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.

Diffuse CNS involvement in systemic lupus erythematosus: intrathecal synthesis of the 4th component of complement.

In extracerebral systemic lupus erythematosus (SLE), the complement system plays a prominent pathogenic role, and decreased serum concentration of the 4th component (C4) is a reliable indicator of systemic disease activity. In diffuse CNS-SLE, however, the pathogenic role of complement is less clear. In 12 patients with active diffuse CNS-SLE presenting with delirium (4), organic personality syndrome (3), or generalized seizures (5), we determined the CSF indexes of the complement components C3, C4, and factor B, and of IgG, IgA, and IgM. There was a significant increase of the C4 index in these patients compared with controls and a significantly higher CSF C4 index in patients with an increased IgM index. We conclude that intrathecal C4 is being produced in diffuse CNS-SLE.

The effects of high-dose methylprednisolone on gadolinium-enhanced magnetic resonance imaging and cerebrospinal fluid measurements in multiple sclerosis.

Blood-brain barrier (BBB) disruption is probably the first event in the lesion development in multiple sclerosis (MS). This stage can be visualized by gadolinium-enhanced magnetic resonance (MR) imaging of the brain. Serial MR imaging studies have indicated a continuous spectrum of disease activity with waxing and waning of acute lesions, even in clinically stable MS patients. High-dose intravenous methylprednisolone (MP) has a beneficial clinical effect; reduces gadolinium enhancement, indicating improvement of BBB integrity; and, in MS patients, decreases intrathecal immunoglobulin synthesis with reduction of cerebrospinal fluid (CSF) myelin basic protein (MBP). A correlative triad is noted between gadolinium enhancement, clinical improvement, and decrease of CSF MBP following MP treatment, indicating a relationship between restoration of BBB integrity, clinical improvement and decrease of myelin breakdown. It is not clear whether MP interferes primarily with the process of demyelination or reacts non-specifically with its mediators.

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.

Effect of intensive immunosuppression on the course of chronic progressive multiple sclerosis.

39 patients with chronic-progressive multiple sclerosis were treated with a short course of intensive immunosuppression in high doses of cyclophosphamide and prednisone. The follow-up period varied between 1 and 5 years with a mean of 21/2 years. Progression of the disease ceased in 27 patients for varying periods, with a mean of two years. In 13 patients the progression ceased during the whole follow-up period. The treatment gave the most favourable results in patients who were DRw2 positive in histocompatibility testing, whose disease started at an early age (around 28 years), whose disease duration before treatment was short (6 years), whose progression was fast and whose disability before treatment was low. If CSF levels of IgG3 months after the treatment remain low, this is a sign of good prognosis.

Familial Leigh's syndrome: association with a defect in oxidative metabolism probably restricted to brain.

Four siblings with Leigh's syndrome are described. The diagnosis was confirmed by pathological examination in one case. Chemical and biochemical investigations of serum and urine revealed no abnormalities of pyruvate metabolism, but all patients had marked elevations of CSF pyruvate and lactate concentrations. In three of the siblings, [1-14C]pyruvate oxidation rates were normal in fibroblasts and leucocytes. In one patients, extensive biochemical and histochemical studies of liver and muscle tissue revealed no mitochondrial dysfunction. A defect of oxidative metabolism restricted to brain seems probable.

Intravenous pyruvate loading test in Leigh syndrome.

Diagnosis of defective pyruvate metabolism can present difficulties in clinical practice. In search of a diagnostic procedure that can give a clear indication of a disturbance of pyruvate metabolism, we have developed an intravenous pyruvate loading test. The loading test was applied to 9 patients with Leigh syndrome. Results and characteristics are described. The test proved to be a sensitive procedure to detect disturbances in pyruvate oxidation. The intravenous pyruvate loading test can be a useful tool in the diagnosis of mitochondrial (encephalo) myopathies.

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.

CSF concentration and CSF/blood ratio of fuel related components in children after prolonged fasting.

