GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study.

BACKGROUND: Biomarker levels in blood after traumatic brain injury (TBI) may offer diagnostic and prognostic tools in addition to clinical indices. This study aims to validate glial fibrillary acidic protein (GFAP) and S100B concentrations in blood as outcome predictors of TBI using cutoff levels of 1.5 µg/L for GFAP and 1.13 µg/L for S100B from a previous study. METHODS: In 79 patients with TBI (Glasgow Coma Scale score [GCS] ≤12), serum, taken at hospital admission, was analyzed for GFAP and S100B. Data collected included injury mechanism, age, gender, mass lesion on CT, GCS, pupillary reactions, Injury Severity Score (ISS), presence of hypoxia, and hypotension. Outcome was assessed, using the Glasgow Outcome Scale Extended (dichotomized in death vs alive and unfavorable vs favorable), 6 months post injury. RESULTS: In patients who died compared to alive patients, median serum levels were increased: GFAP 33.4-fold and S100B 2.1-fold. In unfavorable compared to favorable outcome, GFAP was increased 19.8-fold and S100B 2.1-fold. Univariate logistic regression analysis revealed that mass lesion, GFAP, absent pupils, age, and ISS, but not GCS, hypotension, or hypoxia, predicted death and unfavorable outcome. Multivariable analysis showed that models containing mass lesion, pupils, GFAP, and S100B were the strongest in predicting death and unfavorable outcome. S100B was the strongest single predictor of unfavorable outcome with 100% discrimination. CONCLUSION: This study confirms that GFAP and S100B levels in serum are adjuncts to the assessment of brain damage after TBI and may enhance prognostication when combined with clinical variables.

Glial and neuronal proteins in serum predict outcome after severe traumatic brain injury.

OBJECTIVE: To study the ability of glial (glial fibrillary acidic protein [GFAP] and S100b) and neuronal (neuron specific enolase [NSE]) protein levels in peripheral blood to predict outcome after severe traumatic brain injury. METHODS: Eighty-five patients with severe traumatic brain injury (admission Glasgow Coma Score [GCS] < or = 8) were included. Blood samples taken at the time of hospital admission were analyzed for S100b, GFAP, and NSE. Data collected included demographic and clinical variables. Outcome was assessed using the Glasgow Outcome Scale (GOS) at 6 months post injury. RESULTS: The median serum levels of S100b, GFAP, and NSE were raised 18.3 fold (S100b), 4.6 fold (GFAP), and twofold (NSE) compared to normal reference values. S100b, GFAP, and NSE serum levels correlated significantly with the injury severity score and CT findings but not with age, sex, or GCS. S100b, GFAP, and NSE levels were significantly higher in patients who died or had a poor outcome 6 months post injury than in those who were alive or had good outcome. S100b level >1.13 microg/L was the strongest predictor of death with 100% discrimination, but GFAP (>1.5 microg/L) and NSE (>21.7 microg/L) levels also strongly predicted death (adjusted odds ratios 5.82 [for GFAP] and 3.91 [for NSE]). S100b, GFAP, and NSE all strongly predicted poor outcome (adjusted odds ratios 5.12 [S100b], 8.82 [GFAP], and 3.95 [NSE]). CONCLUSIONS: These results suggest that determination of serum levels of glial and neuronal proteins may add to the clinical assessment of the primary damage and prediction of outcome after severe traumatic brain injury.

Protein S-100B, neuron-specific enolase (NSE), myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) and blood of neurological patients.

In this study, data about protein S-100B, neuron-specific enolase, myelin basic protein and glial fibrillary acidic protein in cerebrospinal fluid and blood of patients with an acute or chronic progressive neurological disorder with brain damage are reviewed. Especially in disorders with acute brain damage, determination of these proteins in CSF and blood can be helpful to establish structural and/or functional brain damage to determine severity and prognosis of the disease process and to monitor treatment effects.

Peri-operative levels of s-100 protein in serum: marker for surgical manipulation and postoperative complications.

