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 » Introduction
 »  Materials and Me...
 » Results
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Table of Contents    
ORIGINAL ARTICLE
Year : 2012  |  Volume : 60  |  Issue : 1  |  Page : 18-22

Predictors of mortality in patients with meningeal tuberculosis


1 Government Pharmacy College, Thiruvananthapuram, Kozhikode, India
2 Department of Neurology, Government Medical College, Thiruvananthapuram, Kozhikode, India
3 Department of Internal Medicine, Government Medical College, Thiruvananthapuram, Kozhikode, India
4 Department of Obstetrics and Gynecology, Government Medical College, Thiruvananthapuram, Kozhikode, India
5 Department of Community Medicine, Government Medical College, Thiruvananthapuram, Kozhikode, India

Date of Submission09-Aug-2011
Date of Decision01-Sep-2011
Date of Acceptance27-Nov-2011
Date of Web Publication7-Mar-2012

Correspondence Address:
Thomas Iype
Government Medical College, Thiruvananthapuram - 695 011
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.93583

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 » Abstract 

Background: Meningeal tuberculosis (TB) has higher mortality compared to other forms of central nervous system TB. However, data on predictors of mortality is limited. Aims: To determine the predictors of mortality in patients with meningeal TB. Materials and Methods: This study retrospectively analyzed the data of patients admitted with a diagnosis of meningeal TB between January 2006 and December 2008. Thwaites' index score of four or less was used for the diagnosis of meningeal TB which is a weighted diagnostic index score for dichotomised clinical variables. Predictors of mortality were analyzed separately for both patients with human immunodeficiency virus (HIV) infection and without. Statistical Analysis: Univariate analysis and multinomial logistic regression was done. Results: Univariate analysis showed age >40 years, Glasgow Coma Scale (GCS) score <8, absence of headache, cerebrospinal fluid (CSF) protein ≤60 mg% and Medical Research Council (MRC) Stage III at presentation to predict in-hospital mortality. In multinomial logistic regression age >40 years was a risk factor for mortality when HIV patients were included (P=0.049) as well as when they were excluded (P=0.048). CSF protein ͳ 60 mg% was found to be a significant risk factor when both HIV seropositive persons (P=0.011) as well as seronegative persons (P=0.004) were included. HIV seropositivity, steroid treatment or delay in treatment did not affect mortality. Conclusions: Identification of factors predictive of in-hospital mortality will help to prognosticate patients with meningeal TB at the time of admission.


Keywords: Chronic meningitis, drug-induced liver injury, rifampicine, steroids, treatment outcome


How to cite this article:
George EL, Iype T, Cherian A, Chandy S, Kumar A, Balakrishnan A, Vijayakumar K. Predictors of mortality in patients with meningeal tuberculosis. Neurol India 2012;60:18-22

How to cite this URL:
George EL, Iype T, Cherian A, Chandy S, Kumar A, Balakrishnan A, Vijayakumar K. Predictors of mortality in patients with meningeal tuberculosis. Neurol India [serial online] 2012 [cited 2019 Oct 16];60:18-22. Available from: http://www.neurologyindia.com/text.asp?2012/60/1/18/93583



 » Introduction Top


Diagnosis, treatment and prognostification of tuberculosis (TB) of the central nervous system (CNS) still pose a formidable challenge and account for about 1% of all cases of TB. Tuberculous meningitis (TBM) is the severest form of CNS TB and is associated with significant morbidity and mortality. Diagnosis of TBM is often based on the clinical features and cerebrospinal fluid (CSF) findings. [1] Early diagnosis is crucial for successful disease management as the case fatality of untreated TBM is almost 100%, and delay in treatment often associated with permanent neurological damage. [2] In a long-term follow-up study of 135 patients with proven meningeal TB on daily directly observed therapy, survival at the end of treatment was 73.3% and 39.76% at the end of 8.71-year mean follow-up. [3] Some of the predictors of mortality included: Age, altered sensorium, underlying comorbidities, and leukocytosis. [4] Admission Glasgow Coma Scale (GCS) score has been shown to predict in-hospital mortality in patients with culture-proven meningeal TB. [5] Delay in the diagnosis is also associated with poor outcome. In a Taiwan study, there was a delay in diagnosis in 47.6% of patients resulting in further progression of the disease stage in 36.2% of patients which was associated with poor outcome. [6] In this study we analyzed the predictors of mortality in patients with meningeal TB.


