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Changing trends of presentation of central nervous system tuberculosis: Relative prevalence of cranial and spinal tuberculosis and drug resistance patterns
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.263176
Objective: Inappropriate use of antituberculosis drugs and a poor compliance has led to an increase in the prevalence of resistant Mycobacterium tuberculosis. The aim of this study was to document the changing trends in clinical presentation and drug resistance in patients with tuberculosis (TB) of the brain and the spine. Keywords: Brain, drug resistance, India, infection, spine, tuberculosis
Worldwide, tuberculosis (TB) and human immunodeficiency virus (HIV) are leading causes of death.[1] India, along with China and Indonesia, accounted for a combined total of 43% of global cases of TB in 2014.[1] Central nervous system (CNS) TB accounts for 10% of extrapulmonary TB and 0.7% of all TB infections. Prevalence of CNS TB in a geographical region is directly proportional to the prevalence of all TB infections in that region. There has been concern about the rising incidence of drug-resistant TB in Indian patients. This trend has been discerned from data in patients with pulmonary TB.[2],[3] It is unclear whether a similar situation prevails in patients with CNS TB. Furthermore, there are no in-hospital data from India on the changes in the trends of presentation of CNS TB – that is, cranial (TB brain) versus spinal (TB spine) presentation. In recent years, we have noticed an increase in patients presenting with spinal TB. This study was performed to determine whether there was a change in the relative prevalence of TB brain and TB spine and whether there was an increase in the prevalence of resistant TB in patients presenting to our neurosurgical unit in a tertiary care center.
Study population All patients admitted and treated as TB brain [TB meningitis (TBM), tuberculoma, hydrocephalus, and tubercular abscess] and TB spine from 2000 to 2013 in our Neurosurgical Unit were included in the study. The demographic profile, clinical details, laboratory results, and radiological investigations were retrieved from in-patient records and the picture archiving and communication system (PACS). Study design We divided the patients arbitrarily into two groups (covering 7 years each of the study period): Group A – admitted from 1st January 2000 to 31st December 2006; Group B – admitted from 1st January 2007 to 31st December 2013. The clinical profile, presentation, and treatment in these groups were compared. Antituberculosis therapy All patients received antituberculosis therapy (ATT) for a minimum of 18 months, consisting of 3 months of three-drug regime followed by 15 months of two-drug regime. Adults received 3 months of ethambutol (15–20 mg/kg/day), rifampicin (10 mg/kg/day), and isoniazid (5 mg/kg/day), followed by 15 months of rifampicin and isoniazid. Pyridoxine (10 mg/day) was administered throughout the 18 months of ATT. Children received 3 months of pyrazinamide (20–35 mg/kg/day), rifampicin (10 mg/kg/day), and isoniazid (5 mg/kg/day), followed by 15 months of rifampicin and isoniazid. Pyridoxine (5 mg/day) was administered throughout the course of ATT.
Primary resistance Primary resistance was defined as that detected in cultures from patients who have never received ATT in the past (i.e., patients who have been infected with resistant organisms) or who have possibly received undisclosed prior treatment.[4] Secondary resistance Secondary resistance was defined as that detected in cultures from patients with a record of any previous treatment (i.e., patients in whom drug resistance may have emerged following a course of therapy). This definition includes patients who relapsed or for whom treatment failed as well as defaulters who interrupted treatment for >1 month.[4] Statistical methods Continuous variables were compared using the Student's t-test, and categorical variables were compared using chi-square analysis. Significance was defined as P < 0.05. All calculations were performed using Statistical Package for the Social Sciences [SPSS], (IBM corporation, New York), version 20.
There were a total of 243 patients that included 141 patients with TB brain and 102 patients with TB spine. Group A had a total of 121 of 243 (49.8%) patients and Group B had a total of 122 of 243 (50.2%) patients. [Table 1] shows the different forms of TB brain and different sites of involvement of TB spine in the two groups.
Relative prevalence of brain and spine TB There was a significant difference in the number of brain and spine cases. In Group A, there were 79 of 121 (65.3%) patients with TB brain and 42 of 121 (34.7%) patients with TB spine, whereas in Group B, there were 62 of 122 (50.8%) patients with TB brain and 60 of 122 (49.2%) patients with TB spine (P = 0.02). TB brain has declined by 14.5% (65.3%–50.8%) in Group B (P = 0.03) [Table 1]. TB spine has increased by 14.5% (34.7%–49.2%) in Group B (P = 0.02) [Table 1]. Presentation and management of brain tuberculosis There was a significant reduction in the number of patients with a brain tuberculoma in Group B (P = 0.017) [Table 2]. A significant reduction in the number of procedures other than cerebrospinal fluid (CSF) diversion was noted in Group B (P = 0.0004) [Table 2]; 45 of 79 (57%) patients with TB brain underwent procedures other than CSF diversion in Group A, whereas only 24 of 62 (39%) of patients with TB brain underwent the same in Group B; 5 of 79 (6.3%) patients in Group A and 10 of 62 (16%) patients in Group B did not undergo any surgical intervention (P = 0.06).
