Cerebrospinal fluid (CSF) findings in amyotrophic lateral sclerosis

Summary The cerebrospinal fluid (CSF) was examined in 90 amyotrophic lateral sclerosis (ALS) patients and in 50 age-matched normal controls. Total protein concentration was significantly higher in ALS patients than in normal controls. CSF IgG and albumin, quantitatively determined by single radial immunodiffusion, were significantly increased in ALS. No difference in serum concentrations was observed between ALS patients and normal controls. On isoelectric focusing a clear-cut fingerprint pattern was observed in 11 of 12 cases. These findings support the hypothesis that blood-brain barrier damage occurs in ALS. The finding of a higher mononuclear cell count in young ALS patients is briefly discussed in the light of the hypothesis that an exogenous agent might be of some relevance in pathogenesis. An alteration of at least one of the CSF parameters considered was found in 45.5% of ALS cases.

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Zusammenfassung In 90 Fällen von amyotrophischer Lateralsklerose und bei 50 auch im Alter entsprechenden Kontrollen wurde der Liquor untersucht. Der Eiweißgehalt war bei den Patienten mit ALS signifikant höher als bei den Kontrollen. Die Albuminfraktion und das IgG, die mit Immunodiffusionsmethoden quantitativ bestimmt wurden, waren bei der ALS im Liquor signifikant erhöht, während sie sich im Serum gleich wie bei den Kontrollfällen verhielten. Bei der isoelektrischen Fokusierung ließ sich ein eindeutiges Finger-print-pattern in elf von zwölf Fällen beobachten. Diese Befunde sprechen dafür, daß bei der ALS eine Störung der Blut-Hirnschranke vorliegt. Es wird kurz auf die Beobachtung einer vermehrten Zahl mononukleärer Zellen bei jungen Patienten mit ALS eingegangen und im besonderen die Frage diskutiert, in wieweit ein exogenes Agents in der Pathogenese eine Rolle spielen könnte. Mindestens eines der obern erwähnten Parameter war bei 45% aller ALS Fälle im Liquor verändert.

     

Die Bedeutung von Plasmakreatin und neurologischen Erkrankungen für den Kreatingehalt im Liquor cerebrospinalis beim Menschen

Zusammenfassung Die individuell-vergleichende Gegenüberstellung des Kreatingehaltes im Serum und Liquor cerebrospinalis bei Normalpersonen und bei Patienten mit neurologischen Erkrankungen zeigte, daß für den Kreatingehalt im Liquor keine gesetzmäßige Abhängigkeit von der Höhe des Kreatinspiegels im Plasma besteht. Abgesehen von experimentell erzeugten extremen Erhöhungen kann deshalb der Plasmakreatinspiegel bei der Beurteilung der Kreatinkonzentration im Liquor außer acht gelassen werden.Bei Patienten mit verschiedenen neurologischen Erkrankungen des ZNS war der durchschnittliche Kreatingehalt im Liquor erniedrigt. Davon unterschieden sich als einheitliche Gruppe Patienten mit amyotrophischer Lateralsklerose, die ohne Ausnahme einen erhöhten Kreatingehalt im Liquor aufwiesen. Die Bestimmung des Kreatingehaltes im Liquor könnte bei dieser Erkrankung diagnostische Bedeutung gewinnen, wenn sich die hier beobachtete Erhöhung des Kreatinspiegels bei einer größeren Anzahl von Patienten bestätigen sollte.Aus den Ergebnissen kann gefolgert werden, daß das Kreatin im Liquor zwar primär aus dem peripheren Blut stammt, seine Konzentration jedoch durch Faktoren reguliert wird, die im Bereich des zentralnervösen Parenchyms und seiner Grenzflächen mit dem Blut zu suchen sind und für eine Homöostase von Kreatin in Liquor, Extracellulärflüssigkeit und zentralnervösem Gewebe sorgen.

