ABSTRACT

CORRESPONDING AUTHOR:
Dr. Halesha B. R,
Assistant Professor,
Department of General Medicine,
Hassan Institute of Medical Sciences,
Hassan-573201, Karnataka, India.
Email: haleshbr81@yahoo.co.in

ABSTRACT: OBJECTIVE: The study was carried out to describe the current epidemiology, clinical features, complications and outcomes in patients with tuberculous meningitis (TB Meningitis) in a tertiary care hospital of southern India. SETTING: Sri Chamarajendra District Hospital which is attached to Hassan Institute of Medical Sciences, Hassan, Karnataka, India. STUDY DESIGN: A record-based retrospective descriptive study. MATERIALS AND METHODS: Seventy cases of confirmed cases of tuberculous meningitis were studied between January 2011 and December 2013.The diagnosis of TB Meningitis was based on clinical and laboratory features. The data on the demographic factors, clinical features, complications, details of treatment and the outcome of these patients were recorded and analyzed. RESULTS: The mean age of the patients was 39.27 +/- 7.8 years with slight male predominance 39 (55.7%). Most common presenting features were fever (92.8%), altered sensorium (80%), and neck stiffness (77.2%). Among CNS (Central Nervous System) signs 63(90%) had signs of meningeal irritation, 21(30%) had cranial nerve palsies and 13 (18.57%) presented with Hemiplegia. 48(68.5%) patients presented in MRC (Medical Research Council) stage 2. The study revealed overall mortality of 11.42%, 38(54.28%) patients recovered completely without any residual deficits and 24(34.30%) patients had residual neurological sequelae. CONCLUSIONS: Tubercular meningitis is a serious central nervous system infection associated with significant mortality and high morbidity among survivors. The only way to reduce mortality and morbidity is by early diagnosis, timely recognition of complications and institution of appropriate treatment strategies.

KEYWORDS: Anti tubercular drugs, Hydrocephalus, Morbidity, Tuberculoma, Tuberculous Meningitis.

INTRODUCTION: Tuberculous meningitis (TB Meningitis) is a debilitating form of CNS tuberculosis with a high morbidity and mortality in spite of treatment. It is the most dangerous form of extra-pulmonary tuberculosis.

Though India is the second-most populous country in the world one fourth of the global incident tuberculosis (TB) cases occur in India annually. In 2012, out of the estimated global annual incidence of 8.6 million cases, 2.3 million were estimated to have occurred in India.

TB Meningitis is characterized by a slowly progressing granulomatous inflammation of the basal meninges. This inflammatory reaction can lead to a number of complications such as hydrocephalus, cerebral vascular infarction, cranial nerve palsy and if untreated, death.

Rapid diagnosis and initiation of treatment is necessary to reduce high mortality and severe sequelae associated with the disease.

Diagnosis of TB Meningitis can be difficult as the symptoms are unspecific and mimic those of meningitis caused by other microbiological agents or other cerebrovascular events.

MATERIALS AND METHODS: This record-based, retrospective, descriptive study was carried out at Sri Chamarajendra District Hospital which is attached to Hassan Institute of Medical Sciences, Hassan, Karnataka, India. This institute is a referral government hospital in southern Karnataka, India catering to the patients hailing from Hassan, Madikeri and Chikkamagalur districts.

Seventy confirmed cases of TB Meningitis between January 2011 and December 2013 were retrospectively studied. In the study protocol, all confirmed cases of TB Meningitis, above the age of 12 years of both sex and informed consent were included.

The criteria for exclusion were age younger than 12 years, patients with CNS pathologies which can mimic TB Meningitis like Bacterial Meningitis, Viral Encephalitis, Subarachnoid Hemorrhage, Intra-Cranial Bleed, Cerebral Malaria, Stroke or Epilepsy.

Patients’ hospital records were evaluated for clinical features, chest radiography, Monteux test, sputum smear for Acid Fast Bacilli (AFB), routine investigations, CSF (Cerebro-Spinal Fluid) studies, CT (Computerized Tomography) scan and MRI (Magnetic Resonance Imaging) scan of the head. On the basis of clinical presentation, patients of TB Meningitis were classified into 3 clinical stages according to the British MRC system.

