Atormac
Neurology India
Open access journal indexed with Index Medicus
  Users online: 2474  
 Home | Login 
About Editorial board Articles NSI Publications Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Search
 
  
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (3,133 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

 
  In this Article
 »  Abstract
 »  TBM: After 5 Dec...
 » Role of Endoscopy
 »  The Take-Home Me...
 » Material and Methods
 » Results
 » Discussion
 » Summary
 » References
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed152    
    Printed2    
    Emailed0    
    PDF Downloaded79    
    Comments [Add]    

Recommend this journal

 


 
Table of Contents    
NI FEATURE: JOURNEY THROUGH THE EONS - COMMENTARY
Year : 2018  |  Volume : 66  |  Issue : 6  |  Page : 1550-1571

Tuberculous meningitis: Challenges in diagnosis and management: Lessons learnt from Prof. Dastur's article published in 1970


1 Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication28-Nov-2018

Correspondence Address:
Dr. Manish Modi
Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.246224

Rights and Permissions

 » Abstract 


It has been approximately five decades since Dastur et al., published their seminal work on pathology of tuberculous meningitis (TBM). Though most of their findings find relevance in today's era, there is an important difference; these findings can now be replicated during life using modern day technology. In this article, we review the seminal words of Professor Dastur and colleagues, analyse their findings, interpret how these revolutionized our understanding of TBM and highlight their relevance in today's era. We also discuss challenges in the management of TBM, which we continue to face today and the various options required to overcome these challenges.


Keywords: Antituberculous treatment, challenges, complication, tuberculosis, tuberculous meningitis
Key Message: Newer imaging modalities enable radiologists and treating physicians to diagnose tuberculous meningitis (TBM) with a reasonable degree of certainty at an early stage, thereby enabling the initiation of an early treatment for TBM. All these imaging findings are in congruence with the findings lucidly described in the gross pathology by Professor Dastur and his colleagues. This article discusses how this article revolutionized our understanding of TBM and its relevance in the modern era.


How to cite this article:
Modi M, Goyal MK, Jain A, Sawhney SS, Sharma K, Vyas S, Ahuja CK. Tuberculous meningitis: Challenges in diagnosis and management: Lessons learnt from Prof. Dastur's article published in 1970. Neurol India 2018;66:1550-71

How to cite this URL:
Modi M, Goyal MK, Jain A, Sawhney SS, Sharma K, Vyas S, Ahuja CK. Tuberculous meningitis: Challenges in diagnosis and management: Lessons learnt from Prof. Dastur's article published in 1970. Neurol India [serial online] 2018 [cited 2018 Dec 19];66:1550-71. Available from: http://www.neurologyindia.com/text.asp?2018/66/6/1550/246224


Nec minus a phlegmone et abcessu quam hujasmodi meningitis et tuberculis, cephalgiaelethales et incurabilesoriuntur

(Sometimes the headaches, fatal and incurable, follow abscesses and swellings of the envelopes of the brain, as well as plaques and tubercles of these membranes)

Willis, 1672.[1]

First described by Willis in the 17th century, tuberculous meningitis (TBM) is the most severe form of tuberculosis (TB). TB in all its forms remains a challenging clinical problem and a public health issue of considerable importance and magnitude, the world over. It continues to be a worldwide burden, with majority of new active cases occurring in underdeveloped countries.[2] As per the World Health Organisation (WHO) statistics, five countries, viz., India, China, Pakistan, Indonesia and South Africa, account for over 70% of the global burden of disease.[3] Mycobacterium tuberculosis (MTB) causes approximately 10.4 million new cases of TB and 1.5 million deaths annually, with an additional 0.4 million deaths in individuals co-infected with human immunodeficiency virus (HIV). Patients coinfected with HIV are at more than 20 times higher risk of developing TB compared to non-infected individuals.[3] Although central nervous system TB accounts for 5-10% cases of extrapulmonary TB and only 1% of all cases of TB, it is responsible for more deaths than any other form of TB, owing to the inherent seriousness of this illness.[4]

Almost 5 decades back, Dastur and colleagues in their seminal paper[5] had highlighted the gross pathological changes in 100 patients of TBM, who succumbed to this illness.

The work of Professor Dastur and colleagues continues to be highly relevant in the modern era.

