Mortality was higher in very severe disease, at extremes of age and delay in initiating treatment.

Tuberculosis (TB) continues to be a major health problem throughout the world. About 2 billion (one third of the world's population) people are infected with TB of which about 10% develop clinical disease.1,2 The incidence of central nervous system (CNS) tuberculosis is related to the prevalence of tuberculosis in the community and resurgence of 1990s because human immunodeficiency virus (HIV) has again declined due to availability of antiretroviral drugs and increased funding. In 1997, CNS tuberculosis represented 5.2% of all extrapulmonary cases and 0.7% of all reported TB cases. In 2004, Nelson et al3 reported tuberculous meningitis (TBM) as 2.1% of pediatric cases and 9.1% of extrapulmonary cases.

The developing world has 1.3 million cases of TB and 40,000 TB-related deaths annually among children younger than 15 years. In adults, there is 50% mortality or severe sequelae due to TBM in spite of treatment.4 In general, TBM is more common in children in the first 5 years of life, and in adults, males are effected more than females.6 The diagnosis of TBM is still very difficult, and delay in diagnosis is associated with adverse outcome.7 Steroids have improved the outcome but have no effect on the occurrence of sequelae.4 Although computed tomography (CT) scan and magnetic resonance imaging have revolutionized neuroimaging, changes of TBM to be recognized on imaging could be delayed for 4 to 6 weeks, thus negative results; and that is the period to start treatment and improve outcome.15 To avoid the adverse outcome, clinical suspicion is very important in early diagnosis. Because of the high prevalence of TB and TBM in our part of the world, we conducted this study to see the use of available tools in helping diagnosis of TBM and the effective regimen of treatment.

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METHODS

This study was carried out in hospitalized patients at Sheri-Kashmir Institute of Medical Sciences, Srinagar-kashmir (India) for a period of 3 years. Sixty-eight patients were enrolled out of which only 38 fulfilled the criteria of study which were as follows: follow-up for the specified period, compliance to treatment, and response to treatment or death. Patients were grouped into 3 stages according to severity of illness at presentation as per the criteria of modified British Medical Research Council.13 Complete blood counts, erythrocyte sedimentation rate (ESR), Mantoux test, acid-fast staining on available materials like sputum, cerebrospinal fluid (CSF) (also culture), urine, lymph node aspirate, liver function tests (using kinetic assays on an automatic system-HITACHI 704 for enzyme estimations), HIV serology, x-ray chest, lumbar puncture for CSF cell counts differential counts, protein, glucose were the routine tests done in addition to CSF India-ink staining and serum and CSF enzyme-linked immunoabsorbent assay (ELISA) for immunoglobulin M (IgM) antibody using A 60 Mycobacterial antigen (anda Biologicals, rue de la Course B.P. 76-67067 Strausbough Cedex, France). Lumbar puncture was done in only 35 patients (as guarded in those with features of raised intracranial pressure from clinical status and fundoscopy). Plain and contrast-enhanced CT scan brain was done in 34 patients at admission as 4 patients could not afford the cost of procedure and follow-up CT scans were done in those with tuberculomas, hydrocephalus, cerebral edema, and infarcts and those who could bear the cost using SOMATOM-DR-SIEMENS LTD. Treatment was started with 4 drugs daily, that is, isoniazid 5 mg/kg (maximum 300 mg, rifampicin 10 mg/kg, pyrazinamide 25 mg/kg, and ethombutol 20 mg/kg or streptomycin 20 mg/kg (maximum 1 g) for 2 months and isoniazid and rifampicin daily for 4 to 24 months depending upon the response. The response to treatment was determined by clinical improvement, repeat CSF analysis after 2 weeks of treatment if done at start; CT-scan in those with tuberculomas or other findings at the start of treatment. The patients with tuberculomas needed prolonged treatment although most were cured by 12 months. Steroids were added for first 4 weeks and tapered over a similar period in stage II and III disease. Dexamethasone at a dose of 0.2 to 0.4 mg/kg intravenously in first 2 weeks and half of this dose in next 2 weeks followed by per oral or nasogastric tubing at a dose of 4 mg/d with tapering by 1 mg/wk over the next 4 weeks.

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STATISTICAL METHODS

The statistical program for the social sciences (Release 10, 0, 1, PC windows, SPSS Ins., Chicago, IL) was used for data analysis. In addition χ2 test and Student t test were used for comparison between categorical and continuous variables respectively. Data were expressed as mean ± SD, unless stated otherwise. P value less than 0.05 was considered statistically significant.