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The relevance of plasma creatine and neurological disorders to the creatine content of cerebrospinal fluid in man

Summary By comparing to each other the creatine content of plasma and cerebrospinal fluid (CSF) in individual normal subjects and patients with various neurological disorders creatine of CSF was shown not to be quantitatively related to the concentration of plasma creatine in a consistent way. Therefore the creatine content of plasma may be disregarded in evaluating the creatine concentration of CSF, except for extremely high experimentally produced plasma concentrations (e.g. creatine 2 g by mouth).The average creatine content of CSF was lowered in patients with various neurological disorders. In contrast, increased levels of CSF creatine were found in a group of 8 patients suffering from amyotrophic lateral sclerosis. The determination of CSF creatine therefore appears to be of diagnostic value in this disease and its validity should be tested in a larger number of patients.It is concluded that creatine present in CSF is taken up from blood to an extent that is controlled by factors inherent in the central nervous system and its interfaces, and it is suggested that these factors account for a homeostasis of creatine in CSF, central nervous tissue and its extracellular fluid.

     

Neurotoxic effects of aluminium on embryonic chick brain cultures

Toxic damage of brain cells by aluminium (A1) is discussed as a possible factor in the development of neurodegenerative disorders in humans. To investigate neurotoxic effects of A1, serum-free cultures of mechanically dissociated embryonic chick (stage 28–29) forebrain, brain stem and optic tectum, and for comparison meningeal cells, were treated with A1 (0–1000 M) for 7 days. Effects of A1 on cell viability (lysosomal and mitochondrial activity) and differentiation (synthesis of cell-specific proteins) were found to the brain area specific with the highest sensitivity observed in optic tectum. No inhibiting effects on cell viability could be observed in cultures of forebrain and meninges in the concentration range tested. In all three brain tissue cultures, threshold levels for the reduction of cell differentiation parameters were found at lower concentrations [concentration resulting in a 50% decrease (IC₅₀)>180 M] than for the inhibitionof cell viability (IC₅₀>280 M) indicating a specific toxic potential of A1 for cytoskeletal alterations. The culture levels of nerve cellspecific markers microtubule-associated protein type 2 (the most sensitive parameter) and the 68-kDa neurofilament were inhibited at lower concentrations (IC₅₀ 180–630 M) than the astrocyte-specific glial fibrillary acidic protein (IC₅₀ 700–1000 M), demonstrating a particularly high sensitivity of neurons in comparison to astrocytes. Based on these differences in A1 sensitivity observed for different cell markers in the various brain tissue cultures, the in vitro system used in the present study proved to be a suitable model to assess brain area and cell type-specific neurotoxic effects of A1.This study is part of the Ph. D. thesis of Judith P. Mueller.Preliminary results were presented at the 24th Annual Meeting of the Swiss Societies for Experimental Biology (USGEB/USSBE)     

Diagnostic value of brief microzone electrophoresis of unconcentrated CSF and agar gel electrophoresis of concentrated and unconcentrated CSF

Summary This paper reports a comparison between brief microzone electrophoresis and agar gel electrophoresis of CSF proteins; 41 different CSFs were examined simultaneously by all three methods. Fractionation of -globulins was found by brief microzone electrophoresis in 53.7% of unconcentrated CSF. This fractionation was found in 63.4% of unconcentrated CSF after agar gel electrophoresis, in 48.8% of concentrated CSF. Serum-like pherogram and the rapid a-globulin type were found equally often.This work was supported by the Deutsche Forschungsgemeinschaft, D-5300 Bonn 2 (FRG)     

Amino acid levels in human CSF after generalized seizure

Summary We studied the possible role of excitatory and inhibitory amino acids and their balance during generalized convulsions. The levels of amino acids in postictal cerebrospinal fluid (CSF) were compared with amino acid concentrations in interictal CSF of ten patients with generalized tonic-clonic convulsions. Glu, Gln, Asp, Asn, Tau, Gly, total GABA (t-GABA), free GABA (f-GABA), and homocarnosine levels and Glu/Gln, Asp/Asn, t-GABA/Glu, f-GABA/Glu, f-GABA/Asp, and Glu/Asp ratios were similar in both samples (Student's paired t-test). Our results suggest that in humans possible changes in amino acids in brain tissue during the ictal stage are not reflected in the lumbar CSF.Part of this study was presented in the Sixth European Society for Neurochemistry General Meeting in Prague, Czechoslovakia, 1986, and published in: Tucek S, Stipek S, Stastny F, Krivanek J (eds) Molecular basis of neural function. Abstract Book, Prague, p 200     

