Brain Imaging and Transcriptomics Reveal Cerebral Infarctions in Pediatric TBM

Overview

In children with tuberculous meningitis (TBM), cerebral infarctions were common, occurring in 63% of cases and frequently presenting as acute, multiple, and bilateral lesions. These infarctions correlated with higher cerebrospinal fluid protein, lower glucose levels, and increased systemic expression of matrix metalloproteinase-8 (MMP-8), highlighting a link between inflammation and cerebral injury.

Background

Cerebral infarctions affect 40% to 70% of children with TBM and are associated with poor neurological outcomes and mortality. These infarcts often result from vasculitis caused by basal inflammatory exudates affecting cerebral arteries, particularly in the basal ganglia and internal capsules. TBM triggers macrophage and microglial activation, releasing proinflammatory cytokines such as TNF-α, IL-1β, and IFN-γ, which contribute to blood-brain barrier disruption and neuronal injury. Current adjunctive therapies like corticosteroids reduce mortality but have limited impact on infarct incidence, underscoring the need for better understanding of TBM-associated infarct pathophysiology.

Data Highlights

Key Findings

• 63% of children with TBM had cerebral infarctions, predominantly acute, multiple, and bilateral.
• Infarcts were most commonly located in cerebral hemispheres, basal ganglia, and thalamus.
• Children with infarctions showed higher cerebrospinal fluid protein and lower glucose levels, indicating greater blood-brain barrier disruption and inflammation.
• Systemic expression of matrix metalloproteinase-8 (MMP-8) was significantly elevated in children with infarcts, linking extracellular matrix degradation to infarct development.
• Targeted transcriptomic analysis identified inflammatory mediators including MMPs, cytokines, and growth factors as key players in TBM pathogenesis and infarction.

Clinical Implications

The association of cerebral infarctions with elevated MMP-8 and altered CSF parameters suggests that targeting matrix metalloproteinases and inflammatory pathways may be a promising strategy to prevent or mitigate infarcts in pediatric TBM. Brain MRI remains essential for early detection of infarctions, guiding timely adjunctive therapies. Further research into host-directed treatments beyond corticosteroids is warranted to improve neurological outcomes.

Conclusion

This study demonstrates that cerebral infarctions are frequent and multifocal in children with TBM and are closely linked to systemic inflammatory responses, particularly MMP-8 expression. Integrating brain imaging with transcriptomic profiling enhances understanding of TBM pathophysiology and may inform development of targeted therapies.

References

1. Author/Source/Year -- Utilizing Brain Imaging and Targeted Transcriptomic Analysis of Whole Blood to Investigate Cerebral Infarctions in Pediatric Patients with Tuberculous Meningitis