In order to obtain information about blood and cerebrospinal fluid (CSF) concentrations, and CSF/blood ratio data of fuel related substrates at the end of a prolonged fast in children, we have selected biochemical data from fasting test procedures in 11 control children aged 3-5 yr, fasted 24 h, and 58 control children aged 6-15 yr, fasted 40 h. There was a good correlation between blood and CSF concentrations for glucose, acetoacetate and beta-hydroxybutyrate. The relation with age and sex has been analyzed only in the older children. CSF and blood values for glucose are positively related with age, and both ketones are negatively related with age. Lactate, pyruvate and alanine concentrations in blood and CSF are not related with age, except for CSF pyruvate. With respect to the CSF/blood ratio for the above mentioned components, only the value for acetoacetate is sex and age related. The calculated median caloric values for the sum of glucose, lactate, pyruvate and ketones in CSF are independent of age at the end of a 40-h fast. The diminished glucose contribution on the CSF caloric homeostasis in younger children is fully compensated by the ketone bodies.

The concentration of blood components related to fuel metabolism during prolonged fasting in children.

In order to study the relationship between sex, age and glucose, and the concentrations of various fuel related blood substrates in children during prolonged fasting, we have selected data of fasting procedures in 13 control children aged 3-5 yr, fasted 24 h, and 58 control children aged 6-15 yr, fasted 40 h. Compared to the blood results after overnight fast, glucose is decreased, and lactate, pyruvate, ketones and non-esterified fatty acids (NEFA's) are all clearly increased at the end of fast. The concentrations of alanine and triglycerides remain unchanged. The relation with sex, age and glucose has only been analyzed in the older children group. A sex-dependency is indicated for the ketones. Ketones are negatively related with age. NEFA's pyruvate and alanine are not age-related, whereas glucose, lactate and triglycerides are moderately age-dependent. Ketones are negatively related with glucose, whereas pyruvate, NEFA's and triglycerides are not glucose-related. Lactate and alanine are weakly related to glucose. The data demonstrate diminished glucose homeostasis and increased ketogenesis in younger children compared to older ones during prolonged fasting.

Reference values of blood components related to fuel metabolism in children after an overnight fast.

The interrelation between blood components, involved in fuel metabolism, and age, sex and glucose was studied in 72 control children (26 girls and 46 boys, aged between 3 and 15 yr) after an overnight fast (14 h). Glucose, lactate, pyruvate, triglycerides and cholesterol are age-independent. Alanine is positively correlated, whereas beta-hydroxybutyrate, acetoacetate and NEFA's are negatively correlated with age. With respect to blood sugar, acetoacetate, NEFA's and cholesterol are glucose-independent. Lactate, pyruvate, alanine and triglycerides are positively correlated with glucose, and beta-hydroxybutyrate--and total ketone bodies--are negatively correlated with glucose. Except for triglycerides, no differences in the concentrations of the above mentioned blood substrates are seen between boys and girls. These data demonstrate that after an overnight fast lipolysis and ketogenesis already are active in young children, probably related to inadequate gluconeogenesis and improvement of carbohydrate regulation with age.

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.

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.

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.

Treatment of the chronic progressive form of multiple sclerosis with a combination of cyclophosphamide and prednisone.

32 patients with the chronic progressive form of the multiple sclerosis were treated with high doses of cyclophosphamide and prednisone during 20 days, to produce immunosuppression. The effect of treatment was measured by scoring three different Kurtzke scales just before treatment (1), just after treatment (II), and 3 months after treatment (III). The results indicate that in the treatment period I to II most patients improve, some dramatically. The improvement continues in 15 of 25 patients scored between 6 and 33 months after treatment. Better results were found in patients with shorter duration of their disease. More improvement is found as the IgG percentage of the spinal fluid at I is higher. The improvement is less when the initial condition (I) is more serious.

Spinal angiomas. The meaning of cerebrospinal fluid lactic acid in the etiology and differential diagnosis of transverse myelopathy.