Although minimally invasive neurosurgical techniques are highly sophisticated nowadays, almost any operative procedure causes an inevitable surgical trauma to the brain. As a consequence unfavorable functional outcomes are not rare. Intraoperative biochemical monitoring can be helpful first to detect but also to prevent brain damage. We investigated if serum S-100 protein (S-100) levels are a reliable marker for the extent of acute cerebral damage caused by surgical trauma or postoperative complication. S-100 is present in the cytosol of glial cells. This protein leaks into the extracellular space after cell damage and can be detected both in the cerebrospinal fluid (CSF) and serum. To determine S-100 protein levels, serum samples from 20 patients with various intracranial tumors were collected before surgery, and at one day, as well as at seven days after surgery. It was hypothesised that the size of the tumor-brain contact surface (TBCS) was closely related to the dimension of the surgical trauma. TBCS was measured from radiological imaging. The pre- and postoperative (day 1 and day 7) clinical condition of each patient was assessed. The S-100 levels were correlated with the TBCS and the clinical condition. Levels of S-100 on day 1 and day 7 were significantly higher as compared with levels on day 0 ( p = 0.02, respectively p = 0.01). There was a significant relationship between rise of S-100 level and worsening of clinical condition between day 0 and day 1 ( p = 0.001). Also a significant positive relationship between TBCS and the level of S-100 could be found on day 1 and on day 7 ( R = 0.71, p = 0.0009, respectively R = 0.73, p = 0.004). Furthermore, a significant relationship between the rise of S-100 level between day 0 and day 1, as well as between day 0 and day 7, and TBCS could be documented ( R = 0.61, p = 0.01, respectively R = 0.64, p = 0.005). In conclusion, serum S-100 levels are a reliable marker for acute or recent CNS damage caused by neurosurgical manipulation or as a result of secondary postoperative complications. Therefore, intraoperative monitoring of serum S-100 levels seems very promising. In such a setting the negative effects of surgical manipulation can be measured instantaneously, which should bring the neurosurgeon to change his strategy. As a consequence the surgical trauma can be minimized and functional outcome can be optimized.

Intraoperative values of S-100 protein, myelin basic protein, lactate, and albumin in the CSF and serum of neurosurgical patients.

OBJECTIVES: To assess the concentrations of S-100 protein, myelin basic protein (MBP), and lactate, and the (CSF)/serum albumin ratio (Qalb) during intracranial neurosurgical procedures. METHODS: Samples of CSF from 91 patients with various CNS diseases were obtained by aspiration of cisternal CSF at the beginning of surgery (before starting surgical manipulation of the brain) and concentrations of S-100 protein, MBP, and lactate, and Qalb were determined. At the same time blood was sampled for determination of serum S-100 protein concentration. Patients were divided into three groups according to the aetiology of their CNS disease (intracranial haemorrhage, n=11; benign intracranial mass lesion, n=52; malignant neoplastic disease, n=28). Radiological and intraoperative characteristics were documented. RESULTS: In each of these three groups median values of all four CSF variables measured were raised. The occurrence of brain oedema and a midline shift correlated significantly with raised concentrations of MBP and Qalb. Breaching of the arachnoid layer, documented at surgery for benign lesions, correlated with higher concentrations of MBP, lactate, CSF S-100 protein, and Qalb. CONCLUSIONS: Intraoperative values of S-100 protein, MBP, lactate, and Qalb are increased in patients with intracranial haemorrhage, benign intracranial mass lesion, and malignant neoplastic disease. Breaching of the arachnoid layer and oedema is associated with higher concentrations of some of the aforementioned proteins. These biochemical data can serve as a basis for further research into CSF specific proteins.

S100B protein, glia and Gilles de la Tourette syndrome.

Activated glial cells play an important role in a variety of neurological disorders. This study examines S100B protein levels in the serum of patients with Gilles de la Tourette syndrome, as potential marker for glial cell function. Two groups of children were examined: 61 reference patients and 33 patients with Gilles de la Tourette syndrome. It was found that S100B serum concentrations in the reference group decrease with increasing age. Furthermore it was found that the mean S100B concentration in serum of children with Gilles de la Tourette syndrome is significantly higher than in the reference group. These preliminary results suggest that glial tissue might be involved in the pathophysiology of the syndrome.