Four of the five patients in Group A who did not undergo any surgical intervention had a solitary tuberculoma and were treated empirically with ATT and one patient had multiple tuberculomas with extensive spinal arachnoiditis and was in a poor general condition. Six of the 10 patients in Group B who did not undergo any surgical intervention had a solitary tuberculoma and were treated empirically with ATT. Two other patients had multiple tuberculomas with extensive spinal arachnoiditis, one patient had multiple infarcts, and one patient had improving symptoms while on ATT. Presentation and management of spine tuberculosis Thoracic spine was the commonest site of involvement, but there was an increase in patients with lumbar spine involvement in Group B [Table 1]. In Group A, 35 of 42 (83%) of patients with TB spine underwent an invasive intervention; and in Group B, 57 of 60 (95%) of patients with TB spine underwent an invasive procedure. The number of patients undergoing image guided biopsy has increased in Group B to 20 of 60 (33%) as against 9 of 42 (21.4%) in Group A [Table 3].
Culture yield In patients with TB brain, culture yield from the tissue obtained at open surgery was 10 of 50 (20%) as against 8 of 72 (11%) from culture of CSF [Table 4].
In Group A, 8 of 38 (21.1%) patients grew Mycobacterium tuberculosis from tissue culture against 2 of 12 (16.7%) patients in Group B (P = 0.75) [Table 4]. In Group A, 1 of 34 (2.9%) patients grew Mycobacterium tuberculosis from CSF cultures versus 7 of 38 (18.4%) patients in Group B (P = 0.04). Better CSF culture yield was noted in Group B [Table 4]. In patients with TB spine, the culture yield was 7 of 35 (20%) in Group A and 18 of 57 (31.6%) in Group B (P = 0.27). In both patients with TB brain and TB spine, no significant difference was noted in the yield on culture [Table 4]. Resistance pattern In Group A, nine patients with TB brain grew Mycobacterium in culture and none had resistance; while in Group B, nine patients grew the bacilli and five (5/9; 55.6%) had resistance to first-line ATT (P = 0.03). Among patients with a positive culture of resistant TB, all had received prior ATT (100% secondary resistance). None of the patients with TB spine in Group A had resistant organisms, but in Group B, 5 of 18 (27.8%) samples that grew Mycobacterium tuberculosis in culture had resistant organisms (P = 0.27). Of the five patients with TB spine with resistance in Group B, three of five (60%) had secondary resistance and two of five (40%) had primary resistance [Table 5].
Overall, 10 of 27 (37%) patients with a positive culture had resistant organisms in Group B, while none of 16 patients in Group A with a positive culture had resistant organisms (P = 0.0069) [Table 6].
Prior ATT Among the patients with TB brain, 45 of 79 (56.9%) of Group A patients and 41 of 62 (66.1%) of Group B patients had received ATT prior to our management. Among the patients with TB spine, 9 of 42 (21.4%) of Group A and 20 of 60 (33.3%) of Group B had received prior ATT. These differences were not statistically significant. Concurrent HIV infection Two patients with TB meningitis who required a ventriculoperitoneal shunt had HIV coinfection and neither of these patients had positive CSF cultures.