We report five out of eleven patients with transverse myelopathy due to spinal angiomas. Transverse myelopathy can be caused by a number of disorders. The formation of lactic acid points to ischaemia within the spinal cord, due to altered haemodynamics as in spinal angiomas. The meaning of cerebrospinal fluid lactic acid is discussed with respect to etiology and differential diagnosis of transverse myelopathy. The combined finding of CSF lactic acid and protein elevation in the absence of cell count and immunological and/or serological abnormalities points to an isolated vascular cause of the transverse myelopathy.

Adult metachromatic leukodystrophy. Arylsulphatase-A values in four generations of one family and some reflections about the genetics.

The authors describe an investigation of Adult Metachromatic Leukodystrophy in a Dutch family, of which two persons were affected. The studies of leukocyte arylsulphatase-A activity were made in 47 members of 4 generations of the same family. The propositus, a 30-year old man, showed a conspicious organic brain syndrome, that progressed in two years to a complete dementia. His leukocyte, liver and kidney arylsulphatase-A activities (ASA) were very low; leukocyte-ASA activity increased after aceto-salicylate. His brother had died at 34 years, after a progressive debelitating neuropsychiatric illness of eight years; postmortem metachromatic leukodystrophy was diagnosed. In all living family members, urine and leukocyte arylsulphatase-A activities were determined. The findings are discussed in relation to the genetics and pathogenesis of this adult form of metachromatic leukodystrophy. Allelic heterozygoty is proposed as inheritance model in this family. Suggestions for further research are made.

Blood pressure and both venous and urinary catecholamines after cerebral infarction.

Blood pressure, both venous and urinary catecholamines and plasma renin activity (PRA) were studied in 10 patients (6 men and 4 women, mean age 70 +/- 10 years) on the first three days after cerebral infarction. Blood pressure fell significantly (p less than 0.02) on the second and third day after stroke. There was a small but significant (p less than 0.01) decrease in plasma epinephrine concentration on the third day. The norepinephrine values remained constant on the three days. The PRA showed a significant (p less than 0.01) rise on the third day. No significant correlation was detected between the course of the blood pressure and the plasma catecholamines or PRA. When blood pressure was correlated with the urinary catecholamines, however, a significant correlation with epinephrine (r = 0.45; p less than 0.05) and with norepinephrine (r = 0.44; p less than 0.05) was found. We conclude that the changes in blood pressure after stroke are at least partly mediated by the changes in catecholamine production.

GM2-gangliosidosis. Clinical and biochemical aspects of four cases.

We discuss four cases of GM2-gangliosidosis. In one of them the biochemical diagnostic confirmation was difficult. This case revealed striking discrepancies between the results of different methods of enzyme assay. The hexosaminidase A determination based on pH inactivation is not always reliable; assay with natural substrate may be necessary. However, the results with the newly developed substrate 4-MU-GlcNac-6-SO4 are promising and it seems to be a good alternative to the traditional (pH or heat) inactivation procedures. The deficiency can be shown in leukocytes, plasma and fibroblasts with the 6-sulfated substrate. The carrier state seems better reflected in plasma hexosaminidase A than in leukocyte hexaminidase A levels.

The effects of acute cerebrovascular disease on serum and cerebrospinal fluid parameters.

In order to evaluate the effects due to acute cerebrovascular disease on serum and cerebrospinal fluid (CSF) parameters, biochemical data from 312 patients were studied. In serum, CK, LD and alpha 1 protein fraction showed a moderately close relationship to the severity of stroke. In CSF there could not be observed any relation between enzymatic activities (LD, ASAT, CK) and the severity of the disease. The same result was found for CSF protein and the ratio CSF albumin/serum albumin, parameters which are indicative for Blood Brain Barrier (BBB) disturbances. Substances from the intermediate metabolism in the Central Nervous System (CNS) (lactate and pyruvate) were evidently raised in CSF and there was a clear relation between the CSF concentration and the severity of stroke. No indication for IgG immunoglobulin abnormalities in CSF was found. The concentration of neurotransmitter metabolite 5HIAA in CSF was significantly higher in (in)completed stroke than in Transient Ischaemic Attack.