Release of glial tissue-specific proteins after acute stroke: A comparative analysis of serum concentrations of protein S-100B and glial fibrillary acidic protein.

BACKGROUND AND PURPOSE: This study was aimed at the comparative analysis of serum concentrations of glial fibrillary acidic protein (GFAP) and protein S-100B in patients with acute stroke. METHODS: We investigated 32 patients with stroke symptoms consistent with cerebral ischemia in the anterior territory of vascular supply. Serial venous blood samples were taken after admission to the hospital and during the first 4 days after onset of stroke. Evaluation of lesion topography and volume of infarcted brain area was based on cranial CT data. The patients' clinical status was consecutively evaluated by the National Institutes of Health Stroke Scale (NIHSS) and the Barthel Index score at discharge from the hospital. RESULTS: Protein S-100B and GFAP release was found to be significantly correlated (r=0.96; P:<0.001). The release of both biochemical markers was associated with the volume of brain lesions (S-100B: r=0.957, P:<0.0001; GFAP: r=0.955, P:<0.0001) and the neurological status at discharge from the hospital (S-100B: r=0.821, P:=0.0002; GFAP: r=0.717, P:=0.0003). The highest correlation between both S-100B and GFAP serum concentration and Barthel score was calculated at the last time of blood sampling, 4 days after stroke onset (S-100B: r=0.621, P:<0.001; GFAP: r=0.655, P:<0.001). The release of both astroglia derived proteins differed between different subtypes of stroke. GFAP was found to be a more sensitive marker of brain damage in patients with smaller lacunar lesions or minor strokes. CONCLUSIONS: Our results indicate that postischemic release patterns of GFAP and S-100B protein may allow insight into the underlying pathophysiology of acute cerebral infarcts and may be used as a valuable tool of clinical stroke treatment.

Cerebrospinal fluid C3 and C4 indexes in immunological disorders of the central nervous system.

OBJECTIVES: Validation of cerebrospinal fluid (CSF) indexes as a measure for intrathecal C3 and C4 production. Examination of their role in differential diagnosis of immunological disorders of the central nervous system (CNS). MATERIAL AND METHODS: Correlative study in controls (low back pain without disk herniation) between the CSF/serum ratio (Q) for albumin, and Q C3 and Q C4. Comparative study of C3 and C4 indexes in patients with CNS dysfunction due to relapsing-remitting (RR) multiple sclerosis (MS), secondary progressive (SP) MS, systemic lupus erythematosus (SLE), and human immunodeficiency virus (HIV) infection. RESULTS: Strong and statistically highly significant correlations between Q albumin and Q C3 (r=0.89, P=0.0001), and Q C4 (r=0.68, P= 0.0001). In MS patients decreased mean values for serum (RR, SP) and CSF (RR) C3, and increased C3 index mean value (RR, SP). In CNS SLE increase of mean C3 and C4 index values. In CNS HIV increase of mean C3 and C4 index values, and CSF C3 and C4 concentrations. Most individual index values were within the reference range. CONCLUSION: CSF index is a valid tool to detect intrathecal C3 or C4 production. C3 or C4 index contributes little to the differential diagnosis of immunological CNS disorders. C3 might play a pathogenic role in various immunological CNS disorders.

Composite cerebrospinal fluid score in relapsing-remitting and secondary progressive multiple sclerosis.

We investigated whether cerebrospinal fluid (CSF) analysis may differentiate between relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS). In 17 RR and 16 SP patients we determined: albumine CSF/PB ratio; mononuclear cell (MNC) number, CD4+, CD8+, and B1+ subsets, CD4+/CD8+ ratio; IgG, IgG index, IgM, IgM index, complement components C3 and C4, and C3 and C4 indexes; myelin basic protein; neuron-specific enolase (NSE); S100; and lactate. For each parameter the statistical distance was calculated. Then, using linear discriminant analysis, we computed a discriminant score, including only variables with a P value less than or equal to 0.15: albumin CSF/PB ratio, MNC number, IgM, IgM index, C3, C4, NSE, S100, and lactate. The discriminant score allocated all 17 RR patients to the RR group and 15 of 16 SP patients to the SP group. We conclude that RR and SP MS patients differ with respect to CSF profile and that in individual patients a composite CSF score may differentiate between RR and SP MS.