Correlation between protein data in normal lumbar CSF and morphological findings of choroid plexus epithelium: a biochemical corroboration of barrier transport via tight junction pores

Summary Specific reference areas were derived from relationships between the proteins prealbumin, albumin, alpha₁-acid glycoprotein, alpha₂-macroglobulin, total transferrin, IgG, IgA, IgM, and the corresponding total protein in normal lumbar CSF samples. The procedure for calculating the boundary lines of these reference areas was carried out on the basis of double standard deviations in subgroups with total protein differences of 50 ml/l within the whole range of 150–400 ml/l CSF. The resulting biochemical data, hydrodynamic radii of the individual proteins investigated, and van Deurs' and Koehler's morphological findings on the existence of pores in the barrier-forming tight junctions of the choroid plexus epithelium could be surprisingly well correlated with one another, although these morphological findings were obtained in choroid plexus of the rat brain. The correlation allowed the conclusion that proteins undergo ultrafiltration via a pattern of tight junction pores with various diameters. However, the molecular mechanism seems to include an additional facilitating component.Dedicated to Professor H. Matthies (Magdeburg) on the occasion of his 60th birthdayParts of this paper were presented at the Conference on Progress in CSF Research of the CSF Research Group of the World Federation of Neurology, 6–7 September 1984, Rostock, GDR     

CSF homocysteine is not elevated in schizophrenia

Summary. Homocysteine is a neurotoxic amino acid originally found to be an independent risk factor for cardiovascular and cerebral vascular disease and more recently suggested to be a risk factor for Alzheimers disease. Several authors have observed high plasma homocysteine levels among schizophrenia patients. We reported that such high levels characterize young male schizophrenia patients.We now studied two groups of schizophrenia patients (N=41) and controls (N=29) for CSF homocysteine levels. No difference was found for CSF homocysteine levels between schizophrenia patients and controls (p=.041 for Study A and p=.52 for Study B).     

Wilson's disease with cerebral manifestation: monitoring therapy by CSF copper concentration

The clinical courses, cerebrospinal fluid (CSF) and serum copper concentrations and urinary copper excretions under different schemes of drug treatment in four patients with cerebral manifestations of Wilson's disease were monitored over 6–11 years. CSF copper concentration measurements were performed from the beginning of therapy onwards in three patients and from 16 months after initial treatment onwards in the fourth. CSF copper levels decreased slowly over the years in parallel with clinical improvements, and increased in one patient who interrupted therapy for 2 years. These findings confirm our hypothesis that the concentration of copper in the CSF is a valuable quantitative parameter reflecting the normalization of copper in the brain. Copper measurements during phases of initial neurological deterioration in two patients receivingd-penicillamine, and in one patient receivingd-penicillamine and zinc sulphate, revealed decreased free serum copper and CSF copper levels.     

Investigations on enzyme activity in the serum and CSF of patients with neuromuscular diseases

Summary The CPK, aldolase, GOT, GPT, and LDH concentrations in the serum and lumbar CSF of 80 patients with neuromuscular diseases and 20 controls were measured. The value obtained in serum were essentially in agreement with the data in the literature. This is the first publication reporting on regular CSF enzyme examinations in different neuromuscular disorders, particularly the results obtained in neurogenic muscular atrophies, which have certain characteristic features. The LDH activity in CSF was decreased in peroneal muscular atrophy, the GPT concentration in CSF was elevated in spinal muscular atrophy, and the mean activity of CSF aldolase was increased in amyotrophic lateral sclerosis. The simultaneous determination of enzymes in serum and CSF can provide valuable information in the research of certain details of pathomechanisms and thus lead to further improvement of diagnosis.     