All patients had been treated with conventional treatment according to the RNTCP (Revised National Tuberculosis Control Programme) Guidelines. Steroids were used in all of the patients.

The data on clinical features, laboratory findings and neuro-imaging reports were analyzed by SPSS software ver. 10. Clinical outcome of the patients studied were categorized as Complete Recovery, Recovery with Residual Neurologic Deficits (sequelae) and Death.

RESULTS: Of the 70 cases of TB meningitis studied, 39 (55.75%) were male and 31 (44.3%) were female. The mean age of the study population was 39.27 +/- 7.8 years with a range from 12 to 78 years (Median 37.5 years).

16 patients (22.8%) gave a past history of tuberculosis. 21 patients (30%) reported a contact with tuberculous patient. 26 patients (37.2%) were found to have tuberculous infection affecting other organs at presentation. Of which pulmonary tuberculosis was found to be the most common association (21.43%), other types being disseminated tuberculosis (5.72%), abdominal tuberculosis (4.28%), lymph node tuberculosis (4.28%) and spinal tuberculosis (1.43%). Co-morbid diseases associated with tuberculosis are shown in table/fig 1.

Symptoms and signs at admission are summarized in the table/fig 2. Fever was the most frequent symptom which was experienced by 65 patients (92.8%), followed by altered level of consciousness in 56 (80%) cases and neck stiffness in 54 (77.2%) cases. (Table/fig 2). Objective clinical signs elicited by clinical examination are presented in table/fig 2. The mean GCS (Glasgow Coma Scale) score at presentation was found to be 12.5+/- 2.6.

Chest radiograph revealed pulmonary infiltrates in 8 patients, miliary pattern in 2 patients and pleural effusion in 3 patients and cavity in 2 patients.

CT and MRI neuro-imaging findings are summarized in table/fig. 3. 19 patients (27.15%) developed hydrocephalus, out of which 13 (18.5%) were of the communicating type, while 6 (8.6%) were of the obstructive type. Among these patients of hydrocephalus, Ventriculo-peritoneal shunt had to be placed in 12 cases and the rest were managed conservatively.

Duration of hospital stay ranged from 9 to 50 days with a mean of 20.08 +/- 6 days.

At the end of standard duration of treatment, 38 patients (54.28%) recovered completely without any residual neurologic deficits, whereas, 24 patients (34.30%) recovered with residual neurologic deficits like Hemiplegia, cranial nerve palsy(s), seizures and 8 patients (11.42%) died due to complication(s).

DISCUSSION: Mean age of patients was 39.27 +/- 7.8 years which is similar compared to previous studies.¹ Slight male predominance in this study is comparable to other studies.^2,3

Most of the patients presented in clinical stage 2 MRC, which is in accordance with most of the other studies.^{2, 3} Delayed presentation leads to increased morbidity and mortality. Fever was the most frequent subjective symptom present in 65 patients (92.8%), followed by altered level of consciousness in 56 patients (80%) and neck stiffness in 54 (77.2%) cases. Clinical diagnosis of TB meningitis is difficult as the clinical features are non-specific and widely variable, and is often diagnosed when brain damage has already occurred.^4-6

The clinical triad of meningitis viz. fever (adults – 60 -95 %; Children – 67%), headache (adults – 50-80 %; children – 25%) and signs of meningismus (adults – 40-80 %; children – 98%) – may NOT be present in all the patients.⁵ Altered mental status is a more common presenting feature in children as compared to adults.⁶ In the elderly, signs of meningismus may be absent and seizures occurs more commonly.⁷ Patients with HIV co-infection may less commonly have fever, headache and meningismus, and they are more likely to present with altered mental status.^8,9

CSF Pleocytosis with predominant lymphocytosis, increased protein and reduced sugar was found in >92.8%. However, 5 patients were found to have Neutrophilic pleocytosis. AFB smear was found positive in only 3 patients out of the total studied, which correlates well with other similar studies.^{2, 3} Evidence shows that atypical findings in CSF do not rule out tuberculous meningitis.¹ Acellular CSF has been reported in the elderly and in patients with HIV co-infection.^{4, 6, 10, 11}