Myelin basic protein in CSF as indicator of disease activity in multiple sclerosis.

There is an evident need for a quantitative laboratory marker for ascertaining disease activity and treatment effects in multiple sclerosis (MS) patients. Activity of the disease process in MS is accompanied by myelin breakdown and appearance of myelin basic protein (MBP) in cerebrospinal fluid (CSF). In this paper MBP in CSF of relapsing-remitting (RR) MS patients is reviewed. MBP in CSF is a fragment containing an epitope corresponding to amino acid residues 45-89 of the native molecule. From several relevant studies about CSF MBP in RR MS the following relations can be concluded: CSF MBP levels in active MS patients are frequently increased (45-100%), remain increased until 5 to 6 weeks after onset symptoms and are higher in polysymptomatic exacerbations and correlate with number of gadolinium-enhanced (Gd) lesions on MRI, severity of relapses, EDSS score and CSF intrathecal IgM synthesis. After an intravenous methylprednisolone treatment the increased CSF MBP levels return to normal values and reduction in CSF MBP is related to reduction in EDSS score, number of Gd lesions and CSF intrathecal IgM synthesis.

Abnormalities of biogenic amines affecting the metabolism of serotonin and catecholamines.

This paper describes the relevance of measuring biogenic amine metabolites in cerebrospinal fluid in order to detect inborn errors affecting catecholamines and serotonin biosynthesis. Defects in tetrahydrobiopterin and a deficiency of aromatic L-amino acid decarboxylase, tyrosine hydroxylase or dopamine-beta-hydroxylase are candidate inborn errors for neurotransmitter metabolites screening. This investigation has to be considered in any child with motor retardation and extrapyramidal signs.

Cerebrospinal fluid analysis differentiates between relapsing-remitting and secondary progressive multiple sclerosis.

OBJECTIVES: To find whether CSF analysis may differentiate between relapsing-remitting and secondary progressive multiple sclerosis. METHODS: In 17 patients with relapsing-remitting and 16 patients with secondary progressive multiple sclerosis, all without current or recent relapses, albumin CSF: peripheral blood ratio, mononuclear cell number, CD4+, CD8+, and B1+ subsets, CD4+:CD8+ ratio, IgG, IgG index, IgM, IgM index, complement components C3 and C4, and C3 and C4 indices, myelin basic protein, neuron specific enolase, S100, and lactate were determined. For each measure the statistical distance measure D2 was calculated. For computation of a discriminant score variables with a P value< or =0.15 were included (two sided univariate t test). These were albumin CSF: peripheral blood ratio, mononuclear cell number, IgM, IgM index, C3, C4, neuron specific enolase, S100, and lactate. Simultaneous distributions of the variables were compared between both groups (multivariate t test) and a discriminant score was computed (linear discriminant analysis). RESULTS: The discriminant score allocated all 14 relapsing-remitting patients to the relapsing-remitting group (positive score) and 12 of 13 secondary progressive patients to the secondary progressive group (negative score). One secondary progressive patient was allocated to the relapsing-remitting group. CONCLUSIONS: Patients with relapsing-remitting or secondary progressive multiple sclerosis differ in CSF profile and CSF analysis may help to differentiate between relapsing-remitting and secondary progressive multiple sclerosis.

Neuron-specific enolase, S-100 protein, myelin basic protein and lactate in CSF in dementia.

The pattern of injury of the specific cell structures of the central nervous system (CNS) is different in the various types of the dementia syndrome. We challenged the hypothesis that this could be reflected in specific patterns of brain-specific proteins in the cerebrospinal fluid (CSF). The neuron-specific enolase (NSE), S-100, myelin basic protein (MBP) and lactate levels were retrospectively analyzed in the CSF of 159 patients with various types of dementia. A previous study from our department demonstrated age-related reference values for the brain-specific proteins in the CSF. The present study affirmed the strikingly high NSE and S-100 values in the CSF of patients with autopsydiagnosed Creutzfeld-Jacob disease: NSE, S-100 and MBP levels in the CSF of patients with various other types of dementia, and controls, did not differ significantly. Therefore we concluded that a single determination of CSF concentrations of these brain-specific proteins were of little value in the differential diagnosis of the dementia syndrome. In the diagnosis of normal pressure hydrocephalus increased levels of CSF lactate may be helpful.