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RESULTS

Out of 38 patients 21 (55.26%) were in the age group 20 to 39 years and (23) 60.2% were females. The demographic characteristics of patients are shown in Table 1. Twenty-nine patients (76.31%) belonged to rural areas and 9 (23.69%) were of urban background. Only 3 patients (7.89%) had a history of treatment of TB and 4 (10.52%) gave a family history suggestive of TB. Fever, headache, vomiting, signs of meningeal irritation, altered sensorium, papilloedema, and cranial nerve palsy were the most common symptoms and signs (Table 2).

Table 1
Table 1
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Table 2
Table 2
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Duration of illness was longer than 4 weeks in 20 patients (52.63) at presentation. Thirty-four patients (89.5%) were in stage II and stage III disease of the British Medical Council Research Centre (BMRC) staging (Table 3).

Table 3
Table 3
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Elevated ESR was found in 81% of the cases and Mantoux test was positive in 21% to 70% of cases (n = 30). Hyponatremia was found in 5 cases (13.5%). Cerebrospinal fluid lymphocytic leucocytosis (47.68%), CSF glucose less than 60% of corresponding blood glucose (73.68%), elevated protein positive (73.68%) acid fast staining (5.7%) were the important results (Table 4). Cerebrospinal fluid and serum ELISA was positive in 16 (42.10%) and 23 (60.52%) patients, respectively (Table 5). Most common CT scan abnormality was basal enhancement in 9 patients (26.47%) and tuberculomas 13 (38.23%) hydrocephalus 7 (28.58%; Table 6). Hypertension, cholelithiasis, and biliary ascariasis were the few coexisting diseases, but none had any effect on morbidity or mortality as ascariasis is endemic in this part of the world. Twelve-month 4-drug regimen was the most effective one, and steroids improved the outcome (Table 7).

Table 4
Table 4
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Table 5
Table 5
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Table 6
Table 6
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Table 7
Table 7
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Residual deficits were seen in 12 cases (34.28%), and persistent cranial nerve palsy, endocrinopathy and limb weakness were the most common (Table 8).

Table 8
Table 8
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Amenorhea-galactorrhea syndrome was seen in 1 patient. Sequelae and deaths were more in stage III disease (Table 9), and sequelae were more in those who presented beyond 4 weeks (Table 10).

Table 9
Table 9
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Table 10
Table 10
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Mortality was higher at extremes of age (Table 11) and in those who had stage III disease at presentation (Table 12).

Table 11
Table 11
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Table 12
Table 12
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DISCUSSION

Tuberculosis is a global disease, and almost 2 billion people (one third of the world's population) are infected.1 The most common form of TB is pulmonary, and the most dangerous form is that of CNS accounting for 5.2% of clinical TB and almost 50% morbidity.2 Recent data show that 2.1% of the cases are in pediatric population.3

In the developing world, 1.3 million people are infected, accounting for 40,000 TB related deaths annually.2 Among children younger than 15 years, TBM complicates approximately 1 of every 300 untreated primary TB infections,5 and incidence of TBM in a community depends upon prevalence of TB in that community especially if the latter are of poor socioeconomic status and live in overcrowded conditions. In our study three fourth of the cases (76.31%) belonged to rural areas of the Kashmir valley. Tuberculous meningitis has no age limit, but the highest incidence before the era of HIV was reported in children aged 0 to 5 years and is rare before 4 months of age.3 In our study, females (60.52%) outnumbered males (39.42%). The higher percentage of females in our study can be explained as the greater number of cases were from rural areas of the valley where female education is still meager, health awareness is far less, females remain mostly indoors, poverty is a great problem, and females are overworking but underfed.8,9,34

In populations with low prevalence of TB, most cases of TBM occur in adults, and HIV has definitely increased the risk in adults although there is again a decline in the number of cases reported in adults due to the widespread availability of antiretroviral drugs and more funds allocation.6 However, 55.26% of the case in our study were in the age group 20 to 39 years with a mean age of 29.14 ± 16.28 years which is close to that reported by Juan Barengufer et al,7 that is, 38.8 ± 21.7 years. Duration of illness varies in TBM and patients present with acute fulminant illness or as sub-acute dementing illness.10 Fifty-five percent of the cases present with symptoms of less than 2 weeks duration,11 and duration varies from 1 day to 9 months. In this study, 52.6% of the cases presented with symptoms of greater than 4 weeks duration and this was statistically significant (P ≤ 0.01) with a range of 4 to 180 days. Slightly greater duration of symptoms in our study could be attributed to difficult access to specialized medical centers due to poor road network and underdeveloped primary health care10 history of TB could be elicited in 7.89% of the cases which is in accordance with the literature.12 Co-existing illnesses like immunosuppressed states, HIV infection, drug abuse, and other medical illnesses have been reported in 42% of the cases,7 the most common being alcoholism (21%). In our patients, only 18.42% of the cases had co-existing illnesses like cholecystitis, biliary ascariasis (ascariasis is endemic in our part of world), and hypertension. Alcoholism is rare in our part of the world especially Kashmir valley because of religious reasons and of course affordability.