 » Materials and Methods Top


Setting

This retrospective study was undertaken in the Department of Neurology, Government Medical College Hospital, Trivandrum, Kerala, a tertiary care referral centre for neurological diseases in south India. From the prospectively maintained database, the case records of all patients with meningitis between January 2006 and December 2008 were reviewed. Through the Revised National Tuberculosis Control Program (RNTCP), the Government of India is providing directly observed thrice weekly anti-tuberculosis treatment (ATT) (RNTCP regimen) free of cost. Isoniazide 10 mg per kg, rifampicin 10 mg per kg, ethambutol 30 mg per kg, and pyrazinamide 35 mg per kg are given thrice a week during the intensive phase for two months followed by isoniazide and rifampicin alone thrice a week for seven months in the continuation phase. Since there is no evidence that the RNTCP regimen is effective in meningeal TB, in this study some patients received daily regimen and some others got intermittent regimen of ATT. All patients with elevated intracranial pressure, altered consciousness, and focal neurological deficits received parentral dexamethasone 12 mg daily during the hospital stay.

Subjects

From among the patients with meningitis admitted during the study period, patients with features suggestive of meningeal TB and satisfying Thwaites' index, which has a sensitivity of 97% and specificity of 91%, [7] were identified. Thwaites' index is obtained by adding up the weighted diagnostic index scores for dichotomised clinical variables including age, blood white cell count, duration of illness, CSF total white cell count and neutrophil percentage. Patients with diagnosis of TB meningitis with Thwaites' index of four or less [Appendix 1] were included in the analysis irrespective of the ATT regimen, daily regimen or the RNTCP regimen.



Exclusion criteria

We excluded patients with incomplete data, patients with clinical features consistent with bacterial meningitis, patients seropositive for Weil's disease or dengue infection, patients with peripheral smear positive for malarial parasite, patients with malignant cells in CSF and patients positive for CSF India ink stain.

Data collected included demographic features like age and sex of patients, smoking habits, alcohol abuse and clinical features including fever, headache, neck stiffness, weakness, seizures, aphasia, and papilloedema. Severity of meningeal TB was assessed by the Medical Research Council (MRC) staging. [8] Other factors collected included evidence of a TB focus elsewhere, history of contact with TB, and human immunodeficiency virus (HIV) co-infection. CSF parameters like cell counts, glucose level, and protein level were noted. Neuroimaging features noted included hydrocephalus, infarction(s) and tuberculoma(s). Treatment variables studied included duration of illness before initiating ATT, delay in initiating ATT after admission, duration of hospital stay, number of days on ATT (in days), adverse drug reactions (liver enzymes >3 times upper limit of normal) and steroid use. Response to treatment was judged by clearance of clinical features with concurrent improvement in appetite and weight. Patients were discharged when they had good clinical response.

Statistics

Statistical analysis was done using SPSS 16.0 for Windows. Continuous variables were analyzed by independent Student's t test and categorical variables were analyzed by Chi square test and Fisher's exact test. Multinomial logistic regression was done to find out the risk factors. Risk was expressed as odds ratio. A P value <0.05 was considered to indicate statistical significance.


 » Results Top


During the study period 98 patients fulfilled the exclusion and inclusion criteria including Thwaites' index for the diagnosis of meningeal TB. None of the patients were positive for CSF acid-fast bacillus (AFB) smear or culture. CSF TB_ polymerase chain reaction (PCR) was done in only 15 patients, only four were positive. Of the 98 patients, 55 patients were on the RNTCP regimen and 43 were on daily regimen. The in-hospital mortality was 27.55% (27 patients: 15 on the RNTCP regimen and 12 on daily regimen). Our preliminary experience with intermittent short-course ATT showed similar in-hospital mortality. [9] Patients who died on RNTCP regimen got five days median treatment compared to three days median treatment with daily regimen (P < 0.005). The median duration of illness prior to hospitalization between the patients who died (15 days) and patients who were alive (14 days) was significantly different (P < 0.0001). The median duration of hospital stay between these two groups was also significantly different, 10 days vs. 13 days (P < 0.0001). The clinical profile of patients who died is given in [Table 1]. The imaging abnormalities in the patients who were alive and who died are given in [Table 2]. The causes of mortality included elevated intracranial pressure (nine patients), sepsis (four patients), aspiration pneumonia (three patients), disseminated TB (three patients), immune reconstitution inflammatory syndrome (IRIS) (one patient) and arteritis (one patient) and in six patients no definite cause for death could be established.
Table 1: Profile of 27 patients who died of meningeal tuberculosis