The landmark paper by Dastur et al.,[5] gave us an insight into the pathophysiology and pathological changes of CNS TB, which is being replicated in today's era by advanced imaging techniques. With the advent of magnetic resonance imaging (MRI), more so the newer sequences like magnetisation transfer (MT), gradient recalled echo (GRE), susceptibility-weighted (SW), diffusion weighted (DW) and fluid attenuating inversion recovery (FLAIR) images, the cause and extent of the disease, its underlying pathophysiology, its complications, and the favourable or adverse response to treatment can now be gauged with almost the same precision during life as what was reported in post mortem samples by Dastur et al.[5] A careful interpretation of the data provided by Dastur et al., suggests that majority of their patients had one or more life-threatening complications in the form of hydrocephalus, infarcts, severe arachnoiditis, including spinal arachnoiditis and tuberculomas, which correspond to Stage 3 of Medical Research Council (MRC) staging [Table 1].[5],[6] As almost all the cases analysed by Dastur et al., had advanced TBM, it is reasonable to expect that the findings presented by them may not be evident in some patients, especially those in an early stage of TBM. In these patients, magnetization transfer (MT) MR imaging detects the earliest evidence of meningitis in the form of hyperintense signal changes on T1 weighted MT sequences, whereas the conventional spin echo sequences may be normal.[7] The common sites for basal meningeal enhancement include the interpeduncular fossa, the pontine, perimesencephalic and suprasellar cisterns, and the Sylvian fissures [Figure 1]a. The degree of enhancing exudates varies from a thin layer to a thick sheet [Figure 1]b, as documented by Professor Dastur and colleagues. In more advanced cases, as described by Dastur et al., these exudates may block the flow of CSF (cerebrospinal fluid) producing hydrocephalus, which may be communicating (dilatation of all the ventricles) [Figure 1]c primarily due to basal exudates, or non-communicating either due to narrowing of the cerebral aqueduct or obstruction to the CSF flow at the level of foramen of Lushka and Magendie, through various mechanisms. All these pathological findings can now be revealed during life with the available imaging modalities. While contrast enhanced computed tomography (CECT) scan is the imaging modality of choice for establishing the diagnosis of TBM in an emergency setting, MRI gives a much more objective information about the degree of exudates, degree of hydrocephalus, the associated periventricular ooze as well as other complications like the development of infarcts and borderzone encephalitis (BZE). The latter was a phenomenon described by Dastur et al., that occurs in the form of localised necrosis of the underlying brain parenchyma in relation to the infiltrative exudates [Figure 2]a, [Figure 2]b and [Figure 2]c, [Figure 3]a and [Figure 3]b.
Table 1: British Medical Research Council (MRC) criteria for assessing disease severity

Click here to view
Figure 1: Pathological and radiological correlation in a patient who succumbed to tuberculous meningitis. (a) Post-mortem brain showing opaque meninges with thick exudates at base of the brain. (b and c) Contrast enhanced computed tomographic scan showing thick enhancing exudates at base of the brain in basal cisterns (white arrows) in the same patient while he was alive. Also note the dilatation of ventricles suggestive of hydrocephalus

Click here to view
Figure 2: Border-zone encephalitis (BZE) affecting the brainstem in a patient with tuberculous meningitis. (a and b) Note hyperintense signal changes (white arrows) on T2W MR (T2 weighted magnetic resonance) images involving the pons and left temporal lobe; (c) Axial section at the level of pons in the post-mortem brain of the same patient showing diffuse necrosis of almost the entire pons that is suggestive of BZE (white arrow)

Click here to view
Figure 3: Border-zone encephalitis (BZE) affecting the left peri-Sylvian region in TBM. (a) Intensive hyperintense signal changes (white arrows) seen on T2W MR (T2 weighted magnetic resonance) image involving the left temporo-parietal region (white arrows). Also note the dilatation of temporal horn on the right side and an infarct in the left thalamus; (b) Gadolinium enhanced MR image of the brain showing thick enhancing exudates in the left Sylvian fissure and basal cisterns (white arrows)

Click here to view


Dastur et al., noted gross compression and narrowing of large arteries (especially the middle cerebral arteries) due to meningovasculitis at the base of the brain with resultant brain infarctions (mainly in basal ganglionic and thalamic regions) in almost 50% of children and 33% of adults. With the advent of new MRI sequences, these changes can be seen during life as areas of diffusion restriction on DWI [Figure 4]a and [Figure 4]b. Complications like optochiasmatic arachnoiditis [Figure 5]a, [Figure 5]b and [Figure 5]c, as well as spinal arachnoiditis and tuberculomas [Figure 6]a and [Figure 6]b can be documented with precision on the contrast enhanced MRI.
Figure 4: Infarction in a patient with tuberculous meningitis. (a) Diffusion weighted magnetic resonance imaging showing an infarction in the left putaminal, thalamic and temporal regions (white arrows). (b) Gadolinium enhanced magnetic resonance imaging showing thick enhancing exudates in the left Sylvian fissure encasing the middle cerebral artery (white arrows) in the same patient

Click here to view
Figure 5: Optochiasmatic arachnoiditis in a patient with tuberculous meningitis. (a and b) Gadolinium enhanced magnetic resonance imaging of the brain showing disc and ring enhancing lesions (white arrows) involving the sellar and suprasellar as well as the left medial temporal regions. (c) Autopsy section (coronal) of the same patient showing organised thick exudates with fibrosis affecting the pituitary and left temporal regions (white arrows)

Click here to view
Figure 6: Tuberculomas in a patient with tuberculous meningitis. (a) T2 weighted axial magnetic resonance imaging of the brain showing multiple hyperintense lesions; note the central hypointensity (T2 shortening) in most of the lesions suggestive of tuberculomas. (b) Gadolinium enhanced magnetic resonance imaging of the brain showing multiple ring enhancing lesions (white arrows)

Click here to view


To summarise, newer imaging modalities have empowered the radiologists and treating physicians to diagnose TBM with a reasonable degree of certainty at an early stage, thereby providing an early treatment of TBM. All these imaging findings are in concurrence with the findings lucidly described in the gross pathology by Professor Dastur and his colleagues. This clinico-pathologico-radiological correlation has given an edge to the clinicians for establishing an early diagnosis of TBM and in treating the condition.