There is no literature on the changing trends of CNS TB in neurosurgical practice in India, except for resistance to first-line ATT.[5] In this retrospective analysis, we noticed an increase in TB spine, decline in TB brain, and a significant reduction in the number of procedures other than CSF diversion in the past 7 years. In patients with TB spine, an increase in lumbar involvement and a rise in image guided biopsies have been noted in the recent years. Both in patients with TB brain and TB spine, we noticed an increase in resistance to first-line antituberculosis drugs. TB brain Vs TB spine According to World Health Organization (WHO) Global Tuberculosis report 2015, globally there is a reduction in the incidence of TB since 2000. The incidence reported in 2015 was 133 per 100,000 population versus 163 per 100,000 population in 2000. The prevalence rate has decreased from 326 per 100,000 population in 2000 to 174 per 100,000 population in 2015.[6] In our study, the number of patients with TB admitted for treatment in our neurosurgical unit remained the same over the two eras, but the relative numbers of patients with TB brain and TB spine have changed. A declining trend in TB brain was present over the past 14 years. The cause for this decline in TB brain is unclear. It is also not clear as to why there is a relative increase in TB spine cases. One possible reason for this could be a change in our practice pattern whereby we are admitting more spine cases for surgical care. However, this is not likely as our management protocols have remained unchanged throughout the study period. Our management protocols dictate conservative management in most patients with spine TB if there is no significant neurological deficit. Therefore, the indications for surgical management of spine TB have not changed but we have seen an increase in the number of cases of spine TB. This is in spite of the presence of an orthopedic spine unit in the hospital which also manages patients with spine TB. CSF diversion procedures versus other surgical interventions The primary management of TB brain is with medical therapy with antituberculosis drugs. However, surgery is indicated in certain situations, such as, in patients with TBM with hydrocephalus, when the diagnosis of tuberculoma is in doubt, to reduce the mass effect due to a tuberculoma, or to obtain tissue for testing sensitivity to ATT.[7] In our study, we have noticed that the need of CSF diversion procedures has increased in the past 7 years. Retrospective and prospective studies have shown that the sensorium prior to the surgery is the most significant prognosticating factor determining the outcome after shunt surgery in TBM with hydrocephalus.[8],[9],[10],[11] Based on the above studies, we treated patients in Vellore grades 1, 2, and 3 with VP shunt directly, whereas those in Vellore grade 4 were managed initially with an external ventricular drain. A permanent shunt placement was done in only those patients who improved with the drainage. This increase in shunt surgeries in the past 7 years might be due to a relative increase in patients with TBM presenting in Vellore grades 1–3 and a decline in those presenting in Vellore grade 4. Stereotactic biopsy, stereotactic craniotomy, as well as craniotomy and microsurgical excision are other surgical procedures done in patients with tuberculoma. Stereotactic biopsy is done for deep-seated lesions that may be present in structures like the thalamus, basal ganglia, and brainstem.[11],[12],[13],[14],[15] Stereotactic craniotomy is done for small superficial lesions located in the eloquent cortex. Craniotomy and microsurgical excision is done for lesions located in the noneloquent cortex with significant mass effect, to reduce intracranial pressure. The decline in these procedures in the recent times may be attributed to the establishment of a more confident diagnosis of tuberculomas on magnetic resonance (MR) imaging with the use of MR spectroscopy and the empirical use of antituberculosis drugs. Patients with solitary brain tuberculoma without raised intracranial pressure were treated without surgery if their imaging was representative of a tuberculoma. Culture yield In studies from the 1950s and 1960s, acid-fast bacilli were seen in the CSF of up to 80% of adult patients with TBM.[7],[16] In recent literature, the yield of acid-fast bacilli from the CSF in patients with TBM has been reported to range from 11% to 35%.[17],[18] However, the diagnostic yield depends largely on the volume of CSF. Tissue biopsy has a higher diagnostic yield than CSF in both TB brain and TB spine.[19] We have also noted similar yields in our study. In the past 7 years, we have had an increase in the culture yield in patients with TB spine (31.6% versus 20%), although this was not statistically significant. Resistance pattern Antibiotic resistance was noted as early as in 1940 when antibiotics were introduced for the treatment of TB.[20] According to the WHO Global Tuberculosis report 2015, India has an estimated 2.2% patient population with multidrug resistance (MDR) TB and an estimated 15% retreatment cases with MDR TB.[6] In our study, both patients with TB brain and TB spine showed a significant increase in resistance in the past 7 years. Although there were more cases with secondary resistance among patients with TB brain in recent years, an increased primary resistance was noted in patients with TB spine. Concurrent HIV infection According to the WHO Global Tuberculosis report 2017, the estimated HIV prevalence in new and relapsed TB cases in India is 3.1%.[21] In our study, we had two patients with HIV coinfection. There might have been more HIV-positive patients with brain and spine TB presenting to our hospital, but since they are managed primarily by the infectious disease specialists, they are not reflected in our series. It is likely that most of these patients were managed with empirical ATT and may not have undergone a neurosurgical procedure. Strengths and limitations of the study The strength of the study is that data from a large number of cases admitted in a single unit and treated with a uniform protocol over 14 years have helped in analyzing the trend in variation in presentation and drug resistance in patients with CNS TB, over the years. The limitations of the study are its retrospective nature and that only patients who were admitted were included. Patients with disseminated TB and TBM managed medically by medical units have not been included.
The number of patients with spine TB has increased relative to brain TB. A more worrying statistic is that one-fifth of them are infected with resistant organisms. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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