The pathogenesis of tuberculous meningitis

Abstract

Tuberculosis (TB) remains a leading cause of death globally. Dissemination of TB to the brain results in the most severe form of extrapulmonary TB, tuberculous meningitis (TBM), which represents a medical emergency associated with high rates of mortality and disability. Via various mechanisms the Mycobacterium tuberculosis (M.tb) bacillus disseminates from the primary site of infection and overcomes protective barriers to enter the CNS. There it induces an inflammatory response involving both the peripheral and resident immune cells, which initiates a cascade of pathologic mechanisms that may either contain the disease or result in significant brain injury. Here we review the steps from primary infection to cerebral disease, factors that contribute to the virulence of the organism and the vulnerability of the host and discuss the immune response and the clinical manifestations arising. Priorities for future research directions are suggested.

Keywords: Th17 cells; T Lymphocytes; endothelial cells; granulocytes; microglia cells; monocytes/macrophages; mycobacterial; myeloid cells; neutrophils.

Figure 1:. Summary of the pathogenesis of TBM

A: Mycobacterium tuberculosis bacilli (M.tb) disseminate from the primary site of infection in the lung to seed the brain. The bacilli are able to traverse the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCSFB) through various virulence factors that enable the invasion of and migration through cerebral vascular endothelial cells, or are carried into the central nervous system (CNS) by infected peripheral innate immune cells. B: In the CNS antigen recognition and internalisation by microglia, neurons and astrocytes occurs, mediated by numerous host genetic factors. C: The resulting immune response stimulates the release of pro-inflammatory cytokines and chemokines and other immune mediators that contribute to the breakdown of the BBB and the influx of innate and adaptive immune cells from the periphery. D: A prolific inflammatory response ensues. The inflammatory exudate in the basal cisterns contributes to cerebral vascular pathology and the development of hydrocephalus and raised intracranial pressure. Vasogenic oedema due to an influx of proteins through the leaky BBB, and cytotoxic oedema as a result of cellular damage contribute to the raised pressure. The overall decrease in cerebral blood flow puts the brain at risk of ischaemia, infarction and poor patient outcomes. In some cases the infection is controlled in discrete tuberculomas or abscesses, which resolve with treatment and time. Extension of the disease into the spinal canal manifests as spinal arachnoiditis, tuberculomas, or collection of exudate.

Figure 2:. Mycobacterium tuberculosis and vitamin D impact on the tryptophan metabolism.

M.tb infection activates the inflammatory response resulting in pro-inflammatory cytokines secretion. Along with M.tb, these cytokines can trigger the kynurenine pathway by stimulating IDO. Once the pathway is activated, astrocytes and microglia respectively produce kynurenic acid and quinolinic acid, the latter is neurotoxic. Thus, an imbalance in the synthesis of these two products may result in neurotoxicity. Vitamin D, cofactor of TPH, promotes serotonin production and neurotransmission. Alone or when bound with one of its receptor, VDR, vitamin D attenuates the inflammatory response. M.tb: Mycobacterium tuberculosis; IDO: indoleamine 2, 3-dioxygenase; TPH: tryptophan hydrolase; KAT: kynurenine aminotransferase; KMO: kynurenine-3-monooxygenase; 3-HAO: 3-hydroxyanthranilic acid dioxygenase; NMDA: N-methyl-d-aspartate; VDR: vitamin D receptor. Blue: neuroprotection; red: neurotoxicity; green: influential factors.

Figure 3:. Radiological features of TBM

Top left: Exudate Contrast-enhanced T1-weighted MRI scan images: A: Normal scan showing cerebrospinal fluid in the cisterns (interpeduncular cistern in front of the midbrain, black arrow) and vessels at the base of the brain in normal cisterns (posterior cerebral artery, white arrow); B: Scan of a patient with TBM showing exudate in the basal cisterns of the brain (interpeduncular cistern, anterior to the brainstem and beneath the hypothalamus, black arrow) and vessels coursing through the exudate in the cisterns (posterior cerebral artery, white arrow). Middle left: Hydrocephalus A: Initial head CT scan images of a patient with TBM showing acute hydrocephalus with dilated ventricles and a compressed brain; B: Head CT scan of the same patient after 3 weeks of medical therapy showing resolution of the hydrocephalus. Lower left: Tuberculomas MRI scans demonstrating different patterns and imaging characteristics of brain tuberculomas: A: Contrast-enhanced T1-weighted MRI scan showing multiple ring-enhancing small tuberculomas (arrowed); B: T2-weighted MRI scan showing a large tuberculoma in the cerebellum compressing the brainstem, surrounding oedema, and hydrocephalus from obstruction of the cerebral aqueduct. Right: Infarcts Demonstration of infarction patterns in TBM, A: T2-weighted MRI scan showing normal ventricular size and no infarcts; B: T2-weighted axial MRI scan of a patient with TBM showing discrete unilateral small perforator vessel infarcts (arrowed); C: T2-weighted MRI scan showing more extensive infarcts in the thalami and basal ganglia (arrowed); D: Head CT scan of a patient with TBM showing global infarction with hypodense hemispheres bilaterally and a swollen brain.

Figure 4:. Basal cisterns and pituitary anatomy

A: Basal cisterns affected in TBM are represented here in a sagittal view of the brain. Note the quadrigeminal cistern which extends laterally to become a thin sheet like cistern surrounding the midbrain and posterior thalamus, named the ambient cistern shown in C. B: Anatomy of the pituitary gland and surrounding structures.

Figure 5:. Lenticulostriate arteries

Lenticulostriate arteries branching from the M1 segment of the middle cerebral artery supply the basal ganglia and internal capsule.