 » TBM: After 5 Decades: Current Challenges Top


Despite availability of descriptive literature on the pathological findings in TBM for more than 5 decades, due largely to the seminal work of Professor Dastur and colleagues, the morbidity and mortality in TBM continues to be unacceptably high. Reported mortality figures, as per the MRC stage at the time of presentation, are 4% in Stage 1, 11% in Stage 2 and 50% in Stage 3 in a study from North India[4] and 20% for stage 1, 30% for stage 2 and 50% for stage 3 in a study from Vietnam.[8] Currently, the major challenges to the successful management of TBM include:

  1. An early diagnosis of TBM
  2. An effective treatment of TBM
  3. The management of complications.


A. Early diagnosis of TBM:

This continues to be the biggest challenge in TBM due to following reasons:

A1: Vague and varied clinical symptomatology

A2: Poorly sensitive diagnostic laboratory parameters.

A1. Vague and varied clinical symptomatology

The clinical symptomatology of TBM is often not specific. A prodromal period with non-specific constitutional symptoms (irritability, anorexia, weight loss or sleep disturbance in children; and, fatigue, loss of appetite, loss of weight and night sweats in adults) can last from a few days to several weeks in a majority of patients. This is especially true in the underdeveloped world where rampant misuse of quinolones and other antibiotics often suppresses the initial symptomatology of TB.

The typical duration of symptoms in TBM is usually of a few weeks and even months, though some of the diagnostic criteria require a minimum duration of 5 days only.[9] The typical symptoms include headache, fever, vomiting, meningism, neurological deficits and altered mental status. Photophobia is less common than headache and neck stiffness. In children, vomiting and convulsions are more common than in adults. The classical triad of meningitis, i.e., fever (adults: 60-75%, children: 67%), headache (adults: 50-80%, children: 25%) and vomiting (adults: 40-80%, children: 98%) may not be present in all patients. Neck stiffness is usually absent during the early disease.[4],[10] To overcome the challenges brought about due to the varied symptomatology, a high index of suspicion and performance of appropriate investigations (cerebrospinal fluid [CSF] analysis and neuro-imaging) are needed to clinch the diagnosis especially in the early stages of TBM. Various diagnostic algorithms have been proposed by Ahuja et al.,[11] and Marais et al.,[9] (including the modified algorithm by Ahuja et al.,[12]) for a uniform case definition of TBM especially for research purposes, where definite TBM has been defined in only cases where Mycobacterium has been isolated from the CSF by any of the available microbiological techniques.

A2. Poorly sensitive diagnostic lab parameters 9

TBM is a paucibacillary disease; thus CSF microscopy using the Ziehl Neelsen stain [which can confirm the diagnosis quickly through demonstration of acid-fast bacilli (AFB)] has a very low sensitivity (0-20%).[13] The results of culture of MTB are notoriously slow to obtain, with the conventional solid media (the Lowenstein-Jensen media) yielding results only after 10-35 days.[14] To overcome this challenge, many new diagnostic techniques have become available in the recent years. These have shortened the lag period for establishing the diagnosis of TBM and have improved the sensitivity while retaining a good specificity. Currently, several liquid culture systems including BACTEC MGIT 960 system (Becton Dickinson Microbiology Systems, Sparks, Md), and MB/BacT system (BioMérieux, Durham, N.C) are available, which yield positive results in a shorter period of time with the added advantage of providing drug susceptibility testing (DST) of MTB at the same time.[15]

Commercial NAATs (nucleic acid amplification tests) have shown potential as rapid ‘rule-in’ diagnostic tests for TBM, with a high specificity (98%), but a low sensitivity (56%).[16],[17] A more recent review has shown the promise that multiplex polymerase chain reaction (PCR) techniques offer, which have better sensitivity compared to the commercial NAATs (sensitivity 71-94%, specificity 88-100%). Newer NAATs are showing promising results by increasing the sensitivity and specificity for the detection of MTB as well as for assessing drug resistance in a short duration. However, these tests require specialized laboratory settings with rigorous quality control.[18],[19]

