Cerebrospinal Fluid In Man Research Articles

Adrenocorticotropic hormone in serial cerebrospinal fluid in man – Subject to acute regulation by the hypothalamic-pituitary-adrenocortical system?

Acute regulation of adrenocorticotropic hormone (ACTH) in cerebrospinal fluid (CSF) by the hypothalamic-pituitary-adrenocortical system has not been investigated in man. In a pilot study in healthy male volunteers we measured ACTH every twenty minutes in serial CSF for three hours after an intravenous placebo, hydrocortisone (100mg) or insulin (2mg/kg) injection. No acute inhibitory or stimulatory effects of these interventions were discovered. Our results corroborate previous findings in rhesus monkeys. The regulation of CSF ACTH and its potential relevance for behavioral alterations in health and disease (e.g. major depression or anorexia nervosa) in humans need further study.

Cortisol, dehydroepiandrosterone (DHEA), and DHEA sulfate in the cerebrospinal fluid of man: relation to blood levels and the effects of age.

The relation between blood and cerebrospinal fluid (CSF) concentrations of cortisol, dehydroepiandrosterone (DHEA), and its sulfate (DHEAS) was measured in 62 subjects aged 3-85 yr old, fitted with ventriculo-peritoneal or lumbar-peritoneal shunts for a variety of diagnoses. There were 36 males and 36 females. Forty-eight subjects were not taking exogenous corticosteroids; the other 14 were receiving either systemic or local steroids. A single sample of blood and CSF was taken from each subject within 10 min for measurement of cortisol, DHEA, and DHEAS. The proportional levels of cortisol (5.8%) and DHEA (5.4%) in the CSF compared with those in the blood were similar in subjects not taking steroids. However, CSF DHEAS levels were only 0.15% of those in the blood. Because DHEAS blood levels were so much greater than DHEA, DHEAS in the CSF was still higher than DHEA despite the reduced penetration of the sulfated steroid. The blood/CSF ratios were similar in subjects taking steroids. There were significant correlations in steroid-free subjects between blood and CSF levels for DHEA (r = 0.65) and DHEAS (r = 0.88) but not for cortisol (r = 0.26). Steroid treatment significantly lowered blood cortisol, DHEA and DHEAS, and CSF DHEA, but not CSF cortisol or DHEAS compared with an age- and sex-matched sample of steroid-free subjects. In steroid-free adults (18 yr and over; n = 37), blood cortisol showed no age-related change. However, CSF cortisol was markedly raised in a proportion of steroid-free subjects over the age of 60 yr. Levels of corticoid-binding globulin in plasma did not alter with age. As expected, there were significant age-related decrements in both blood DHEA and DHEAS. CSF DHEA (r = 0.42) and CSF DHEAS (r = 0.39) were significantly negatively correlated with age. In steroid-free juveniles (n = 11) there were no age-related changes in either blood or CSF cortisol, but significant increases with age in DHEA and DHEAS in both blood and CSF. Calculation of the cortisol/DHEA and cortisol/ DHEAS molar ratios in the CSF showed both to be raised in the very young (3-8 yr) and the elderly (60 yr and over) by a factor of 4-5 compared with young adults aged 18-39. There were no sex differences in any of the parameters measured. These findings show that the relation between levels in the blood and CSF differ for each of these three neuroactive steroids. The brain is exposed to relatively high levels of DHEA and DHEAS during later childhood and early adulthood but to relatively or absolutely high levels of cortisol during infancy and older age. In view of the known antiglucocorticoid action of DHEA and DHEAS, and the direct action of these steroids on membrane-bound transmitter events (such as gamma-aminobutyric acidA receptors), these changes may have important implications for age-related alterations in brain function.

Cortisol, dehydroepiandrosterone (DHEA), and DHEA sulfate in the cerebrospinal fluid of man: relation to blood levels and the effects of age

Cortisol, dehydroepiandrosterone (DHEA), and DHEA sulfate in the cerebrospinal fluid of man: relation to blood levels and the effects of age

The diffusion of pirprofen into the cerebrospinal fluid in man.

We have measured the concentrations of pirprofen at various times in plasma and cerebrospinal fluid (CSF) samples, drawn during diagnostic myelography from 28 patients affected by sciatica. After intramuscular injection of 400 mg plasma concentrations of pirprofen reached a peak in 60 min then fell slowly. In contrast, the CSF concentration rose until 12 h and then fell. Pirprofen rapidly crossed the blood-brain barrier and was detectable in CSF at 15-30 min after injection. These results support the suggested hypothesis of a central analgesic action of pirprofen along with the known peripheral one. A new sensitive HPLC method was developed for measuring the concentration of pirprofen in the CSF.

Appearance of pethidine and norpethidine in cerebrospinal fluid of man following intramuscular injection of pethidine.

The plasma and cerebrospinal fluid (CSF) concentrations of pethidine and its main metabolite in plasma, norpethidine, were determined in 20 patients undergoing minor surgery who had received pethidine chloride as premedication in a standard dose of 100 mg intramuscularly. The disposition of pethidine and norpethidine in plasma was followed for 3-8 h after administration. The rate of transfer of the drug and its metabolite from plasma to CSF was assessed on the basis of a single sample of CSF taken from each patient. Pethidine appeared within less than 18 min in the CSF, reaching a maximum after about 90 min. After that, the pethidine concentration ratio CSF/plasma was relatively stable at 0.4-0.5. This is in agreement with the concept that the concentration of a drug in CSF is correlated with the concentration of unbound drug in plasma at equilibrium. Norpethidine which was present in rapidly increasing concentrations in plasma after a delay of 30 min, appeared in CSF in a slower and more erratic fashion as compared to the parent compound. However, after 240 min, the CSF/plasma concentration ratio was similar for pethidine and norpethidine. Thus, transfer from plasma to CSF occurs relatively rapidly. There is little evidence for a functionally significant blood-brain barrier for pethidine and norpethidine.

