Vascular endothelial growth factor and blood-brain barrier disruption in tuberculous meningitis.
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.


OBJECTIVE
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.
van der Flier
Michiel
M
Eijkman-Winkler Institute, Department of Medicine, University Medical Center Utrecht, Utrecht, the Netherlands. m.vanderflier@lab.azu.nl
Hoppenreijs
Sharon
S
van Rensburg
Anita Janse
AJ
Ruyken
Maartje
M
Kolk
Arend H J
AH
Springer
Priscilla
P
Hoepelman
Andy I M
AI
Geelen
Sibyl P M
SP
Kimpen
Jan L L
JL
Schoeman
Johan F
JF
D000418:Albumins / Q000378:metabolism; D000995:Antitubercular Agents / Q000627:therapeutic use; D001812:Blood-Brain Barrier; D001929:Brain Edema / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006849:Hydrocephalus / Q000503:physiopathology; D007223:Infant; D007427:Intracranial Pressure; D008297:Male; D011241:Prednisone / Q000627:therapeutic use; D012720:Severity of Illness Index; D014390:Tuberculosis, Meningeal / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism*
D000418:Albumins; D000995:Antitubercular Agents; D042442:Vascular Endothelial Growth Factors; D011241:Prednisone