Cerebrospinal fluid levels of soluble tumour necrosis factor receptor in acute encephalitis

Soluble tumour necrosis factor receptor (sTNF-R) inhibits the action of TNF-. The level of sTNFR reflects the true biological activity of TNF-. We investigated whether sTNF-R in cerebrospinal fluid (CSF) and serum increases during the acute stage in patients with acute encephalitis by measuring p60 sTNF-R using a sandwich enzyme immunoassay. The levels of sTNF-R were significantly higher in the CSF and serum of children with acute encephalitis than in those of control subjects. The patients with acute encephalitis who died or had severe neurological sequelae had higher CSF sTNF-R levels than those who survived. There were no significant differences in the serum sTNF-R, serum C-reactive protein and CSF protein levels, and CSF cell counts between the two groups. The sTNF-R levels of 4.0 ng/ml or higher identified patients with acute encephalitis who had neurological sequelae with a sensitivity of 100% (8/8), a specificity of 100% (8/8), and a predictive value of 100% (8/8). The 95% confidence interval for these three values is 63–100%. Our findings suggest that the CSF level of sTNF-R during the acute stage of encephalitis is important for predicting neurological sequelae.     

BETA-TRACE PROTEIN CONCENTRATION IN CSF IN NEUROLOGICAL DISORDERS

Beta-trace protein constitutes about 7 % of the total cerebrospinal fluid (CSF) protein concentration. In the present study the concentration of beta-trace protein in CSF has been determined in 59 "healthy" controls and in 174 patients suffering from various neurological diseases. The CSF concentration of beta-trace protein was found to increase with age. No statistically significant difference of the CSF beta-trace protein concentration could be found between patients suffering from various neurological diseases and healthy controls, with the exception of patients with cerebrovascular disease, where increased concentrations were found around the 5th week after the onset of the stroke. This increase was especially marked in patients with the most severe signs of a cerebrovascular lesion. Slightly higher CSF beta-trace protein concentrations were found in patients investigated within one month after an exacerbation of multiple sclerosis when compared with multiple sclerosis patients later investigated. A parallelism between increased concentrations of CSF beta-trace protein and the severity of myelin degradation is postulated.     

Measurement of 5-HIAA levels in ventricular CSF (by LCEC) and in striatum (byin vivo voltammetry) during pharmacological modifications of serotonin metabolism in the rat

Summary The relationship between the concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in the CSF and in the striatum has been evaluated in the rat by measuring the levels of this metabolite in ventricular CSF (by liquid chromatography coupled with electrochemical detection) and in the striatal extracellular fluid (byin vivo voltammetry) after administration of inhibitors of serotonin synthesis or degradation. Pargyline, NSD 1015 and-propyldopacetamide all caused an exponential decline of 5-HIAA in both CSF and striatum. For a given drug, the rate constants for 5-HIAA disappearance were identical in the CSF and in the striatal extracellular fluid. These results confirm the view that CSF 5-HIAA may serve as a good index of brain serotonin turnover.     

Clinical significance of serum and CSF findings in the Guillain-Barré syndrome and related disorders

Summary Clinical data and the serum and cerebrospinal fluid (CSF) findings of 71 patients with Guillain-Barré syndrome (GBS), 7 with Fisher syndrome and 24 with chronic inflammatory polyradiculoneuropathy (CIP), were analysed. Isoelectric focusing of serum and CSF together with different formulae and diagrams were applied to study blood-CSF barrier (BCB) function and possible intrathecal IgG synthesis. The CSF total protein concentration and its IgG percentage depended mainly on the degree of BCB damage, which correlated with the clinical course. Our investigations suggest that oligoclonal IgG of CSF from these patients comes essentially from serum. In the group of GBS patients, oligoclonal IgG was transitory and correlated significantly with the development of BCB damage, cranial neuritis and severity of the disease. CIP patients showed a stable IgG pattern, which varied slightly after immunosuppressive therapy.     