Xpert MTB/RIF (Cepheid, Sunnydale, CA, USA; an automated diagnostic test that can identify Mycobacterium tuberculosis [MTB] DNA and resistance to rifampicin [RIF]) is the most recently endorsed diagnostic test for TB by the WHO (World Health Organization) in 2010. The main advantages of this test are that its technique can be learned easily, the machine can be used in decentralized settings, the turnaround time is just 2 hours, and the closed disposable cartridge system reduces the risk of contamination.[20] The sensitivity of Xpert MTB/RIF in a large Vietnamese study was 59.3% [(n = 108/182 (95% confidence interval (CI) 51.8; 66.5)], which is (significantly though only slightly) lower than that of the mycobacteria growth indicator tube (MGIT) culture [66.5% (n = 121/182), (95% CI 59.1; 73.3)]. However its specificity was comparable to that reported for other commercial NAATs [99.5% (95% CI 97.2; 100)]. An important advantage of Xpert MTB/RIF is that it can detect rifampicin (RIF) resistance within two hours. In the above study, four patients of RIF resistance (n = 4/109, 3.7%) were identified by Xpert, of which 3 were confirmed to be suffering from multi-drug resistance (MDR) TBM.[21] These numbers are too small to draw robust conclusions on the positive or negative predictive value of rifampicin resistance testing by Xpert MTB/RIF. However, as rifampicin resistance is associated with a very high mortality in TBM, it is advised that a positive result for rifampicin resistance, in the context of a clinical picture that fits drug resistant TB, should prompt clinicians to consider immediate second-line treatment. Xpert MTB/RIF has the ability to improve tthe establishment of an early diagnosis of TBM, and in particular, to open the field for clinical trials researching on the treatment optimization for patients with MDR-TBM.

It is pertinent to note that Dastur et al., reported evidence of TB elsewhere in the body (especially in the lungs and lymph nodes) in almost all the autopsied bodies. Taking an important lead from this finding, we analysed 70 cases of TBM patients [(either definite (n = 26) or probable (n = 44)] with whole body FDG PET (flouro-deoxy glucose positron emission tomography) and found evidence of TB elsewhere in the body in 66 (94.3%) of the patients. The FGD-PET showed evidence of pulmonary involvement in 62 (88.6%) and lymph nodes involvement in 61 (87.1%) patients [Figure 7]. Therefore, if there is any doubt about the diagnosis, additional body imaging in the form of chest X ray, a computed tomographic (CT) image of the chest and abdomen, and if required, a whole body FDG PET, can help in taking a decision regarding the start of ATT. Taken together, it is reasonable to conclude that newer techniques such as Xpert MTB/RIF, NAATs, multiplex PCR for MTB as well as whole body FDG-PET have the potential to help in establishing an early diagnosis of TBM and thus, in aiding to change the management scenario of TBM completely.
Figure 7: Whole body Flouro-deoxyglucose positron emission tomography (FDG-PET) in a patient of tuberculous meningitis. (a) The maximum intensity projection (MIP) image shows an increased tracer uptake in the supraclavicular, mediastinal and upper abdominal regions (black arrows). (b) FDG avid ring enhancing lesion (Standarized uptake value [SUV] max ~1.5 × 1.1 cm) involving the left cerebral peduncle. (c) FDG avid (SUVmax 12) mediastinal lymph nodes (white arrows). (d) FDG avid gastro-hepatic lymph nodes (black arrows)

Click here to view


B. Effective treatment of TBM

The drug regimens recommended for the management of TBM are derived from short course treatments of pulmonary TB. However, the current algorithms for the treatment of TBM have ignored an important fact, i.e., brain should be considered as a distinctive compartment, and thus, the dosage and duration of therapeutic regimen for TBM should be established taking into account the pharmacokinetic (PK) and pharmacodynamic (PD) evidence. Even today, the optimal drug dosage and the appropriate duration of treatment for TBM have not been unequivocally established by large clinical trials. The challenges surrounding the effective treatment of TBM continue to be related to:

B1. Drugs, dosages and duration of antituberculous therapy (ATT)

B2. Treatment of multi-drug resistance (MDR) TBM.

B1. Drugs, dosages and duration of ATT

The first-line anti-TB agents recommended for the treatment of TBM include rifampicin (RIF), isoniazid (H), pyrazinamide (PZA), ethambutol (EMP) and/or streptomycin (S). Among the first-line drugs used in TBM, RIF, EMP and streptomycin have poor penetration across the blood-CSF barrier.[22] Currently, WHO recommends a 2-month treatment with 4 first-line drugs in the intensive phase, followed by a continuation phase with at least rifampicin and isoniazid for 4-10 months.[2] However as mentioned earlier, there is no data from randomized controlled trials to form the basis for these recommendations. Some authors have advocated a longer course of therapy for up to 2 years or even more, whereas other authors have suggested that short term RIF based regimens for 6 to 9 months may be adequate.[23],[24] Accordingly, treatment of TBM varies from place to place. The current United Kingdom guidelines suggest treatment with rifampicin, isoniazid, pyrazinamide and a fourth agent (streptomycin, ethambutol, or prothionamide) for the first two months followed by rifampicin and isoniazid for 10 months for uncomplicated cases of TBM (including cerebral tuberculomas without meningitis). ATT should be given for 18 months if PZA is not a part of the initial treatment regimen.