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Table 2: Imaging features

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Univariate analysis showed age >40 years, Glasgow Coma Scale (GCS) score <8, absence of headache, CSF protein ≤60 mg% and MRC Stage III at presentation as predictors of in-hospital mortality [Table 3]. However, other variables found to not influence mortality included: Sex, fever, neck stiffness, focal weakness, seizures, presence of hydrocephalus, tuberculoma or infarction on imaging, CSF features: White blood cell count <200/mm 3 , sugar <30 mg%, positive CSF TB PCR, treatment delay of > 21 days, concomitant use of steroids, hyponatraemia <130 mEq/L, complications like hepatitis, and presence of pulmonary TB. The same variables were predictive of mortality when HIV patients who were alive were excluded [Table 4].
Table 3. Predictors of mortality in all 98 patients with tuberculous meningitis(HIV positive included)

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Table 4: Significant predictors of mortality among HIV-negative patients with tuberculous meningitis

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In multinomial logistic regression: Age >40 years was a risk factor for mortality when HIV patients were included (OR = 2.942 (1.004 - 8.616), P=0.049) as well as when they were excluded (OR = 3.237 (0.989 - 10.927), P=0.048). We also found CSF protein ≤60 mg% to be a significant risk factor in HIV positive patients (OR = 4.154 (1.394 - 12.377), P=0.011) and immunocompetant persons (OR = 4.329 (1.585 - 11.905), P=0.004). HIV seropositivity, steroid treatment and delay in treatment did not affect the mortality in the current study.


 » Discussion Top


In this study, age and CSF protein ≤60 mg% were found to predict mortality in patients with meningeal TB in both HIV-seropositive as well as seronegative persons. The mortality observed was comparable to the reported mortality in culture-negative meningeal TB. [3] On the contrary, the in-hospital mortality in culture-positive meningeal TB in the literature is high. [10] In our study, age >40 years at presentation was associated with higher mortality. Higher age at presentation (>60 years) showed a trend to higher in-hospital mortality in a study in Taiwan. [6] Absence of headache at presentation was found to be associated with higher mortality on univariate analysis. Similar was the observation in the study by Sheu and colleagues. [6] We speculate that the absence of headache would result in the delay of the diagnosis, thus leading to higher mortality. In-hospital GCS score and stage of the disease predicted mortality in our study on univariate analysis. In the earlier studies admission GCS score [5],[11],[12],[13] and stage of the disease were found to independently predict in-hospital death. [5],[14],[15]

Factors which were found to be significant predictors of mortality or poor outcome in previous studies like delayed or interrupted treatment, [6],[16] presence of syndrome of inappropriate secretion of antidiuretic hormone (SIADH), [7],[17] presence of hydrocephalus, [8],[14] focal weakness, [10] infarction, [11] female gender, [12] high CSF protein concentration, [6],[14],[15] low CSF glucose levels, [6],[15] and low CSF/blood glucose ratio [6],[11],[15] were not found to be significant predictors of mortality in our study. HIV seropositivity has been shown not to affect the mortality of meningeal TB in the short term [18] and this has been reiterated in our study. In this study patients with elevated intracranial pressure, altered consciousness, and/or focal neurological deficit received intravenous dexamethasone. The administration of parenteral steroids is known to benefit patients with meningeal TB. [13] Probably this would be the reason for early resolution of symptoms in our patients.