Fevers, headache, vomiting, and altered sensorium are the most common symptoms at presentation. Neck rigidity, altered sensorium, cranial nerve palsies, and papilloedema are the most common signs observed.7 Similar observations were made in our study. About 89.47%34 of the patients presented with severe disease, that is, stage II (50%) and stage III (39.47%) as per BMRC13 criteria. Because the patients in advanced stage have alarming symptoms which are attention seeking in contrast to stage I illness with nonspecific symptoms which are ignored by the patient as well as caregivers.

Diagnosis of TBM is difficult and often a dilemma because the dreaded infection can mimic a variety of CNS diseases.14 Goodhart and Still have rightly said that "added experience only makes it clear how treacherous is the disease and how impossible in some cases it is to avoid mistakes." Same sentiments are being echoed by all those who still encounter the disease.15 Clues to diagnosis of TBM come from history of contact with a known case of TB. Such history is available in 20% to 30% of the cases only.11 We could elicit history of contact in 10.5% of the cases only which we account for the fact that majority of our population is illiterate and who because of social stigma attached with the disease hide the history.

Routine investigations are seldom striking in TBM. Anemia and leucocytosis are frequently reported abnormalities. About 39.47% of our patients had anemia, and 21.05% had leucocytosis and it is likely for the anemia to be nutritional in our patients. Hyponatremia reflecting inappropriate secretion of antidiuretic hormone if present in a patient with aseptic meningitis suggests a tuberculous etiology.17 Hypnatremia has been reported in 47.69% of the cases. This abnormality was observed in 13.15% of our cases. Elevated ESR is a frequently noted laboratory abnormality and was noted in 81.57% of our cases. The presence of pulmonary TB in a patient with aseptic meningitis strongly favors a tuberculous etiology, but its absence does not rule it out. Elderly patients have a normal chest x-ray. However, 50% of the adults and 90% of the children have an abnormal chest x-ray.16 About 39.47% of our patients had abnormalities on their chest x-ray suggestive of active pulmonary disease like military infiltrates, apical infiltrates, cavitary shadow, hilar adenopathy, and pleural effusion. Positive Mantoux test is quite helpful in diagnosis.11 Seventy percent of our patients had positive Mantoux test.

Cerebrospinal fluid analysis is an important diagnostic aid in TBM. Moderate degree of pleocytsis usually not exceeding 500 cells/mm3 is common. Cerebrospinal fluid white blood cell count greater than 1200 cells/mm3 is extremely rare in TBM.11Cerebrospinal fluid may be normal in rare cases in wherein the disease has been definitively diagnosed.17 Kocen and Parsons suggested that this occurs because miliary cerebral tuberculomas may give rise to neurological symptoms and signs before involvement of leptomeninges. In our study, 28.97% of the cases had total cell count greater than 200 cells/mm3 with mean ± SD of 175 ± 247.51 cells/mm3. Three patients had no cells in CSF which could be explained by Kocen and Parsons hypothesis. Most of the cells in CSF are lymphocytes11 and CSF lymphocytosis greater than 50% has been reported in 80% to 83% of the patients.7,16 About 47.68% of our patients had greater than 90% lymphocytes in CSF which is statistically significant (P = 0.013) suggesting that CSF lymphocytic ratio greater than 90% should be considered a strong diagnostic pointer toward TBM. Low CSF glucose and elevated protein are other characteristic abnormalities seen in TBM. Berengufer et al have reported low CSF glucose in 89% of their patients.7 Tandon et al have reviewed large series of publications and reported the incidence of low CSF glucose as varying from 50% to 95% patients. About 78.96% of our patients had CSF glucose less than 60% of the corresponding blood glucose which is again statistically significant (P = 0.001). Elevated CSF protein (> 50 mg%) has been found in 75% to 85% of the patients.18 In our series, 73.68% patients had elevated CSF protein which was statistically significant (P = <0.02). Considering the statistical power of CSF findings in our study, we conclude that CSF lymphocytosis (>90%), hypoglycorrhachia (60% of the corresponding blood glucose), and elevated CSF protein (>50 mg/dL) in a suitable clinical setting are strong diagnostic pointers toward TBM. Mycobacterium TB CSF smear positivity has been reported in 10% to 90% of cases by some17 and less than 10% of the cases by others.19 Those who had higher yield of acid-fast bacillus have devoted more time for searching (30 to 90 minutes), have examined more specimens, few have prepared thick smears from centrifuged specimens. Only in 5% of the cases could we get smear positivist CSF in spite of all the precautions. The identification of specific CSF or serum antibody against a variety of mycobacterial antigen preparations has been applied by immunodiagnostic techniques like ELISA.20-22 These techniques are inherently more sensitive than specific, compromised by the presence of low-level circulating, cross-reactive antibodies that may hamper their diagnostic accuracy at all but the cut-off levels. Coovadia et al reported serum and CSF ELISA positive for IgM antibody against A60 mycobacterial antigen in 48.1% and 73.24% of the cases. Zou et al made similar observations. Our results were positive in 42.10% for serum and 60.52% of the cases for CSF, using A60 mycobacterial antigen for IgM antibody (Table 5).