The American Thoracic Society recommends the initiation of therapy with isoniazid (INH 10mg/kg/day up to 300 mg/day), rifampicin (RIF 10-20mg/kg/day up to 600 mg/day), pyrazinamide (PZA 15 mg/kg/day up to 2 gm/day) and ethambutol (EMB 20mg/kg/day up to 1.2 gm/day). After the initial 2 months, INH and RIF alone are continued for an additional 7-10 months, although the optimal duration of therapy is not defined.[25]

Recently, several studies have shown that high doses of RIF in TBM regimens are associated with higher levels in CSF and improved survival, though these studies have enrolled only a small number of patients.[26] Also, there is lack of data about the use of fluoroquinolones in TBM, which remain an attractive option as they are active against MTB, are well tolerated, have an extensive safety data, have relatively little resistance to MTB and have a good penetration in the CSF; their clinical use, however, has shown inconsistent results.[26],[27]

Taken together, it is clear that there are still doubts regarding the optimal dosages, regimen and duration of ATT in TBM, and thus, large randomised trials are the need of the hour to sort out these issues.

B2. Treatment of MDR TBM

Drug resistant TB is a growing problem globally. Resistance to rifampicin is associated with a very high mortality in TBM, a finding which emphasizes the importance of including rifampicin in successful treatment regimens.[28] Globally, approximately 20% of isolates in TB are resistant to at least one antituberculous drug, and 7% are resistant to at least isoniazid.[29] Isolated resistance to isoniazid with or without resistance to streptomycin is more frequently found in high-burden settings. Isoniazid resistance has been associated with increased mortality due to TBM, especially in those infected with human immunodeficiency virus (HIV).[30] An unfavourable outcome may be prevented by the use of pyrazinamide throughout the treatment period. [RRR] MDR-TBM (resistance to at least rifampicin and isoniazid in multi-drug resistance tuberculous meningitis) is highly lethal. Most patients die within two months after the treatment initiation.[28] The management of MDR-TBM continues to be far from satisfactory mainly for two reasons. Firstly, timely detection of drug-resistance is limited by the lack of rapid diagnostics. Thus, the timing of an adjusted treatment schedule for drug resistant TBM based on the currently available culture and sensitivity results is often too late to prevent neurological disability or death. Second, due to the lack of good detection techniques, there are no studies evaluating the optimal regimen for drug resistant TBM. It is pertinent to mention that newer diagnostic techniques (Xpert MTB/RIF, multiplex PCR, liquid based culture medium) have shown promise for detection of MDR/DR in the early stages of TBM. Whole genome sequencing of MTB may help in defining the drug resistance related genes and may help in the rapid diagnosis of MDR TB and in the better management of patients.[31],[32] However, large studies remain to be done to validate their routine use. If found successful, these methods may reveal MTB strains resistant to rifampicin at an early stage and open the field for trials focusing on the second-line treatment for drug resistant TBM.

D. Management of complications

The optimal management of complications of TBM like optochiasmatic arachnoiditis, spinal arachnoiditis, vasculitic infarcts, tuberculomas (especially, paradoxical as well as persisting lesions) and hydrocephalus, remains to be defined. The paradoxical response (i.e., clinico-radiological deterioration after start of ATT) is frequently reported. This can be observed in all tissues, but most often in the lungs, lymph nodes and the brain.[33] In the brain, the paradoxical response often occurs in the form of appearance of new tuberculomas or enlargement of pre-existing tuberculomas, once ATT has been started (usually within 1-4 months after the start of ATT). It may be accompanied by worsening of symptoms or the appearance of signs of a space occupying lesion. This paradoxical response is considered to be more related to a heightened immune response rather than a manifestation of drug resistance. Once other causes of deterioration (such as drug resistance or the development of new infarcts) have been ruled out, these patients should be managed by continuation of ATT and administration of high dose systemic corticosteroids. Some authors have suggested the implimentation of a more aggressive immunomodulation with drugs. The proposed therapies for various complications are:

C1. Use of immuno-modulatory drugs

C2: Treatment of stroke and vasculitis

C3: Surgical treatment of complications.

C1: Medical therapy including the use of immuno-modulatory drugs:

The various options being used to treat these complications include a longer duration of treatment, introduction of second line ATT, use of high dose steroids for a longer duration, use of immunomodulatory drugs like thalidomide, levamisole, adjuvant interferon gamma therapy and administration of intrathecal hyaluronidase, etc., In our personal experience of >50 patients, the use of thalidomide (in a dose of 2 mg/kg body weight) for 4-6 months in patients with TBM suffering from various sequel (such as optochiasmatic arachnoiditis, a paradoxical increase in the size of tuberculomas, an increase in size and number of lesions, and spinal arachnoiditis), has resulted in an improvement in the clinical condition of the patients and has resulted in radiological resolution of the lesions in >70% of patients, who had already received >2 months of ATT and steroids. Certain recently published studies on a small number of patients have also demonstrated resolution of lesions by using thalidomide.[34] It is pertinent to mention that robust scientific evidence for the use of any of above options is lacking, and thus, the need of properly conducted large multi-centre trials to provide guidelines for better management of these patients cannot be overemphasized.