Bacteriological diagnosis by demonstration of acid-fast bacilli of Mycobacterium tuberculosis by Zeihl-Neelson stain (Sensitivity = 25%) and bacterial culture (Sensitivity = 18-83%) is highly specific (100%).⁶ Tests to detect Mycobacterium tuberculosis specific antibodies and antigen in CSF of patients with TB meningitis are rapid and less expensive. But these techniques are limited by the inability to differentiate acute infection from previous infection and by problems with cross-reactivity, in addition to variable and often poor sensitivity and specificity.¹⁰

Most common Neuro-imaging finding in this study is meningeal enhancement which is comparable to other studies.¹² A recent study found that MRI is superior to CT in identifying basal meningeal enhancement as well as infarcts. In the same study, hydrocephalus was detected equally by MRI and CT scans.¹³ In conclusion, MR scans should be considered as the primary choice for Neuro-radiological imaging in the initial diagnostic phase in a high-resource setting.

Cochrane systematic review recommends routine use of corticosteroids in HIV-negative patients with TB meningitis to reduce the incidence of death and disabling neurological deficits among survivors.^14-17 In accordance, all patients in this study were treated with corticosteroids.

This study reveals an overall mortality of 11.42%. The cause of death was hydrocephalus and/or brain damage in all these patients that met with death. Whereas, the mortality as revealed by other studies range from 6.9% to 77% of patients studied in each of them.^{7, 18, 19} (Table 5.). Higher mortality rate in other studies may be due to extensive disease (Stage 3 MCR), poor GCS status, MDR (Multi-Drug Resistant) or XDR (Extensively-Drug Resistant) strains of M. tuberculosis infection and delayed presentations.

At the end of standard duration of treatment, 38 patients (54.28%) had complete recovery without residual neurological deficits; 24 patients (34.2%) recovered with residual neurological deficit(s) including limb weakness, cranial nerve palsy(s) and seizures. Similar observations were made by few previous studies quoted.¹²

HIV co-infection does not alter the neurologic features of tuberculous meningitis but dramatically decreases the survival rate, although the incidence of severe disability in HIV-infected survivors may be equivalent or less than that in HIV-negative patients.²⁴

CONCLUSIONS: TB Meningitis is a serious CNS infection associated with significant mortality and high morbidity among the survivors of the disease. Most factors found to correlate with poor outcome can be directly traced to the stage of the disease at the time of diagnosis.

The single most important strategy to reduce mortality and morbidity is probably early diagnosis, timely recognition of complications and institution of appropriate and prompt treatment modalities. However still, the most challenging aspect is the certainty of early diagnosis which is further hampered by slow and insensitive diagnostic methods. The other emerging yet dreaded challenge is the treatment of MDR-TB and XDR-TB cases.

REFERENCES:

1.    Qureshi HU, Merwat SN, Nawaz SA, Rana AAK, Malik A, Mahmud MK, et al. Predictors of inpatient mortality in 190 adult patients with tuberculous meningitis. J Pak Med Assoc 2002; 52: 159-63.
2.    Fazel P A, Makki KU, Haroon H, Soomro I B, Afzal U. Clinical spectrum and outcome of patients with tuberculous meningitis. Med Channel 2006; 12: 21-3.
3.    Malik ZI, Ishtiaq O, Shah NH, Anwer F, Baqai HZ. Analysis an outcome of 30 patients with tuberculous meningitis. Pak J Med Res 2002; 41: 137-41.
4.    Thwaites GE, Hein TT. Tuberculous meningitis: Many questions, too few answers. Lancet Neurol 2005; 4: 160-70.
5.    Udani PM, Parekh UC, Dastur DK. Neurological and related syndromes in CNS tuberculous meningitis: Clinical features and pathogenesis. J Neurol Sci 1971; 14: 341-57.
6.    Van Well GT, Paes BF, Terwee CB, Springer P, Roord JJ, Donald PR, et al. Twenty years of pediatric tuberculous meningitis: A retrospective cohort study in the western cape of South Africa. Pediatrics 2009; 123: e1-8
7.    Karstaedt AS, Valtchanova S, Barriere R, Crewe-Brown HH. Tuberculous meningitis in South African urban adults. QJM 1998; 91: 743-7.
8.    Katrak SM, Shembalkar PK, Rijwe SR, Bhandarkar LD. The clinical, radiological and pathological profile of tuberculous meningitis to patients with and without human immunodeficiency virus infection. J Neurol Sci 2000; 181: 118-26.
9.    Whiteman M, Espinoza L, Post MJ, Bell MD, Falcone S. Central nervous system tuberculosis in HIV-infected patients: Clinical and radiographic findings. AJNR Am J Neuroradiol 1995; 16: 1319-27.
10.    Rock RB, Olin M, Baker CA, Molitor TW, Peterson PK. Central nervous system tuberculosis: Pathogenesis and clinical aspects. Clin Microbiol Rev 2008; 21: 243-61.
11.    Sinner SW, Tunkel AR. Approach to the diagnosis and management of tuberculous meningitis. Curr Infect Dis Rep 2002; 2: 324-31.
12.    Salekeen S, Mahamood K, Naqvi IH, Baig MY, Akhter ST, Abbasi A. Clinical course, complications and predictors of mortality in patients with tuberculous meningitis — an experience of fifty two cases at Civil Hospital Karachi, Pakistan. J Pak Med Assoc 2013; 63: 563-7.
13.    Pienaar M, Andronikou S, van Toorn R: MRI to demonstrate diagnostic features and complications of TBM not seen on CT. Childs Nerv Syst 2009; 25: 941-7
14.    Murthy J. Tuberculous meningitis: The challenges. Neurol India 2010; 58: 716-22.
15.    Thwaites GE, Bang ND, Dung NH, Quy HT, Oanh DTT, Thoa NTC et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004; 351: 1741-51.
16.    Escobar JA, Belsey MA, Dueñas A, Medina. Mortality from tuberculous meningitis reduced by steroid therapy. Pediatrics 1975; 56: 1050-5.
17.    Prasad K, Volmink J, Menon GR. Steroids for treating tuberculous meningitis. Cochrane Database Syst Rev 2000; (3): CD002244.
18.    Kent SJ, Crowe SM, Yung A, Lucas CR, Mijch AM. Tuberculous meningitis: A 30 year review. Clin Infect Dis 1993; 17: 987-94.
19.    Kilpatrick ME, Girgis NI, Yassin MW, Ella AE. Tuberculous meningitis— clinical and laboratory review of 100 patients. J Hyg (London) 1986; 96: 231-8.
20.    Iype T, George LE, Cherian A, Kumar A, Ajitha BK, Chandy S. In hospital mortality of intermittent vs. daily Antitubercular regimen in patients with meningeal tuberculosis- A retrospective study. Indian J Tuberc 2012; 59: 6-11.
21.    Shaikh MA, Shah Mujtaba, Channa F. Criteria indicating morbidity in tuberculous meningitis. J Pak Med Assoc 2012; 62: 1137-9.
22.    Christensen AH, Andersen AB, Thomsen V, Andersen PH, Johansen IS: Tuberculous meningitis in Denmark: a review of 50 cases. BMC Infectious Diseases 2011; 11: 47.
23.    Roca B, Tornador N, Tornador E. Presentation and outcome of tuberculous meningitis in adults in the province of Castellon, Spain: a retrospective study. Epidemiol Infect 2008; 136: 1455–1462.
24.    Thwaites GE, Bang ND, Dung NH, Quy HT, Oanh DTT, Thoa NTC et al. The influence of HIV infection on clinical presentation, response to treatment and outcome in adults with tuberculous meningitis. The Journal of Infectious Diseases 2005; 192: 2134-41.

1.       Qureshi HU, Merwat SN, Nawaz SA, Rana AAK, Malik A, Mahmud MK, et al. Predictors of inpatient mortality in 190 adult patients with tuberculous meningitis. J Pak Med Assoc 2002; 52: 159-63.

2.       Fazel P A, Makki KU, Haroon H, Soomro I B, Afzal U. Clinical spectrum and outcome of patients with tuberculous meningitis. Med Channel 2006; 12: 21-3.

3.       Malik ZI, Ishtiaq O, Shah NH, Anwer F, Baqai HZ. Analysis an outcome of 30 patients with tuberculous meningitis. Pak J Med Res 2002; 41: 137-41.