Attempts have been made to develop scoring systems to assess the severity of illness at presentation specific to meningeal TB which may correlate with mortality better. Chou et al., found Acute Physiology and Chronic Health Evaluation (APACHE) II to be as effective as GCS within 24 h of admission and superior to MRC grading to predict in-hospital mortality. [19] But these scoring systems are cumbersome, time-consuming and difficult for bedside practice. The four mortality-predicting factors emphasized in our current study are simple, easy to reproduce and help the practitioner make pragmatic conclusions.

The limitations of the current study are that it is a retrospective study and none of our patients had culture positivity. In addition long-term mortality and morbidity data of this hospital cohort could not be collected.

 
 » References Top

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3.Shaw JE, Pasipanodya JG, Gumbo T. Meningeal tuberculosis: High long-term mortality despite standard therapy. Medicine (Baltimore) 2010;89:189-95.  Back to cited text no. 3
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4.Yasar KK, Pehlivanoglu F, Sengoz G. Predictors of mortality in tuberculous meningitis: A multivariate analysis of 160 cases. Int J Tuberc Lung Dis 2010;14:1330-5.  Back to cited text no. 4
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5.Thwaites GE, Chau TT, Caws M, Phu NH, Chuong LV, Sinh DX, et al. Isoniazid resistance, mycobacterial genotype and outcome in Vietnamese adults with tuberculous meningitis. Int J Tuberc Lung Dis 2002;6:865-71.  Back to cited text no. 5
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6.Sheu JJ, Yuan RY, Yang CC. Predictors for outcome and treatment delay in patients with tuberculous meningitis. Am J Med Sci 2009;338:134-9.  Back to cited text no. 6
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7.Thwaites GE, Chau TT, Stepniewska K, Phu NH, Chuong LV, Sinh DX, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Lancet 2002;360:1287-92.  Back to cited text no. 7
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8.Streptomycin treatment of tuberculous meningitis. Lancet 1948;1:582-96.  Back to cited text no. 8
    
9.Iype T, Chacko S, Raghavan S, Mathew R, Mohan M. Preliminary report of directly observed treatment, short course in tuberculous meningitis. Ann Indian Acad Neurol 2010;13:57-60.  Back to cited text no. 9
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10.Karstaedt AS, Valtchanova S, Barriere R, Crewe-Brown HH. Tuberculous meningitis in South African urban adults. QJM 1998;91:743-7.  Back to cited text no. 10
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11.Hosoglu S, Geyik MF, Balik I, Aygen B, Erol S, Aygencel TG, et al. Predictors of outcome in patients with tuberculous meningitis. Int J Tuberc Lung Dis 2002;6:64-70.  Back to cited text no. 11
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12.Misra UK, Kalita J, Roy AK, Mandal SK, Srivastava M. Role of clinical, radiological, and neurophysiological changes in predicting the outcome of tuberculous meningitis: A multivariable analysis. J Neurol Neurosurg Psychiatry 2000;68:300-3.  Back to cited text no. 12
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13.Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Nguyen TC, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351:1741-51.  Back to cited text no. 13
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14.Girgis NI, Sultan Y, Farid Z, Mansour MM, Erian MW, Hanna LS, et al. Tuberculosis meningitis, Abbassia Fever Hospital-Naval Medical Research Unit No. 3-Cairo, Egypt, from 1976 to 1996. Am J Trop Med Hyg 1998;58:28-34.  Back to cited text no. 14
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15.Hosoglu S, Ayaz C, Geyik MF, Kökoðlu OF, Ceviz A. Tuberculous meningitis in adults: An eleven-year review. Int J Tuberc Lung Dis 1998;2:553-7.  Back to cited text no. 15
    
16.Torok ME, Chau TT, Mai PP, Phong ND, Dung NT, Chuong LV, et al. Clinical and microbiological features of HIV-associated tuberculous meningitis in Vietnamese adults. PLoS One 2008;3:e1772.  Back to cited text no. 16
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18.Dube MP, Holtom PD, Larsen RA. Tuberculous meningitis in patients with and without human immunodeficiency virus infection. Am J Med 1992;93:520-4.  Back to cited text no. 18
    
19.Chou CH, Lin GM, Ku CH, Chang FY. Comparison of the APACHE II, GCS and MRC scores in predicting outcomes in patients with tuberculous meningitis. Int J Tuberc Lung Dis 2010;14:86-92.  Back to cited text no. 19
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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