Central nervous system tuberculosis is the most severe form of extrapulmonary tuberculosis disease. We aim to review the diagnostic and radiological features, pathogenesis, and biomarkers of tuberculous meningitis. We also aim to look at the latest development of research of the disease. The diagnosis of tuberculous (TB) meningitis is difficult because the disease presents with unspecific clinical features. However, the disease has excellent clinical response to antituberculous therapy. Good prognosis depends on prompt diagnosis with treatment and radiological findings are very important. There is an increase in the levels of serum and cerebrospinal fluid (CSF) TNF-in TB meningitis patients. IL-6 level is also increased in patients with tuberculoma and exudates. There is an increase in the levels of serum and CSF TNF-α and IFN-γ in TB meningitis patients. There is also a rise in the levels of IL-8, IFN-alpha, IFN-gamma, IL-10, CSF matrix metalloproteinases, CSF tissue inhibitors of matrix Metalloproteinases, VEGF level, caspase-1 and IL-1β. Signal-regulatory protein alpha is overexpressed at mRNA level. High dose intravenous rifampicin (800 mg daily) is associated with reduced mortality in patients with advanced disease.
Tuberculosis (TB) is a major health and clinical problem in the world [1-3]. There are eight million new cases annually [
The diagnosis of TB meningitis is difficult because TB meningitis presents with unspecific symptoms and signs [4,7]. Later in the disease, confusion, change in behavior, seizures and cranial nerve palsies can develop [
Diagnosis is based on the characteristic clinical features, radiological abnormalities, cerebrospinal fluid changes (acid-fast bacilli by direct staining of CSF or positive culture of acid-fast bacilli from CSF) [
The clinical features are fever for more than seven days, headache, and neck stiffness [1,6,10-12]. The other common clinical features are vomiting, focal neurological deficits, vision loss, cranial nerve palsies and raised intracranial pressure [5,13]. In human immunodeficiency virus (HIV) infection, TB is often atypical in presentation, frequently causing extrapulmonary disease, and patients have a high incidence of TB meningitis [1,5].
Presence of recent exposure to tuberculosis and signs of active extrameningeal tuberculosis on clinical assessment is important [
A diagnostic rule based on age (less than 36 years old), white blood cell count (less than 15,000), duration of illness (less than six days), cerebrospinal fluid white cell count (less than 750) and percentage of neutrophils in the CSF (less than 90%) had 86% sensitivity and 79% specificity [
The diagnosis of TB meningitis is limited by the poor sensitivity of CSF microscopy. In addition, Mycobacterium tuberculosis (M. tuberculosis) culture takes a few months to come back [
M. tuberculosis nucleic acid amplification PCR can be used for rapid diagnosis of TB meningitis [1,3]. Real time PCR allows direct observation of amplicon reaction [
In a recent study, IS6110-PCR had the highest positivity rate (68%) in comparison to Ziehl-Neelsen microscopy (11%) and mycobacterial culture (36% - 44%) [
BACTEC MGIT 960 can be used as a rapid test for the diagnosis of TB meningitis [
A recent study reported that the ELISA test for Mycobacterium tuberculosis anti-antigen A60 antibodies (IgM) is a rapid and sensitive tool for the rapid diagnosis of TBM [
The cerebrospinal fluid (CSF) shows a high CSF white-cell count, which is predominantly lymphocytic, with a high protein and low glucose level (CSF plasma glucose is <50%) [
Neutrophils can be the predominant cells, especially early in the disease, and high proportions of neutrophils in the cell count have been associated with improved survival [
Multiple CSF sampling improves the sensitivity of Ziehl-Neelsen stain to more than 80% [
The severity of TB meningitis at presentation is divided into three stages according to the patient’s Glasgow coma score and the presence/absence of focal neurological signs [
Movement disorders can present after basal ganglia stroke [
Pathologically from autopsies, there was a subcortical or meningeal focus (“Rich focus”) from which bacteria had access to the subarachnoid space [
TB meningitis can also result in infiltrative, proliferative and necrotising vessel pathologies causing luminal thrombosis [
Good prognosis depends on prompt diagnosis and treatment; therefore the importance of radiological findings is emphasized [
MRI is also useful to monitor the development of complications of disease [
Stroke in tuberculous meningitis (TBM) occurs in 15% - 57% of patients especially in advanced stage and severe disease [
Bilaterally symmetrical strokes of the TB zone were common with TB meningitis (71%) but rare with noninflammatory ischemic stroke (IS) (5%) [
The locations of strokes were studied in 14 patients with TB meningitis and 173 patients with noninflammatory ischemic stroke (IS) in a study in Taiwan [
MRI features of stroke due to TBM are divided into anterior (caudate, genu, anterior limb of internal capsule, anteromedial thalamus) and posterior (lentiform nuclei, posterior limb of internal capsule, posterolateral thalamus) [
Choroid plexus enhancement with ventricular enlargement on imaging is highly suggestive of TBM [
In summary, the typical changes of TB meningitis are hydrocephalus, tuberculomas, basal cistern, sylvian fissure and gyral enhancement, with stroke at areas supplied by medial striate and thalamoperforating arteries [2,13].
