Septic Encephalopathy: Relationship to Serum and Cerebrospinal Fluid Levels of Adhesion Molecules, Lipid Peroxides and S-100B Protein

 

 Buy Article Permissions and Reprints

Abstract

Severe septic illness is often associated with cerebral manifestations such was disturbed consciousness and delirium. Little was known about its effect on the CNS. This is the first study in children that has assessed the direct mediators of brain inflammation and injury with sepsis. The serum and CSF concentrations of soluble intracellular adhesion molecule-1 (sICAM-1) (marker of endothelium-leukocyte interaction), nitric oxide (NO) and lipid peroxide (LPO) (markers for lipid peroxidation) and S-100B protein (marker of astrocytes activation and injury), were measured in 40 children with sepsis of whom 40% had moderate to severe septic encephalopathy. Serum from 25 normal children was used for comparison. Serum values of sICAM-1, NO, LPO and S100B were elevated in patients compared to controls. The greater elevation of the CSF:serum albumin ratio suggests loss of blood-brain barrier integrity. After normalising for CSF:serum albumin ratio, we demonstrated a significant intrathecal synthesis of NO, LPO and S100B. Patients with encephalopathy had elevated serum and CSF levels of sICAM-1, NO, LPO and S100B compared to sepsis only. This study indicates that the brain is vulnerable in children with sepsis. It also suggests that coordinated interactions between immune system, vascular endothelial cells, CNS barriers, astrocytes and brain lipid peroxides, may contribute to septic encephalopathy.