Cerebrospinal fluid free kappa light chains versus IgG findings in neurological disorders: qualitative and quantitative measurements.

In this study free kappa light chains in cerebrospinal fluid (CSF) were determined both by an affinity mediated capillary blotting technique after isoelectric focusing (IEF) in agarose gel and by a quantitative enzyme linked immunosorbent assay (ELISA). The free kappa results were compared with the IgG findings in 4 neurological patient groups with a distinct CSF IgG pattern: (1) CSF without oligoclonal IgG bands, (2) CSF with serum derived IgG bands, (3) CSF restricted IgG bands and (4) CSF restricted and serum derived IgG bands. Oligoclonal free kappa bands are nearly absent in CSF of groups 1 + 2, and present in 88% of group 3 and 84% of group 4 patients. We could also establish free kappa indices from specimens in the 4 groups in analogy to IgG indices. Group 1 had a median free kappa index of 1.1, group 2: 1.0 and groups 3 + 4: 10.0. The correspondence between immunoblot and index findings for free kappa is better than for IgG. Free kappa index is more sensitive but somewhat less specific than IgG index for establishing intrathecal immune production.

Cerebrospinal neuron-specific enolase, S-100 and myelin basic protein in neurological disorders.

In this study levels of neuron-specific enolase (NSE), S-100 protein (S-100) and myelin basic protein (MBP) in cerebrospinal fluid (CSF) of children and adults with distinct neurological disorders were examined. A previous study from our department demonstrated age related reference values for these brain-specific proteins in CSF. The median concentration level of the 3 proteins in 17 different neurological disease groups versus the reference group was compared. Significantly higher MBP values were observed in patients with multiple sclerosis (MS), cerebrovascular accident (CVA), metabolic disorder and infection. Furthermore, significantly higher values were demonstrated for S-100 in CVA and for NSE in metabolic diseases. In CVA, the NSE and S-100 values were significantly related with MBP values, whereas in MS the NSE and S-100 were not related with MBP values.

Fasting studies in cerebrospinal fluid and blood in children with epilepsy of unknown origin.

Alterations in the cerebral energy supply are likely to cause cerebral function disturbances. Fasting is a suitable method for studying the energy metabolism. As the cerebrospinal fluid (CSF) compartment reflects the brain metabolism, data in CSF might give information about the metabolism of fuel substrates in brain. We compared the biochemical data on several fuel-related components in blood and CSF at the end of a 40-hours fast of epileptic children with unknown origin of epilepsy (aged 6-15 years) with the values of a reference group of children. In children with primary generalized epilepsy no abnormalities were found. In children with complex partial epilepsy many significant abnormalities were found, such as low blood lactate and alanine and low CSF ketones and CSF blood ratio for ketones. The possible significance of the observed abnormalities are discussed.

['Cerebral running nose': cerebrospinal rhinorrhea]. / 'Cerebrale loopneus': rhinorrhoea cerebrospinalis.

Cerebrospinal fluid rhinorrhoea was diagnosed in two patients, a man of 19 and a woman of 45 years old. This is a relatively rare phenomenon and clinically often difficult to differentiate from nasal secretions caused by a rhinopathy. Although cerebrospinal fluid (CSF) fistulae usually are of traumatic origin as in the first patient, they can also be caused by a congenital malformation as in the second one or by a condition with chronic increased intracranial pressure. With adequate treatment the prognosis is good. CSF can be identified very specifically by beta-transferrin determination.

Follow-up study of MS patients treated with high-dose intravenous methylprednisolone.

