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Pediatric Infectious Disease Journal:
Original Studies

Vascular Endothelial Growth Factor and Blood-Brain Barrier Disruption in Tuberculous Meningitis

van der Flier, Michiel MD, PhD†; Hoppenreijs, Sharon MD*; van Rensburg, Anita Janse Dip Nurs¶; Ruyken, Maartje BSc†; Kolk, Arend H. J. PhD§; Springer, Priscilla MD¶; Hoepelman, Andy I. M. MD, PhD†‡; Geelen, Sibyl P. M. MD, PhD*; Kimpen, Jan L. L. MD, PhD*; Schoeman, Johan F. MD¶

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Abstract

Background: Tuberculous meningitis (TBM) is characterized by disruption of the blood-brain barrier (BBB), cerebral edema and increased intracranial pressure (ICP). Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor and a mediator of brain edema.

Aims: To investigate whether in children with TBM disruption of the BBB relates to VEGF production and to assess the effect of corticosteroids on Mycobacterium tuberculosis-induced VEGF production by mononuclear leukocytes.

Methods: Blood and CSF samples were collected from 26 children with stage 2–3 TBM and 20 controls. All patients received antituberculous and adjuvant corticosteroid therapy. Children were evaluated by ICP recording, computerized tomography scanning and outcome assessment at 6 months follow-up. BBB disruption was quantified by cerebrospinal fluid (CSF)-serum albumin ratios. VEGF concentrations were measured by enzyme-linked immunosorbent assay. In vitro human monocytic THP-1 cells were stimulated with M. tuberculosis sonicate or culture supernatant, and VEGF production was measured in the presence or absence of corticosteroids.

Results: CSF VEGF concentrations were significantly higher in TBM patients than in the controls and correlated with mononuclear cell counts (r = 0.64; P = 0.001) and CSF-serum albumin ratio (r = 0.49; P = 0.015). CSF VEGF did not significantly correlate with elevated ICP. In vitro induction of VEGF production by M. tuberculosis sonicate or culture supernatant could be completely abrogated by corticosteroid treatment.

Conclusions: Inflammatory cells secrete VEGF during TBM. CSF VEGF correlates with BBB disruption. Inhibition of VEGF may explain part of the clinical effect of adjuvant corticosteroid therapy in TBM.

© 2004 Lippincott Williams & Wilkins, Inc.

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