Computed axial tomographic scanning with contrast and magnetic resonance imaging have brought most of the intracranial pathology visible to the naked eye23 Abnormalities reported on CT scan done in stages II and III disease are hydrocephalus, infarcts, basal enhancement, and cerebral edema.24 Normal study is reported in up to 20% of the cases. We did CT scanning in 34 patients irrespective of the stage of disease and abnormal findings were observed in 73.52% patients (Fig. 1 A-C) as basal enhancement in 36%, hydrocephalus in 28%, tuberculomas in 52%, infarcts in 12.0%, cerebral edema in 8.0%, and more than 1 finding in 32.0% of the patients (Table 6). Normal study was in 26.4%. All patients in stage I disease had abnormal CT findings in comparison to 50% of stage II and 83.3% of stage III disease. Thus, CT scan is a useful diagnostic tool even in very early stages of TBM.

Figure 1
Figure 1
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Drug regimens for CNS TB have never been validated-the kind of large-scale randomized treatment studies devised for pulmonary disease. The disease has been too infrequent, too catastrophic, and too difficult to diagnose to fit easily into this kind of research. Instead, modern day treatment is a compromise between older clinical data and modern prescribing habits for other forms of TB. Successful chemotherapy requires the use of multiple drugs to which the organism is sensitive. However, the major challenge is the identification of drugs that reliably penetrate meninges and brain parenchyma. The recommended regimen after keeping in view the pharmacokinetic data and suspicion of isoniazid (INH) resistance includes isoniazid, rifampicin, pyrazinamide with addition of amino glycoside or other drugs like ethombutol, ofloxacin, or ethionamide.2,23 The optimum duration of treatment is still debated and depends on a case to case basis in spite of World Health Organization guidelines of 20032 which recommends a 12-month treatment. Neurosurgical intervention is required to relieve hydrocephalus, to drain the tubercular brain abscess, and to break the optochiasmatic adhesions to prevent blindness.24 In our study, isoniazid, rifampicin, pyrazinamide, and ethombutol in adults and streptomycin in place of ethombutol for children were used. The duration of treatment was based on clinical response, radiological improvement on follow up CT scans and compliance to treatment on the case-to-case basis; 4 drugs for first 2 months and INH and rifampicin for rest of the period with pyridoxine 10 to 40 mg/d in all the patients. Twelve-month regimen was the most effective one and statistically significant even to melt tuberculoms (Fig. 2 A-C), although 17.01% of the cases required treatment for 24 months, the latter included some cases with tuberculomas and where compliance was a problem either due to nonavailability at peripheral rural centers or due to absence of caregivers. Regarding steroids, some authorities now routinely include in stages II and III disease4 as well as for spinal cord disease and significant cerebral edema.25 We used steroids (dexamethasone) in stage II and stage III disease patients, that is, 34 patients. Thirty-one patients (93.93%) improved with medical treatment only, and 5 patients needed surgical intervention in the form of shunt surgery in addition to antitubercular medication and steroids. Overall, there was 92.10% survival and 7.90% mortality. We concluded that medical treatment alone had best results in TBM because out of 7 cases of hydrocephalus, 5 needed shunt surgery with 1 mortality and other 2 improved with medical treatment only. Drug-induced hepatitis was the most common complication observed. Five patients had biochemical evidence but only 2 had clinical evidence. One patient with hepatitis improved after antitubercular medication was withheld, but this patient had stage III disease at presentation and needed shunt surgery for hydrocephalus and died of sepsis after the surgery.

