350
Blood-Brain Barrier Damage in Patients with Bacterial Meningitis: Association with Tumor Necrosis Factor-a but not Interleukin-Id M. K. Sharief, M. Ciardi, and E. J. Thompson
Department of Clinical Neurochemistry, Institute ofNeurology. National Hospital for Neurology and Neurosurgery, Queen Square. London. United Kingdom; Institute ofInfectious Diseases. La Sapienza University. Rome, Italy
Bacterial meningitis continues to be an important cause of death and permanent neurologic disability despite major advances in antimicrobial therapy and rapid diagnostic techniques [I, 2]. As a result, research designed to delineate the molecular pathophysiology of this condition is important in understanding the mechanisms of intrathecal inflammatory response and in planning more effective treatment. Although inflammation in bacterial meningitis is largely limited to neuronal and vascular structures within the subarachnoid space, profound alterations in intracranial physiology are known to occur in patients with this disease. Among the important intracranial processes affected in meningitis are those regulating cerebral endothelial and blood-brain barrier functions. Damage to cerebrovascular cells may lead to increased local vascular resistance, thrombus formation, or even brain infarction. Moreover, damage of blood-brain barriers in meningitis [3,4] results in increased cerebrovascular permeability and may consequently induce potentially fatal brain edema. Tumor necrosis factor-a, (TNFa) plays an important role in modulating endothelial cell functions [5, 6]. Of relevance to meningitis, TNFa results in vascular endothelial damage, alteration of endothelial homeostasis [5], and an increase in vascular permeability leading to vascular leak syndrome [7]. Although TNFa has been extensively studied in meningitis
Received 18 September; revised 9 March 1992. Reprints or correspondence: Dr. M. K. Sharief Institute of Neurology. National Hospital for Neurology and Neurosurgery. Queen Square. London WCIN 3BG. United Kingdom.
The Journal of Infectious Diseases
1992;166:350-8
© 1992 by The University of Chicago. All rights reserved.
0022-1899/92/6602-0018$01.00
[8-12], the mechanism of central nervous system damage caused by this cytokine is incompletely defined. Some of the proinflammatory effects of TNFa were reported to be influenced by interleukin-Id (IL-l(j) [13,14]. Thus, the aim of this study was to analyze the in vivo relationship of TNFa and IL-l {3 to impairment of blood-brain barriers in patients with bacterial meningitis. Patients and Methods Patients. We selected patients with bacterial meningitis who were admitted to Maida Vale Hospital and the National Hospital for Neurology and Neurosurgery, London, and the Institute of Infectious Diseases, Rome, from January 1988 to August 1990. The study was planned prospectively so only patients who had samples of cerebrospinal fluid (CSF) and serum taken within 4 h of admission were included. In addition, the study design required that the clinical diagnosis of meningitis should have been confirmed bacteriologically and that no antibiotics had been administered before sample collection. Fourty-eight patients (age range, 2-69 years; 21 women) who satisfied the inclusion criteria were enrolled, including 18 children (mean age ± SD, 8.5 ± 3.4; range, 2-14 years). Children with bacterial meningitis
Blood-Brain Barrier Damage in Patients with Bacterial Meningitis: Association with Tumor Necrosis Factor-a but not Interleukin-Id M. K. Sharief, M. Ciardi, and E. J. Thompson
Department of Clinical Neurochemistry, Institute ofNeurology. National Hospital for Neurology and Neurosurgery, Queen Square. London. United Kingdom; Institute ofInfectious Diseases. La Sapienza University. Rome, Italy
Bacterial meningitis continues to be an important cause of death and permanent neurologic disability despite major advances in antimicrobial therapy and rapid diagnostic techniques [I, 2]. As a result, research designed to delineate the molecular pathophysiology of this condition is important in understanding the mechanisms of intrathecal inflammatory response and in planning more effective treatment. Although inflammation in bacterial meningitis is largely limited to neuronal and vascular structures within the subarachnoid space, profound alterations in intracranial physiology are known to occur in patients with this disease. Among the important intracranial processes affected in meningitis are those regulating cerebral endothelial and blood-brain barrier functions. Damage to cerebrovascular cells may lead to increased local vascular resistance, thrombus formation, or even brain infarction. Moreover, damage of blood-brain barriers in meningitis [3,4] results in increased cerebrovascular permeability and may consequently induce potentially fatal brain edema. Tumor necrosis factor-a, (TNFa) plays an important role in modulating endothelial cell functions [5, 6]. Of relevance to meningitis, TNFa results in vascular endothelial damage, alteration of endothelial homeostasis [5], and an increase in vascular permeability leading to vascular leak syndrome [7]. Although TNFa has been extensively studied in meningitis
Received 18 September; revised 9 March 1992. Reprints or correspondence: Dr. M. K. Sharief Institute of Neurology. National Hospital for Neurology and Neurosurgery. Queen Square. London WCIN 3BG. United Kingdom.
The Journal of Infectious Diseases
1992;166:350-8
© 1992 by The University of Chicago. All rights reserved.
0022-1899/92/6602-0018$01.00
[8-12], the mechanism of central nervous system damage caused by this cytokine is incompletely defined. Some of the proinflammatory effects of TNFa were reported to be influenced by interleukin-Id (IL-l(j) [13,14]. Thus, the aim of this study was to analyze the in vivo relationship of TNFa and IL-l {3 to impairment of blood-brain barriers in patients with bacterial meningitis. Patients and Methods Patients. We selected patients with bacterial meningitis who were admitted to Maida Vale Hospital and the National Hospital for Neurology and Neurosurgery, London, and the Institute of Infectious Diseases, Rome, from January 1988 to August 1990. The study was planned prospectively so only patients who had samples of cerebrospinal fluid (CSF) and serum taken within 4 h of admission were included. In addition, the study design required that the clinical diagnosis of meningitis should have been confirmed bacteriologically and that no antibiotics had been administered before sample collection. Fourty-eight patients (age range, 2-69 years; 21 women) who satisfied the inclusion criteria were enrolled, including 18 children (mean age ± SD, 8.5 ± 3.4; range, 2-14 years). Children with bacterial meningitis
