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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

The Pediatric Infectious Disease Journal: July 2004 - Volume 23 - Issue 7 - p 608-613
doi: 10.1097/01.inf.0000131634.57368.45
Original Studies

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.

From *Wilhelmina Children's Hospital, †Eijkman-Winkler Institute and the ‡Division of Acute Medicine and Infectious Diseases, Department of Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; §Biomedical Research Department, Royal Tropical Institute, Amsterdam, the Netherlands; and ¶Tygerberg Children's Hospital Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa

Accepted for publication February 27, 2004.

Supported by the Medical Branch of the Dutch Sciences Organization (stipend MW-ZON AGIKO 920-03-077 to M.v.d.F.).

Address for reprints: M. van der Flier, MD, PhD, Wilhelmina Childrens Hospital/University Medical Center Utrecht (UMCU), Room KB 03.023.2, P.O. Box 85090, 3508 AB Utrecht, the Netherlands. Fax 31 30 250 5346; E-mail

© 2004 Lippincott Williams & Wilkins, Inc.