4.       Thwaites GE, Hein TT. Tuberculous meningitis: Many questions, too few answers. Lancet Neurol 2005; 4: 160-70.

5.       Udani PM, Parekh UC, Dastur DK. Neurological and related syndromes in CNS tuberculous meningitis: Clinical features and pathogenesis. J Neurol Sci 1971; 14: 341-57.

6.       Van Well GT, Paes BF, Terwee CB, Springer P, Roord JJ, Donald PR, et al. Twenty years of pediatric tuberculous meningitis: A retrospective cohort study in the western cape of South Africa. Pediatrics 2009; 123: e1-8

7.       Karstaedt AS, Valtchanova S, Barriere R, Crewe-Brown HH. Tuberculous meningitis in South African urban adults. QJM 1998; 91: 743-7.

8.       Katrak SM, Shembalkar PK, Rijwe SR, Bhandarkar LD. The clinical, radiological and pathological profile of tuberculous meningitis to patients with and without human immunodeficiency virus infection. J Neurol Sci 2000; 181: 118-26.

9.       Whiteman M, Espinoza L, Post MJ, Bell MD, Falcone S. Central nervous system tuberculosis in HIV-infected patients: Clinical and radiographic findings. AJNR Am J Neuroradiol 1995; 16: 1319-27.

10.   Rock RB, Olin M, Baker CA, Molitor TW, Peterson PK. Central nervous system tuberculosis: Pathogenesis and clinical aspects. Clin Microbiol Rev 2008; 21: 243-61.

11.   Sinner SW, Tunkel AR. Approach to the diagnosis and management of tuberculous meningitis. Curr Infect Dis Rep 2002; 2: 324-31.

12.   Salekeen S, Mahamood K, Naqvi IH, Baig MY, Akhter ST, Abbasi A. Clinical course, complications and predictors of mortality in patients with tuberculous meningitis — an experience of fifty two cases at Civil Hospital Karachi, Pakistan. J Pak Med Assoc 2013; 63: 563-7.

13.   Pienaar M, Andronikou S, van Toorn R: MRI to demonstrate diagnostic features and complications of TBM not seen on CT. Childs Nerv Syst 2009; 25: 941-7

14.   Murthy J. Tuberculous meningitis: The challenges. Neurol India 2010; 58: 716-22.

15.   Thwaites GE, Bang ND, Dung NH, Quy HT, Oanh DTT, Thoa NTC et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004; 351: 1741-51.

16.   Escobar JA, Belsey MA, Dueñas A, Medina. Mortality from tuberculous meningitis reduced by steroid therapy. Pediatrics 1975; 56: 1050-5.

17.   Prasad K, Volmink J, Menon GR. Steroids for treating tuberculous meningitis. Cochrane Database Syst Rev 2000; (3): CD002244.

18.   Kent SJ, Crowe SM, Yung A, Lucas CR, Mijch AM. Tuberculous meningitis: A 30 year review. Clin Infect Dis 1993; 17: 987-94.

19.   Kilpatrick ME, Girgis NI, Yassin MW, Ella AE. Tuberculous meningitis— clinical and laboratory review of 100 patients. J Hyg (London) 1986; 96: 231-8.

20.   Iype T, George LE, Cherian A, Kumar A, Ajitha BK, Chandy S. In hospital mortality of intermittent vs. daily Antitubercular regimen in patients with meningeal tuberculosis- A retrospective study. Indian J Tuberc 2012; 59: 6-11.

21.   Shaikh MA, Shah Mujtaba, Channa F. Criteria indicating morbidity in tuberculous meningitis. J Pak Med Assoc 2012; 62: 1137-9.

22.   Christensen AH, Andersen AB, Thomsen V, Andersen PH, Johansen IS: Tuberculous meningitis in Denmark: a review of 50 cases. BMC Infectious Diseases 2011; 11: 47.

23.   Roca B, Tornador N, Tornador E. Presentation and outcome of tuberculous meningitis in adults in the province of Castellon, Spain: a retrospective study. Epidemiol Infect 2008; 136: 1455–1462.

24.   Thwaites GE, Bang ND, Dung NH, Quy HT, Oanh DTT, Thoa NTC et al. The influence of HIV infection on clinical presentation, response to treatment and outcome in adults with tuberculous meningitis. The Journal of Infectious Diseases 2005; 192: 2134-41.