References

• 1 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference . Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.  Crit Care Med. 1992;  20 864-874
  CrossrefPubMedGoogle Scholar
• 2 Anderson RE, Hansson LO, Nilsson O. et al . High serum S-100B levels for trauma patients without head injuries.  Neurosurgery. 2001;  48 1255-1258
  CrossrefPubMedGoogle Scholar
• 3 Aycicek A, Iscan A, Erel O. et al . Total antioxidant/oxidant status in meningism and meningitis.  Pediatr Neurol. 2006;  35 382-386
  CrossrefPubMedGoogle Scholar
• 4 Barichello T, Fortunato JJ, Vitali AM. et al . Oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation.  Crit Care Med. 2006;  34 886-889
  CrossrefPubMedGoogle Scholar
• 5 Bello JHSM, Park M. Sepsis-associated encephalopathy as a differential diagnosis with motor deficit plus altered mental status.  Clinics. 2007;  62 199-202
  PubMedGoogle Scholar
• 6 Bevilacqua MP, Nelson RM, Mannori G. et al . Endothelial-leukocyte adhesion molecules in human disease.  Ann Rev Med. 1994;  45 361-378
  CrossrefPubMedGoogle Scholar
• 7 Center for biomarker in imaging . Massachusetts General Hospital Harvard-M.I.T. Division of Health Sciences and Technology Web site. 2004;  , Available at: http://www.biomarkers.org
  PubMed
• 8 Consales G, De Gaudio AR. Sepsis associated encephalopathy.  Minerva Anestesiol. 2005;  71 39-52
  PubMedGoogle Scholar
• 9 Ding AH, Nathan CF, Stuchr DJ. Release of reactive nitrogen intermediate from mouse peritoneal macrophage comparison of activating cytokines and evidence for independent production.  J Immuno. 1988;  141 2407-2412
  PubMedGoogle Scholar
• 10 dos Santos AQ, Nardin P, Funchal C. et al . Resveratrol increases glutamate uptake and glutamine synthetase activity in C6 glioma cells.  Arch Biochem Biophys. 2006;  453 161-167
  CrossrefPubMedGoogle Scholar
• 11 Fassbender K, Schminke U, Ries S. et al . Endothelial-derived adhesion molecules in bacterial meningitis: association to cytokine release and intrathecal leukocyte-recruitment.  J Neuroimmunol. 1997;  74 130-134
  CrossrefPubMedGoogle Scholar
• 12 Gagnon C, Leblond FA, Filep JG. Peroxynitrite production by human Neutrophils, monocytes and lymphocytes challenged with lipopolysaccharide.  FEBS Lett. 1998;  431 107-110
  CrossrefPubMedGoogle Scholar
• 13 Grau A, Guardiola F, Boatella J. et al . Measurement of 2-thiobarbituric acid values in dark chicken meat through derivative spectrophotometry: influence of various parameters.  J Agric Food Chem. 2000;  48 1155-1159
  CrossrefPubMedGoogle Scholar
• 14 Harris RL, Muscher DM, Gathe J. et al . Manifestations of sepsis.  Arch Intern Med. 1987;  147 1895-1906
  CrossrefPubMedGoogle Scholar
• 15 Hauser B, Matejovic M, Radermacher P. Nitric oxide, leukocytes and microvascular permeability: causality or bystanders?.  Crit Care. 2008;  12 104
  CrossrefPubMedGoogle Scholar
• 16 Hu J, Castets F, Guevara JL. et al . S100 beta stimulates inducible nitric oxide synthase activity and mRNA levels in rat cortical astrocytes.  J Biol Chem. 1996;  271 2543-2547
  CrossrefPubMedGoogle Scholar
• 17 Kastenbauer S, Koedel U, Becker BF. et al . Oxidative stress in bacterial meningitis in humans.  Neurology. 2002;  58 186-191
  PubMedGoogle Scholar
• 18 Larsson A, Lipcsey M, Sjölin J. et al . Slight increase of serum S-100B during porcine endotoxemic shock may indicate blood-brain barrier damage.  Anesth Analg. 2005;  101 1465-1469
  CrossrefPubMedGoogle Scholar
• 19 Lewczuk P, Reiber H, Tumani H. Intercellular adhesion molecule-1 in cerebrospinal fluid – the evaluation of blood derived and brain derived fractions in neurological diseases.  J Neuroimmunol. 1998;  87 156-161
  CrossrefPubMedGoogle Scholar
• 20 Marcantonio ER, Rudolph JL, Culley D. et al . Serum biomarkers for delirium.  J Gerontol A Biol Sci Med Sci. 2006;  61 1281-1286
  PubMedGoogle Scholar
• 21 Martin GS, Mannino DM, Eaton S. et al . The epidemiology of sepsis in the United States from 1979 through 2000.  N Engl J Med. 2003;  348 1546-1554
  CrossrefPubMedGoogle Scholar
• 22 Mégarbane B, Marchal P, Marfaing-Koka A. et al . Increased diffusion of soluble adhesion molecules in meningitis, severe sepsis and systemic inflammatory response without neurological infection is associated with intrathecal shedding in cases of meningitis.  Intensive Care Med. 2004;  30 867-874