C2. Tuberculous vasculitis and stroke

The poor outcome from TBM primarily reflects the extent of ischemic damage to the brain resulting from inflammation, necrosis, and thrombosis of blood vessels involved in meningovasculitis. The most common clinical manifestation of TBM-related stroke is hemiplegia, which is more common in young children than in adults, and in patients with advanced disease, as had been highlighted by Dastur et al.[5]

No adjunctive treatment has consistently reduced the incidence of stroke or changed the course of hemiplegia in TBM. Corticosteroids did not significantly affect the number of new infarcts seen on CT or MRI, or the extent of residual hemiplegia in children or adults.[8] Only aspirin may help to reduce the incidence of stroke, but its role needs to be confirmed in larger studies.[35]

C3. Surgical management of hydrocephalus

The mainstay of management of TBM with hydrocephalus is CSF diversion. Surgical management can be planned according to the Vellore grade at presentation [Table 2]. Grade I patients can be monitored on medical management but early surgery has shown a better outcome. Grade II patients definitely show improvement with early surgery. Some authors have advocated a brief period of external ventricular drainage (EVD) before shunt surgery in grade III patients but direct shunt surgery is better. An EVD has been recommended for grade IV patients followed by installation of a CSF diversion in the form of a shunt in only those patients who have shown an improvement following the installation of an EVD.[36] However, some authors have found a good outcome in 20% of grade IV patients who have undergone shunt surgery without installation of a prior EVD.[37] In the above context, it is important to note that while earlier studies[38] showed 100% mortality in grade IV hydrocephalus, a more recent study[37] found a mortality rate of 60% in stage IV hydrocephalus. The lower mortality in this study was attributed to an early shunt surgery in addition to the institution of ATT, steroids and supportive care.
Table 2: Modified Vellore grading system

Click here to view



 » Role of Endoscopy Top


Recently, more and more interest has been generated in the endoscopic CSF diversion procedures for TBM. The endoscopic third ventriculostomy (ETV) is not a favoured procedure in hydrocephalus, at least theoretically, as it is usually of a communicating type in TBM. There are however, several reports on the use of ETV in hydrocephalus due to TBM. The success rate of ETV has been reported to range from 68% to 77% in patients in different studies. The experience of a surgeon well-versed in endoscopic procedures determines the success rate, as TBM exudates and scarring cause difficulty in recognizing the anatomical landmarks at the floor of third ventricle, thus hampering the efforts to perform a successful third ventriculostomy. Patients with longer duration of symptoms and those who have received at least four weeks of ATT are more likely to benefit from ETV.[39]


 » The Take-Home Message Top


  1. An early diagnosis and an early start of antituberculous treatment in a suspected case of TBM save lives. A high index of suspicion in patients with a meningitic syndrome of more than a 5-day duration, especially in endemic regions, is fundamental to the diagnosis of TBM.
  2. TBM is a paucibacillary disease; therefore, the conventional Ziehl Neelsen staining of the CSF sample usually is negative. Use of newer modalities like MGIT BACTEC and Xpert MTB/RIF have improved the sensitivity to more than 50% in a few series. Nucleic acid amplification techniques like multiplex PCR have improved the sensitivity to 80% in some series, but are not readily available. A negative Xpert MTB/RIF does not rule out TBM. Isolation of the Mycobacterium should be tried in every patient by every available method, both to confirm the diagnosis and to determine drug sensitivity.
  3. Evidence of TB elsewhere in the body is present in a majority of the cases of TBM. Hence, every effort should be undertaken to look for evidence of TB of other organs like the lung, lymph nodes, adrenals, gastrointestinal tract, genitourinary tract, etc., by a thorough clinical and radiological examination (including a chest X ray, whole body CT scan and even a whole body PET CT, where facilities are available).
  4. In Professor Dastur's autopsy series, a combination of basal exudates, hydrocephalus, border-zone encephalitis, and parenchymal tuberculomas were the hallmark of TBM. Radiological evidence of this combination in a patient of febrile encephalopathy is almost diagnostic of TBM, especially in endemic countries. Evidence of other findings on imaging like opto-chiasmatic arachnoiditis, spinal arachnoiditis and vasculitic infarcts also favour the diagnosis of TBM.
  5. Treatment should be started early, preferably before neurological deterioration. Isoniazid, rifampicin and pyrazinamide are the key constituents of the treatment regimen and should be used whenever possible. An interruption of the treatment in the intensive phase of therapy increases the risk of death.
  6. Patients may deteriorate despite starting therapy, due to the presence of a paradoxical response. This is the consequence of a heightened immunological response, resulting in progressive fibrosis and arachnoiditis, causing an increase in the size of the tuberculoma or appearance of new tuberculomas and exudates, with an increase in the severity of brain inflammation. This can lead to sudden deterioration in a patient who was initially responding well to treatment. This situation does not warrant escalation of ATT or the start of second line therapy. Anecdotal reports have suggested the use of high dose steroids (including pulses of intravenous methylprednisolone), thalidomide and even immune-suppressive drugs to reduce the inflammatory response related damage.
  7. Raised intracranial pressure due to hydrocephalus is a major challenge. Early CSF diversion by shunt surgery provides a better outcome in patients of TBM with hydrocephalus.