Figure 2
Figure 2
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The famous clinician Edith Lincoln12 voiced concern over the impending availability of drugs to treat TBM: cases will have to be recognized early if we are to cure the disease without leaving a damaged brain, she warned. Sixty years of treatment have amply justified the concern. The lesson of TBM to be repeatedly taught is that treatment should be started as swiftly as possible on clinical grounds. Delay through bewilderment or procrastination through uncertainty is dangerous and often leads to worse prognosis.26 Reliable independent prognosticators in TBM include extremes of age and advanced disease at presentation.27 Mortality in recent series of treated cases is 10% to 30%.27 Mortality in our cases was 7.89%. The risk of neurological impairment despite treatment is also a direct correlate of stage of illness at presentation. Neurologic disabilities ranging from mild to severe are reported in 10% to 50% of both adults and children who survived the infection.4,28 These include mental retardation and behavioral problems in children, organic brain syndromes in adults, ataxia, hemi-paresis, persistent seizure disorders, and cranial nerve palsies.29 Endocrinopathies like delayed or precocious sexual development, diabetes insipidus, gonadtrophin, or growth hormone deficiency are also reported.30,31 Sequelae were seen in 34.28% of our cases with persistent cranial nerve palsies as the most common (41.66%). One patient developed ammenorrhoea-galactorrhoea, 1 diabetes insipidus, and 1 decerebrate posturing (Fig. 3). Steroids reduced the sequelae in our series, that is, 50% of those in stage I disease were left with sequelae as against the 34.84% in stage II and 25.0% in stage III disease where steroids were used (Table 9). The greater the depression of mental status at the initiation of treatment, the worse the outcome,11 was true in our cases also. About 66.66% of the total mortality was seen in stage III disease at presentation. Delay in treatment was associated with adverse prognosis in our study also. About 52.6% of our patients had symptoms longer than 4 weeks duration at presentation which is statistically significant (P ≤ 0.001). Thirty-five percent of such patients were left with sequelae. The longer the duration of symptoms before hospitalization, the more severe was the disease. About 36.84% and 28.94% of our patients presented in stage II and stage III disease respectively and had symptoms of more than 2 weeks at presentation. Kennedy and Fallon32 have also reported the delay in treatment associated with increased neurological sequelae. Age of the patient is of course an independent prognostic factor. Patients younger than 20 years and older than 60 years age presented in stage III disease-26.31% and 7.89%, respectively. Six patients (60.00%) out of 10 were younger than 20 years and all 3 patients (100.00%) were older than 60 years. Mortality was also higher at the extremes of age, that is, out of total 3 deaths, 1 was younger than 12 years and 1 was older than 60 years.

Figure 3
Figure 3
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Thus, our study also proved that extremes of age have more severe disease and high mortality which is in accordance with the literature. The only limitation of our study was less number of pediatric population in whom disease is reported to be more common especially in developing world. Application of diagnostic criteria proposed by Seth and Sharma33 when applied to our patients retrospectively hold validity in resource poor countries especially if altered sensorium and papilloedema are considered along with CSF lymphocytic pleocytosis. This study has provided vital information about the clinical presentation, usefulness of available diagnostic tools in early diagnosis, prognostic factors, and outcome of treatment of the dreaded disease of TBM in our part of the world where poverty illiteracy, ignorance, peculiar cultural patterns still predispose and perpetuate the illness of TB and TBM.

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CONCLUSIONS

From this study, we concluded that TBM was common in the female rural population in the age group 20-39 years. Clinical suspicion in a suitable clinical setting is very important and elevated ESR, positive Mantoux test, CSF lymphocytic predominance, elevated CSF protein, hypoglycorrhacia, CT scan brain are the best available diagnostic tools to strengthen the suspicion especially if evidence of extracranial TB is found. Combination antitubercular drugs with steroids must be started as early as possible to decrease long-term morbidity, decrease sequelae, and decrease mortality, and 12-month regimen is the most effective one even to melt away tuberculomas. Delay in treatment, advanced stage at presentation, extremes of age, and presence of hydrocephalus on computed tomography are the bad prognostic factors.

Importantly, education, funding, and awareness campaigns need to be reinforced and redirected to halt the predisposition and perpetuation of the dreaded disease in communities like ours.

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ACKNOWLEDGMENT

The authors thank Dr S M Saleem (DM Neurology) for supervision of the study.

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