The release of Mycobacterium tuberculosis into the subarachnoid space results in a local T-lymphocyte-dependent response [
In pulmonary tuberculosis, tumour necrosis factor (TNF) is believed to be important for granuloma formation [
Protein levels of interleukin-6 (IL-6) were increased in patients who had presence of tuberculoma and increasing exudates [
TB meningitis results in bacteria replication, which caused an increase in IL-8, interferon-alpha (IFN-alpha) and IFN-gamma [
In addition, other cytokines, such as, IL-6, IL-10, and IL-1β are significantly higher in patients compared to controls, and the levels are reduced after three months of antituberculous therapy [
Serum and CSF IFN-γ levels are significantly associated with a marked rise in TB meningitis patients [
Nitric oxide (NO) causes vascular and perivascular inflammatory central nervous system changes, which are possible aetiologies of tuberculous encephalopathy [
Neutrophils have a role in pathogenesis of TB meningitis [
Signal-regulatory protein alpha (SIRPA) and protein disulfide isomerase family A, member 6 (PDIA6), is overexpressed at the mRNA level in TB meningitis [
Infection with Mycobacterium tuberculosis results in activation of caspase-1 and IL-1β secretion [
TB meningitis patients have higher serum vascular endothelial growth factor (VEGF) level [
In summary, biomarkers such as TNF-α, IL-6, IL-10, IFN-alpha and IFN-gamma aid with the diagnosis of TB meningitis.
Prompt diagnosis and early treatment are crucial [
Streptomycin can be used instead of ethambutol as the fourth anti-TB agent but none of the drugs penetrates the CSF well in the absence of inflammation [
A recent study showed that a higher dose of rifampicin (600 mg, or 13 mg/kg) and standard-dose (400 mg daily) or high-dose moxifloxacin (800 mg daily) during the first two weeks is safe in patients with TB meningitis [
The emergence of drug resistant tuberculosis poses a serious threat to the control of TB, and the development of drugs against the resistant strains is essential [
Corticosteroids (dexamethasone) with antituberculous treatment reduce mortality and morbidity [1,5,6,23,37,38]. Adjunctive corticosteroid therapy more than two weeks improves survival, but treatment for more than 4 four weeks of use do not have effect on mortality [
Patients with hydrocephalus might require ventriculo-peritoneal shunting [
The patients with TB meningitis with hydrocephalus will have worse prognosis and greater mortality [
Neuroimaging factors that are significantly associated with hydrocephalus are basal exudates, tuberculoma and strokes [
The presence of stroke on admission, Glasgow coma scale ≤ 8 on admission, age of ≥30 years and presence of hydrocephalus with ventriculo-peritoneal shunt was significantly associated with mortality [
Poor conscious state was significantly associated with poor prognosis in TB meningitis patients [38,42]. Severity of disease at admission and delayed anti-tuberculous therapy was related to poor outlook for TB meningitis patients [
1/5 of the patients have complete neurological recovery in one year occur in 1/5, but only 50% of them are independent for activities of daily living [
Positive TB culture and polymerase chain reaction of CSF are factors associated with poor prognosis [
Serial CT scan at three and six months is abnormal in most TB meningitis patients [
A third of patients with TB meningitis may deteriorate within six weeks of initiation of treatment [
The diagnosis of TB meningitis is difficult because of nonspecific presentation and clinical features. Good prognosis depends on prompt diagnosis (before further neurological deterioration) with treatment; therefore radiological findings are very important. A recent study has shown that high dose intravenous rifampicin (800 mg daily) is associated with reduced mortality in patients with advanced disease.
Analysis of biomarkers in TB meningitis is important. There is an increase in the levels of serum and CSF TNF- α and IFN-γ in TB meningitis patients. IL-6 level is also increased in patients with tuberculoma and exudates. There is also a rise in the levels of IL-8, IFN-alpha, IFN-gamma, IL-10, CSF matrix metalloproteinases, CSF tissue inhibitors of matrix Metalloproteinases, VEGF level, caspase-1 and IL-1β. Signal-regulatory protein alpha is overexpressed at mRNA level.
There is advancement of research for TB meningitis. The TB meningitis research is rapidly progressing. In future, we will be able to see the development with respect to treatment and management of disease. Through the knowledge of biomarkers, better and more advanced antituberculous therapy can be developed.