Financial support and sponsorship

Nil.

Conflicts of interest

Authors declare that they do not have any conflict of interest. They do not have any source of funding.

[Additional file 1]

 
 » References Top

1.
Ruhrah J. The history of tuberculous meningitis. Med Library Hist J 1904;2:160-5.  Back to cited text no. 1
    
2.
Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis: Estimated incidence, prevalence, and mortality by country. WHO surveillance and monitoring project. JAMA 1999;282:677-86.  Back to cited text no. 2
    
3.
WHO. Global tuberculosis control: WHO report 2016. report. Geneva: World Health Organization, 2016.  Back to cited text no. 3
    
4.
Modi M, Sharma K, Prabhakar S, Goyal MG, Takkar A, Sharma N, et al. Clinical and radiological predictors of outcome in tubercular meningitis: A prospective study of 209 patients. Clin Neurol Neurosurg 2017;161:29-34.  Back to cited text no. 4
    
5.
Dastur DK, Lalitha VS, Udani PM, Parekh U. The brain and meninges in tuberculous meningitis – Gross pathology in 100 cases and pathogenesis. Neurol India 1970;18:86-100.  Back to cited text no. 5
    
6.
Medical Research Council Streptomycin in tuberculosis trials committee. Streptomycin treatment of tuberculosis meningitis. Lancet 1948;2:582-97.  Back to cited text no. 6
    
7.
Gupta RK, Kathuria MK, Pradhan S. Magnetization transfer MR imaging in CNS tuberculosis. Am J Neuroradiol 1999;20:867-75.  Back to cited text no. 7
    
8.
Thwaites GE, Nguyen DB, Nguyen HD, Quy HT. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351:1741-51.  Back to cited text no. 8
    
9.
Marais S, Thwaites G, Schoeman JF, Torok ME, Misra UK, Prasad K, et al. Tuberculous meningitis: A uniform case definition for use in clinical research. Lancet Infect Dis 2010;10:803-12.  Back to cited text no. 9
    
10.
Udani PM, Dastur DK. Tuberculous encephalopathy with and without meningitis: Clinical features and pathological correlation. J Neurol Sci 1970;10:541-61.  Back to cited text no. 10
    
11.
Ahuja GK, Mohan KK, Prasad K, Behari M. Diagnostic criteria for TBM and their validation. Tuber Lung Dis 1994;75:149-52.  Back to cited text no. 11
    
12.
Sharma S, Goyal MK, Sharma K, Modi M, Sharma M, Khandelwal N, et al. Cytokines do play a role in pathogenesis of tuberculous meningitis: A prospective study from a tertiary care center in India. J Neurol Sci 2017;39:131-6.  Back to cited text no. 12
    
13.
Garg RK. Tuberculosis of the central nervous system. Postgrad Med J 1999;75:133-40.  Back to cited text no. 13
    
14.
Sharma K, Sharma M, Singh S, Modi M, Sharma A, Ray P, et al. Real-time PCR followed by high-resolution melting curve analysis: A rapid and pragmatic approach for screening of multidrug-resistant extrapulmonary tuberculosis. Tuberculosis 2017;106:56-61.  Back to cited text no. 14
    
15.
Koh W, Ko Y, Kim C, Park KS, Lee NY. Rapid diagnosis of tuberculosis and multidrug resistance using a MGIT 960 system. Ann Lab Med 2012;32:264-9.  Back to cited text no. 15
    
16.
Sharma K, Appannanavar SB, Modi M, Singh M, Sharma A, Varma S. Role of multiplex polymerase chain reaction using IS6110 and Protein b for the diagnosis of extra-pulmonary tuberculosis: North India. Indian J Pathol Microbiol. 2015;58:27-30.  Back to cited text no. 16
    
17.
Sharma K, Sharma A, Singh M, Ray P, Dandora R, Sharma SK, et al. Evaluation of PCR using Protein b primers for rapid diagnosis of tuberculous meningitis. Neurol India 2010;58:727-31.  Back to cited text no. 17
[PUBMED]  [Full text]  
18.
Sharma K, Modi M, Kaur H, Sharma A, Ray P, Varma S. rpoB gene high resolution melt curve analysis: A rapid approach for diagnosis and screening of drug resistance in tuberculous meningitis. Diagn Microbiol Infect Dis 2015;83:144-9.  Back to cited text no. 18
    
19.
Modi M, Sharma K, Sharma M, Sharma A, Sharma N, Ray P, et al. Multi targeted loop-mediated isothermal amplification (LAMP) for rapid diagnosis of tuberculous meningitis. Int J TB Lung Ds 2016;20:625-30.  Back to cited text no. 19
    
