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It has been hypothesized that immunoactivation may contribute to brain damage and affect outcome after traumatic brain injury (TBI). In order to determine the role of inflammation after TBI, we studied the interrelationship of the immune mediators sICAM-1 and IL-6 with the levels of S-100beta and neuronal specific enolase (NSE), both recognized markers of brain damage. In addition, the extent and type of cerebral injury and the neurological outcome were related to these measured markers of injury. An evident elevation of S-100beta (range of means: 2.7-81.4 ng/mL) and NSE (range of means: 2.0-81.3 ng/mL) was observed in CSF of all 13 patients during the first 3 posttraumatic days and decreased over 2 weeks. In parallel, the production of sICAM-1 (range of means: 0.7-11.9 ng/mL) and IL-6 (range of means: 0.1-8.2 ng/mL) was also markedly enhanced in CSF. The CSF means of S-100beta and NSE per patient correlated with IL-6 (r = 0.60, p < 0.05; and r = 0.64, p < 0.05, respectively), whereas the corresponding means in serum showed a significant correlation only between NSE and IL-6 (r = 0.56, p < 0.05). Maximal CSF values of NSE and sICAM-1 correlated with each other (r = 0.57, p < 0.05). The contusion sizes assessed on the CT scans correlated with the means of S-100beta (r = 0.63, p < 0.05) and NSE (r = 0.71, p < 0.05) in CSF and with the mean of S-100beta in serum, although not statistically significant (r = 0.52, p = 0.06), but not with serum NSE. Interestingly, linear regression analysis demonstrated that means of S-100beta in CSF (r = 0.78, p = 0.002) and serum (r = 0.82, p < 0.001) correlated with the GOS. These results indicate that the elevation of these parameters in CSF depends on the extent of injury and that S-100beta may be a predictor of outcome after TBI, whereas NSE reflects better the inflammatory response.

The dysfunction of the blood-brain barrier (BBB) occurring after traumatic brain injury (TBI) is mediated by intracerebral neutrophil accumulation, chemokine release (e.g., interleukin (IL)-8) and upregulation of adhesion molecules (e.g., intercellular adhesion molecule (ICAM)-1). In patients with severe TBI, we previously found that elevated cerebrospinal fluid (CSF) IL-8 and soluble (s)ICAM-1 correlate with BBB dysfunction, and this prompted us to concomitantly monitor IL-8, sICAM-1 and their stimulator tumor necrosis factor (TNF)-alpha in CSF. Potential mechanisms for upregulation of the IL-8 analogue, murine macrophage inflammatory protein (MIP)-2, and sICAM-1 at the BBB were studied using cultured mouse astrocytes and brain microvascular endothelial cells (MVEC). In CSF of seven patients, IL-8 and sICAM-1 were elevated for 19 days after severe TBI, whereas TNF-alpha exceeded normal values on 9 days. Stimulation of MVEC and astrocytes with TNF-alpha simultaneously induced the release of MIP-2 reaching saturation by 4-8 hr and of sICAM-1 increasing continuously from 2-4 hr to 12 hr. Augmented sICAM-1 production correlated with enhanced membrane-bound (m)ICAM-1 expression in both cell types (r(s) = 0.96 and 0.90, P < 0.0001), but was markedly higher in astrocytes. The release of sICAM-1 was not influenced by IL-8 or MIP-2, although astrocytes and MVEC expressed the IL-8/MIP-2 receptor (CXCR-2) as determined by FACS analysis. Instead, we found that sICAM-1 strongly induced MIP-2 secretion by both cell types with kinetics differing from those evoked by TNF-alpha. If added together, sICAM-1 and TNF-alpha synergistically induced MIP-2 production suggesting the involvement of two different pathways for MIP-2 regulation., (Copyright 2000 Wiley-Liss, Inc.)