Proteins in cerebrospinal fluid and blood: barriers, CSF flow rate and source-related dynamics

Cerebrospinal fluid (CSF) routine analysis for diagnosis of neurological diseases is based on the concepts for discrimination of blood-derived and brain-derived immunoglobulin fractions in CSF. The actual molecular flux/CSF flow theory of the blood/CSF barrier function, which founded the hyperbolic discrimination lines in quotient diagrams, is derived from the laws of molecular diffusion combined with CSF flow rate. It emerged from this theory that the decrease of CSF flow rate is sufficient to explain quantitatively the increase of CSF protein concentrations as observed in many neurological diseases. With this concept of CSF flow rate as the modulator of the normal and pathological blood-CSF barrier function, we got for the first time a theoretical frame work to explain also quantitatively the dynamics of brain-derived proteins and their source related (neurons and glial cells or leptomeningal cells) differences. The review of the anatomical, physiological and biophysical knowledge points to the new interpretations: The changing albumin quotient is an indicator of changing CSF flow rate and not for a morphological "leakage" of the blood-brain barrier. As an application of these concepts the dynamics of brain-derived molecules in blood are discussed with two examples: beta trace protein, flowing with CSF into venous blood, and neuron-specific enolase, passing from tissue into blood the opposite direction of serum proteins, again a gradient-dependent protein diffusion across the intact blood vessel wall.     

The protein composition of myelin in multiple sclerosis (MS) and orthochromatic leukodystrophy (OLD)

Summary In 4 cases of MS, in which the progression of disease differed, and in one case of infantile OLD the proteins of a homogenate and a myelin fraction with and without plaques were separated electrophoretically with polyacrylamide gels in a buffer system of phenol/formic acid/water. The relation of proteolipid protein to basic protein was estimated planimetrically and compared with control cases.In myelin from plaque material of chronic running MS cases an average decrease of 41% in basic protein was observed, while in an acute progressing case no obvious alterations could be discerned. Myelin from apparently normal MS white matter showed an average decrease of 13% in basic protein. The results of the OLD case were similar to those obtained from the chronic MS cases. The decrease of basic protein (chronic MS, OLD) was markedly more in the homogenate fraction than in the purified myelin. In a control case with autolytic alterations (autopsy after 24 hours) the content of basic protein was also diminished.Our findings indicate that the reduction of basic protein in myelin is a non-specific effect in demyelinating diseases.Presented in part at the Third International Meeting of the International Society for Neurochemistry, July 5–9th, 1971, Budapest.Supported by Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 33), Stiftung Volkswagenwerk, and Forschungsmittel des Landes Niedersachsen.     

Serum IgG,IgA and IgM concentration in 1,038 patients with various neurological disorders

Summary Concentration of serum IgG, IgA and IgM in 1,038 unselected patients with various neurological diseases was determined. In 521 instances, the levels of CSF IgG, IgA and IgM were also established. In serum, the most frequent selective quantitative abnormality was found in the IgA concentration. In CSF, an increased level of IgG with normal IgA concentration and undetectable IgM was established about 8 times more frequently than isolated increase of CSF IgA. Selective quantitative abnormalities in serum IgG were observed in 35% of patients with subacute sclerosing panencephalitis as compared to 5% in instances in the definite MS group. Abnormal bands in the serum gamma-globulin field were most frequently seen in electropherograms from patients with subacute sclerosing panencephalitis, in cases of malignant lymphoproliferative disorders and in patients with definite MS. No correlation between the concentration of serum and CSF immunoglobulins could be established. Most frequent quantitative abnormalities in serum IgG, IgA and/or IgM were established in malignant lymphoproliferative disorders, in patients with myopathies including myositides and in subacute or chronic inflammatory CNS disorders. Highest incidence of increased CSF IgG, IgA and/or IgM concentration was detected in patients with inflammatory CNS disease, in instances of definite MS and in malignant lymphoproliferative disorders with CNS symptomatology. Increased CSF IgG and IgA concentration with detectable levels of IgM in patients with elevated CSF total proteins indicated alterations in the blood/CNS barrier structures.Supported by PHS grants NB05450 and 06793.     