In a longitudinal prospective study, we followed 56 patients (17 men, 29 women) with definite multiple sclerosis (MS), who were treated with high-dose intravenous methylprednisolone (IVMP), 10 consecutive days with 1000 mg IVMP daily. Mean follow-up period after entry was 2.6 years (range 1.7-3.5 yrs). All patients were treated because of a symptomatic deterioration. Independent of the disease courses (RR-relapsing remitting/CP-chronic progressive/CP+RR- mixed course), 65% of the 46 MS patients (30/46) showed a clinical improvement after the first IVMP course, expressed by a decrease in the EDSS rating (1.0 point or more). During the follow-up period 59 additional IVMP courses (range 0-5 courses per patient) were given; 8 patients were treated with a combination of cyclophosphamide and prednisone, because of strong continuous progression. During the follow-up period 19 patients (41%) showed an increase in the EDSS-rating (1.0 point or more) compared with the EDSS level just after the first IVMP; 22 patients (48%) had no changes in the EDSS-rating, and 5 patients (11%) showed a clinical improvement (decrease of 1.0 point or more). In the relapsing MS patients (RR and CP+RR, n = 38) mean relapse rate/patient/year prior to the first IVMP was 2.6, which significantly (p < 0.0001) decreased to 0.8 during the follow-up period. Statistically no significant difference was found between baseline EDSS and EDSS ratings after the follow-up period in relapsing MS patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid examinations in cryptogenic West and Lennox-Gastaut syndrome before and after intravenous immunoglobulin administration.

Before and after administration of intravenous immunoglobulin (IVIg), cerebrospinal fluid (CSF) was examined in a homogeneous group of 15 patients with cryptogenic types of West syndrome (WS) and Lennox-Gastaut syndrome (LGS). The purpose of the present CSF study was: (i) to elucidate possible etiological factors and consequences of these severe forms of epilepsy, and (ii) to elucidate mechanisms of action and adverse effects of IVIg. Hypotheses concerning etiological factors like central nervous system infections, neuroimmunological disorders, or disturbances in neurotransmitter metabolites could not be confirmed. These normal CSF findings are in accordance with the concept of a cryptogenic etiology of the epilepsies in the reported patients. Nor could we confirm hypotheses concerning seizure consequences, such as increased blood-CSF permeability, increased markers of brain cell destruction, or increased metabolic components. Following IVIg administration in these patients, all with an on the whole undisturbed blood-CSF barrier permeability as measured by Q albumin, the CSF IgG concentrations increased significantly and proportionally to the Q albumin level. No signs of adverse effects of IVIg such as aseptic meningoencephalitis were found in 165 infusions of IVIg performed in the 15 children.

T-cell subsets in the cerebrospinal fluid and peripheral blood of multiple sclerosis patients treated with high-dose intravenous methylprednisolone.

To determine the effects of high-dose intravenous methylprednisolone (MP) on lymphocytes and lymphocyte subpopulations in the cerebrospinal fluid (CSF) and peripheral blood (PB) in multiple sclerosis (MS) patients, we studied 67 patients with definite MS treated with MP. They were classified according to the disease course: 32 chronic progressive (CP) patients, 25 relapsing-remitting (RR) patients, and 10 patients with a chronic progressive disease course accompanied by relapses and remissions (CP + RR). MS patients were treated with 1000 mgr intravenous MP daily for 10 consecutive days. Before and after MP treatment we simultaneously studied CSF and PB CD3+, CD4+, CD8+, CD20+, and Ia1+ cell subsets. Kurtzke's Expanded Disability Status Scale (EDSS) was used for clinical evaluation. Progression rate was defined as the ratio of EDSS to disease duration. Thirteen patients with lumbar disk herniation were investigated as controls. Before MP, we found in MS patients, especially in the CP group, significantly lower CD4+ T-cell percentages in the PB with respect to controls (p < 0.05). The percentage of CD4+ T-cells in the CSF of MS patients was significantly higher compared with PB (p = 0.0001), and tended to be higher than in controls (p = 0.072). The CSF mononuclear cell counts were significantly correlated with higher percentages of CSF CD3+ (r = 0.40) and CD4+ (r = 0.47) T-cells and lower CSF CD8+ (r = -0.33) T-cell percentages. B-cell percentages in the CSF were significantly elevated compared with controls for all MS groups. No relation could be obtained between T- or B-cell subsets and EDSS or progression rate.(ABSTRACT TRUNCATED AT 250 WORDS)