20.
Evans CA. GeneXpert--a game-changer for tuberculosis control? PLoS Med 2011;8:e1001064.  Back to cited text no. 20
    
21.
Nhu NT, Heemskerk D, Thu do DA, Chau TT, Mai NT, Nghia HD, et al. Evaluation of GeneXpert MTB/RIF for diagnosis of tuberculous meningitis. J Clin Microbiol 2013;52:226-33.  Back to cited text no. 21
    
22.
Donald PR. Cerebrospinal fluid concentrations of antituberculosis agents in adults and children. Tuberculosis (Edinb) 2010; 90:279-92.  Back to cited text no. 22
    
23.
Jullien S, Ryan H, Modi M, Bhatia R. Short course vs prolonged course antituberculous treatment in tuberculous meningitis. The Cochrane library 2016;9:CD012091.  Back to cited text no. 23
    
24.
Donald PR, Schoeman JF, Van zyl LE, De Villiers JN, Pretorius M, Springer P. Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tub Lung Ds 1998;2:704-11.  Back to cited text no. 24
    
25.
American Thoracic Society/Centers for Disease Control and Prevention/Infectious Disease Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-62.  Back to cited text no. 25
    
26.
Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis 2012;13:27-35.  Back to cited text no. 26
    
27.
Heemskerk AD, Bang ND, Mai NTH, Chau TTH, et al. Intensified antituberculosis therapy in adults with tuberculous meningitis. N Eng J Med 2016;374:124-34.  Back to cited text no. 27
    
28.
Thwaites GE, Lan NT, Dung NH, Quy HT, Oanh DT, Thoa NT, et al. Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis. J Infect Dis 2005;192:79-88.  Back to cited text no. 28
    
29.
WHO. Multidrug and extensively drug-resistant TB (M/XDR-TB) 2010 global report on surveillance and response. report. Geneva, Switzerland: World Health Organisation; 2010. Report No.: ISBN 978 92 4 159919 1.  Back to cited text no. 29
    
30.
Tho DQ, Torok ME, Yen NT, Bang ND, Lan NT, Kiet VS, et al. Influence of antituberculosis drug resistance and Mycobacterium tuberculosis lineage on outcome in hiv-associated tuberculous meningitis. Antimicrob Agents Chemother 2012;56:3074-9.  Back to cited text no. 30
    
31.
Sharma K, Verma R, Advani R, Chatterjee O, Solanki HS, Sharma A, et al. Whole genome sequencing of mycobacterium tuberculosis isolates from extrapulmonary sites. OMICS 2017;21:413-42.  Back to cited text no. 31
    
32.
Tho DQ, Torok ME, Yen NT, Bang ND, Lan NT, Kiet VS, et al. Influence of antituberculosis drug resistance and mycobacterium tuberculosis lineage on outcome in HIV-associated tuberculous meningitis. Antimicrob Agents Chemother 2012;56:3074-9.  Back to cited text no. 32
    
33.
Smith H. Paradoxical responses during the chemotherapy of tuberculosis. J Infect 1987;15:1-3.  Back to cited text no. 33
    
34.
Keddie S, Bharambe V, Jayakumar A, et al. Clinical perspectives into the use of thalidomide for central nervous system tuberculosis. Eur J Neurol 2018;25: https://doi.org/10.1111/ene.13732.  Back to cited text no. 34
    
35.
Misra UK, Kalita J, Maurya PK. Stroke in tuberculous meningitis. J Neurol Sci 2011;303:22-30.  Back to cited text no. 35
    
36.
Mathew JM, Rajshekhar V, Chandy MJ. Shunt surgery for poor grade patients with tuberculous meningitis and hydrocephalus: Effect of response to external ventricular drainage and other factors on long-term outcome. J Neurol Neurosurg Psychiatry 1998;65:115-8.  Back to cited text no. 36
    
37.
Savardekar A, Chatterji D, Singhi S, Mohindra S, Gupta S, Chhabra R. The role of ventriculoperitoneal shunt placement in patients of tubercular meningitis with hydrocephalus in poor neurological grade: A prospective study in the pediatric population and review of literature. Childs Nerv Syst 2013;29:719-25.  Back to cited text no. 37
    
38.
Palur R, Rajshekhar V, Chandy MJ, Joseph T, Abraham J. Shunt surgery for hydrocephalous in tubercular meningitis: A long-term follow-up study. J Neurosurg 1991;74:64-9.  Back to cited text no. 38
    
39.
Chugh A, Husain M, Gupta RK, Ojha BK, Chandra A, Rastogi M. Surgical outcome of tuberculous meningitis hydrocephalus treated by endoscopic third ventriculostomy: Prognostic factors and postoperative neuroimaging for functional assessment of ventriculostomy. J Neurosurg Pediatr 2009;3:371-77.  Back to cited text no. 39
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
Print this article  Email this article
   
Online since 20th March '04
Published by Wolters Kluwer - Medknow