Diagnostic accuracy of blood and CSF lactate in identifying children with mitochondrial diseases affecting the central nervous system

Objective: To determine the diagnostic accuracy of blood and cerebrospinal fluid (CSF) lactate and pyruvate concentrations in identifying children with mitochondrial diseases (MD) affecting the central nervous system (CNS). Methods: We studied lactate and pyruvate concentrations in paired samples of blood and CSF collected concurrently from 17 patients with MD (Leigh encephalomyelopathy 10, MELAS 5, Pearson disease 1, PDH deficiency 1) and those from control patients (n = 49). Results: Although blood and CSF variables (lactate, pyruvate concentrations and lactate/pyruvate ratio) were significantly higher in the mitochondrial group than in the control group, there was considerable overlap of individual values between these two groups. The maximum value of the area under the receiver operating characteristic curve (AUC) was observed for the CSF lactate concentration (0.994, optimal cut-off value 19.9 mg/dl, sensitivity 0.941 and specificity 1.00), followed by the CSF pyruvate level (0.983). There was an inverse relationship between blood lactate and lactate CSF/blood ratio. For blood lactate concentrations between 20 and 40 mg/dl, a significant difference was also noted in the lactate CSF/blood ratio between the two groups (AUC 1.0, optimal cut-off value 0.91, sensitivity 1.0 and specificity 1.0). Conclusions: Our study suggests that that CSF lactate level > 19.9 mg/dl is the most reliable variable for identifying patients with MD affecting the CNS. When blood lactate concentrations are marginally elevated (20–40 mg/dl), lactate CSF/blood ratio > 0.91 may also provide diagnostic information.     

Beta-trace protein as sensitive marker for CSF rhinorhea and CSF otorhea

OBJECTIVE: Beta-trace protein concentrations in cerebrospinal fluid (CSF), serum and nasal secretions are investigated with a new quantitative, immunonephelometric assay. RESULTS: The mean beta-trace concentration of normal lumbar CSF (18.4 mg/l) and normal serum (0.59 mg/l), from n = 132 control patients, were 10% higher than reported earlier for smaller control groups. The reference range of beta-trace protein in nasal secretions is very low (median: 0.016 mg/l, range <0.003-0.12 mg/l, for n = 29 controls). Clinically confirmed cases of CSF rhinorhea (n = 20) showed beta-trace concentrations between 0.36 and 53.6 mg/l, with a median of 2.4 mg/l. We propose a cut-off value of 0.35 mg/l above which a CSF contamination in the secretion is plausible. A clinically confirmed CSF otorhea had a value of 1.75 mg/l. CONCLUSION: This new beta-trace protein assay offers a fast, sensitive and reliable routine method to detect a CSF rhinorhea or otorhea.     

脑室冲洗与常规脑脊液置换在脑脊液蛋白增高脑积水中的比较研究

目的比较脑室冲洗与常规脑脊液置换在脑脊液蛋白增高脑积水中的应用价值。方法选取我院2015年1月至2018年8月确诊为脑脊液蛋白增高脑积水病人90例。随机分成脑室冲洗组、脑室外引流组和腰大池外引流组,每组30例。脑室冲洗组行两侧脑室冲洗;脑室及腰大池外引流组行脑室和腰大池引流,3组病人脑脊液蛋白500 mg/L后行脑室腹腔分流术。观察术后7 d、14 d脑脊液蛋白含量、等待分流手术的时间、颅内感染及堵管发生率。结果脑室冲洗组等待分流手术的时间1.87 d,明显短于两常规组(P0.01),术后7 d脑脊液蛋白含量523.45 mg/L,明显高于两对照组(P0.05),14 d后无明显差异。脑室外引流组颅内感染发生率30%,明显高于脑室冲洗组(P0.05)。3组堵管发生率没有明显差异。结论脑室冲洗能明显加快脑脊液蛋白增高脑积水病人的手术进程,值得推广应用。