  CrossrefPubMedGoogle Scholar
• 23 Merck Manual. Modified Glasgow Coma Scale for Infants and Children. http://www.merck.com/mmpe/sec21/ch310/ch310a.html#chdehefh
  PubMed
• 24 Ohtaki N, Kamitani W, Watanabe Y. et al . Downregulation of an astrocyte-derived inflammatory protein, S-100B, reduces vascular inflammatory responses in brains persistently infected with Borna disease virus.  J Virol. 2007;  81 5940-5948
  CrossrefPubMedGoogle Scholar
• 25 Papadopoulos MC, Davies DC, Moss RF. et al . Pathophysiology of septic encephalopathy: a review.  Crit Care Med. 2000;  28 3019-3024
  CrossrefPubMedGoogle Scholar
• 26 Pytel P, Alexander JJ. Pathogenesis of septic encephalopathy.  Curr Opin Neurol. 2009;  22 283-287
  CrossrefPubMedGoogle Scholar
• 27 Reiber H. CSF flow – its influence on CSF concentration of brain-derived and blood-derived proteins. In: Teelken A, Korf J, editors Neurochemistry. New York: Plenum 1997 p. 51-72
  PubMedGoogle Scholar
• 28 Reiber H. Dynamics of brain-derived proteins in cerebrospinal fluid.  Clin Chim Acta. 2001;  310 173-186
  CrossrefPubMedGoogle Scholar
• 29 Reiber H. Proteins in cerebrospinal fluid and blood: barriers, CSF flow rate and source-related dynamics.  Restor Neurol Neurosci. 2003;  21 79-96
  PubMedGoogle Scholar
• 30 Sessler CN, Windsor AC, Schwartz M. et al . Circulating ICAM-1 is increased in septic shock.  Am J Respir Crit Care Med. 1995;  151 1420-1427
  PubMedGoogle Scholar
• 31 Sharshar T, Annane D, de la Grandmaison GL. et al . The neuropathology of septic shock.  Brain Pathol. 2004;  14 21-33
  PubMedGoogle Scholar
• 32 Steiner J, Bernstein HG, Bielau H. et al . Evidence for a wide extra-astrocytic distribution of S-100B in human brain.  BMC Neurosci. 2007;  8 2
  CrossrefPubMedGoogle Scholar
• 33 Sulik A, Wojtkowska M, Rozkiewicz D. et al . Increase in adhesion molecules in cerebrospinal fluid of children with mumps and mumps meningitis.  Scand J Immunol. 2006;  64 420-424
  CrossrefPubMedGoogle Scholar
• 34 Tramontina F, Leite MC, Goncalves D. et al . High glutamate decreases S-100B secretion by a mechanism dependent on the glutamate transporter.  Neurochem Res. 2006;  31 815-820
  CrossrefPubMedGoogle Scholar
• 35 Tsukahara H, Haruta T, Ono N. et al . Oxidative stress in childhood meningitis: Measurement of 8-hydroxy-2V-deoxyguanosine concentration in cerebrospinal fluid.  Redox Report. 2000;  5 295-298
  CrossrefPubMedGoogle Scholar
• 36 Undén J, Christensson B, Bellner J. et al . Serum S-100B levels in patients with cerebral and extracerebral infectious disease.  Scand J Infect Dis. 2004;  36 10-13
  CrossrefPubMedGoogle Scholar
• 37 Van Eldik LJ, Wainwright MS. The Janus face of glial-derived S-100B: beneficial and detrimental functions in the brain.  Restor Neurol Neurosci. 2003;  21 97-108
  PubMedGoogle Scholar
• 38 Weiss SJ. Tissue destruction by neutrophils.  N Engl J Med. 1989;  320 365-376
  CrossrefPubMedGoogle Scholar
• 39 Whalen MJ, Carlos TM, Dixon CE. et al . Reduced brain edema after traumatic brain injury in mice deficient in P-selectin and intercellular adhesion molecule-1.  J Leukoc Biol. 2000;  67 160-168
  PubMedGoogle Scholar
• 40 Williams PA, Dou P, Dudek FE. et al . Epilepsy and synaptic reorganization in a perinatal rat model of hypoxia-ischemia.  Epilepsia. 2004;  45 1210-1218
  CrossrefPubMedGoogle Scholar
• 41 Wunderlich MT, Ebert AD, Kratz T. Early neurobehavioral outcome after stroke is related to release of neurobiochemical markers of brain damage.  Stroke. 1999;  30 1190-1195
  PubMedGoogle Scholar
• 42 Yan SS, Wu ZY, Zhang HP. et al . Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system.  Nat Med. 2003;  9 ((3)) 287-293
  CrossrefPubMedGoogle Scholar
• 43 Youssef FG, El-Sakka H, Azab A. et al . Etiology, antimicrobial susceptibility profiles, and mortality associated with bacterial meningitis among children in Egypt.  Ann Epidemiol. 2004;  14 44-48
  CrossrefPubMedGoogle Scholar

Correspondence

Sherifa A. HamedMBBch, MSc, MD 

Department of Neurology and Psychiatry

Assiut University Hospital

P. O. Box 71516

Assiut

Egypt

Phone: +20/88/237 1820

Fax: +20/88/233 3327

Fax: +20/88/233 2278