Objectives: Brain-injured patients are susceptible to secondary brain damage related to decreased cerebral perfusion pressure associated with edema formation and increased intracranial pressure (ICP). Whenever conventional therapy fails to reduce elevated ICP, barbiturate coma represents an additional intervention that may control ICP. In patients suffering from severe traumatic brain injury, cerebrospinal fluid levels of glutamate, hypoxanthine, and lactate were measured during barbiturate coma and correlated to electroencephalographic recordings and ICP., Design: Prospective, descriptive study., Setting: Ten-bed surgical intensive care unit in a university hospital., Patients: Twenty-one patients with severe traumatic brain injury (Glasgow Coma Scale score < or = 9); 11 required barbiturate coma because of refractory intracranial hypertension, and 10 were manageable with continuous administration of fentanyl and midazolam., Interventions: Thiopental was administered continuously for increased ICP within the first 24 hrs after trauma and adjusted to the burst-suppression pattern (four to six bursts per minute) on continuous electroencephalographic monitoring., Measurements and Main Results: Glutamate and hypoxanthine were analyzed using high-performance liquid chromatography, whereas lactate was measured enzymatically. Patients requiring thiopental presented with significantly higher ICP, glutamate, and hypoxanthine levels than patients receiving fentanyl and midazolam (p < .05). Within the first 24 hrs, thiopental significantly reduced cerebrospinal fluid glutamate and hypoxanthine levels in all patients, i.e., the burst-suppression pattern was successfully induced (p < .001). Interestingly, in five patients cerebrospinal fluid glutamate increased to initial values again despite unchanged neuronal activity. In these patients, ICP, hypoxanthine, and lactate remained significantly elevated compared with the six patients with steadily decreasing cerebrospinal fluid glutamate, hypoxanthine, lactate, and ICP values (p < .02)., Conclusions: Barbiturate coma does not unequivocally preserve energetic stability despite successful suppression of neuronal activity. Despite the use of barbiturate coma in patients with refractory intracranial hypertension, persistent release or impaired uptake of glutamate may be associated with continuous anaerobic metabolism, as shown by increases in cerebrospinal fluid hypoxanthine and lactate levels.

Increased extracellular glutamate levels are related to glial and neuronal damage. Glutamate-mediated toxicity is limited by glial uptake and metabolic transformation of glutamate to glutamine and the energetic compounds alanine and lactate which are utilized by surrounding neurons. Under in vitro conditions, barbiturates have been shown to reduce glutamate uptake and its further metabolism, possibly impeding metabolic coupling between astrocytes and neurons. The aims were to investigate if under clinical conditions, the barbiturate thiopental reduces important detoxification of glutamate, resulting in lower CSF glutamine, alanine and lactate levels as opposed to patients receiving midazolam. During long-term administration of thiopental and midazolam, pathologically elevated ventricular CSF glutamate levels were associated with significantly increased glutamine and alanine levels up to 14 days after trauma. CSF lactate, however, remained normal. These data suggest that long-term administration of thiopental and midazolam under clinical conditions does not impede enzymatic activities responsible for detoxification and metabolism of glutamate.

The intercellular adhesion molecule-1 (ICAM-1) expressed by endothelial cells is crucial in promoting adhesion and transmigration of circulating leukocytes across the blood-brain barrier (BBB). Migrated immunocompetent cells, in turn, release mediators that stimulate glial and endothelial cells to express ICAM-1 and release cytokines, possibly sustaining cerebral damage. Following activation, proteolytic cleavage of membrane-anchored ICAM-1 results in measurable levels of a soluble form, sICAM-1. The aims of this study were to investigate the changes of sICAM-1 levels in ventricular CSF and serum and to elucidate the influence of structural brain damage as estimated by computerized tomography (CT) as well as the extent of BBB dysfunction as calculated by the CSF/serum albumin ratio (QA) in patients with severe traumatic brain injury (TBI). All investigated parameters revealed two subgroups. Patients belonging to group A had sICAM-1 levels in CSF above normal range, presented marked cerebral damage and a disturbance of the BBB (range 0.6-24.7 ng/ml, n = 8). In contrast, patients belonging to group B had no elevation of sICAM-1 values in CSF (range 0.3-3.9 ng/ml, n = 5; p < 0.017) and showed minor cerebral damage with an intact BBB in most cases. In addition, overall analysis showed that sICAM-1 in CSF correlated with the extent of BBB damage as indicated by the QA (r = 0.76; p < 0.001). These results suggest that increased sICAM-1 levels in CSF might depict ongoing immunologic activation and that sICAM-1 correlates with the extent of tissue and BBB damage. The origin of soluble ICAM-1 in CSF and its pathophysiologic role after TBI remains to be clarified.

The excitatory transmitters glutamate and aspartate become toxic whenever their extracellular levels are increased because of neuronal, glial and endothelial impairment. Taurine, a volume-regulating amino acid, is released upon excitotoxin-induced cell swelling. Our aim was to investigate if glutamate and aspartate in cerebrospinal fluid (CSF) reveal neuropathology in neurological patients, and if taurine unmasks glutamate-mediated toxicity. Glutamate and aspartate are doubled in viral meningitis, acute multiple sclerosis (MS) and myelopathy compared with control subjects and patients with peripheral facial nerve palsy. These levels do not coincide with a disturbed blood-brain barrier, as estimated by the albumin ratio, are independent of their precursors (glutamine, asparagine) and are not associated with cell lysis. Taurine is significantly increased in meningitis, acute MS, and myelopathy, suggesting glutamate-mediated toxicity. Analysis of transmitters in lumbar CSF can be used to identify patients with cerebral and spinal pathology who might benefit from specific receptor-modulating agents.