Penetration of lidocaine and its active desethylated metabolite into cerebrospinal fluid in man.

Penetration into lumbar cerebrospinal fluid (CSF) of lidocaine and its active desethylated metabolite, monoethylglycinxylidide (MEGX), has been studied in 10 neurological patients after a single subcutaneous injection of 2 mg/kg prior to lumbar puncture. An HPLC method was used to assay lidocaine, MEGX and glycinxylidide (GX) in serum and CSF. The serum protein unbound fraction of lidocaine was determined by equilibrium dialysis. The mean peak serum lidocaine concentration was found 25 minutes after injection, and the corresponding peak CSF level occurred after 70 min. A similar slow penetration of MEGX into CSF was observed, which indicates low membrane permeability for these two agents. No GX was found. The steadily increasing CSF lidocaine/serum total lidocaine ratio throughout the period of study up to 120 min and the higher level in CSF than the corresponding unbound fraction of the total serum lidocaine indicate that serum protein binding is not the sole determinant of the penetration of lidocaine into lumbar CSF. Rapid accumulation in brain tissue and diffusion back into cerebral extracellular fluid and to lumbar CSF may also occur. The apparent slow membrane penetration of lidocaine and its desethylated metabolite may be one reason for the difficulty of controlling lidocaine infusion rates according to therapeutic effectiveness and side-effects.

Catecholamines and their major metabolites in plasma and cerebrospinal fluid of man

In 36 patients undergoing elective surgery under spinal anesthesia, plasma and cerebrospinal fluid (CSF) concentrations of catecholamines and their major metabolic products were determined. The development of specific and sensitive radioenzymatic assays make these determinations possible. The levels of norepinephrine, epinephrine, and the O-methylated metabolite, normetanephrine, were greater in the plasma then the CSF, although the difference was significant for norepinephrine and epinephrine only (P less than 0.01 for both) On the other hand the levels of both deaminated metabolites dihydroxyphenylglycol (DOPEG) and dihydroxymandelic acid (DOMA) were greater in the CSF the in plasma, but the difference was significant for DOPEG only (P less than 0.01). Although there was a positive and significant correlation between the levels in plasma and CSF of all these compounds, their concentrations in CSF may reflect metabolism of catecholamines in the central nervous system.

The passage of flunitrazepam into cerebrospinal fluid in man.

The passage of flunitrazepam into cerebrospinal fluid (CSF) was studied in 23 surgical patients (group 1), after a single 0.02 mg/kg intravenous injection, in 9 otherwise healthy patients undergoing neurological examination (group 2), after a single 2 mg oral dose, and in 9 chronically-ill neurological patients (group 3), after 2 to 4 successive 2 mg oral doses. Flunitrazepam in plasma and the CSF was determined by gas chromatography and its plasma protein binding by equilibrium dialysis. Uptake of flunitrazepam into human CSF was found to very fast: even 5 min. after intravenous injection the drug level in the CSF was 2.8% of the corresponding plasma concentration. CSF levels increased up to 77 min. after intravenous injection. In group 2 the mean percentage level in the CSF was 23.5 +/- 13.0 (S.D.) and in group 3 it was 16.7 +/- 3.1. In group 1, 22.9+/- 8.0% of flunitrazepam was not bound to plasma protein, in group 2, 12.1 +/- 8.3% and, in group 3, 30.3 +/- 14.1%. Groups 1 and 2 (P less than 0.01) and 2 and 3 (P less than 0.01) differ significantly from each other. In groups 2 and 3 there was no significant correlation between the percentage not bound to protein and CSF levels of flunitrazepam. The uptake of flunitrazepam by CSF provides an explanation for its rapid drug effects. Its binding to plasma protein is affected by disease and, possible, by other drugs.

Immunoglobulins to tick-borne encephalitis in the cerebrospinal fluid of man.

Antibodies of IgM and IgG type were detected in the CSF of patients with recent tick-borne encephalitis (TBE) by means of ELISA. No false-positive results were obtained with CSF specimens from patients suffering from meningitis or other illnesses. The ratio of the antibodies in serum to CSF clearly indicated that both IgM and IgG antibodies were produced in the brain itself. In patients who had previously suffered from TBE now with a different inaseptic meningitis, TBE antibodies could also be detected in CSF but only of the IgG class. Again the serum-to-CSF antibody ratio indicated that the antibodies were produced within the central nervous system. For routine diagnosis the micro-ELISA method was found to be useful; antigen-coated plates can be stored as long as three months at +4 degrees C.

Neurotransmitter metabolites in the cerebrospinal fluid of man following physostigmine

A 3.0 mg dose of physostigmine or normal saline was given intravenously to 23 normal subjects who had been treated with probenecid. Homovanillic acid and 3-methoxy-4-hydroxyphenylglycol concentrations were significantly higher in the lumbar cerebrospinal fluid of subjects who received physostigmine than subjects who received normal saline. This establishes biochemical evidence for a cholinergic link in the central nervous system of man.

Nonhomogeneous distribution of 5-hydroxyindoleacetic acid and homovanillic acid in the lumbar cerebrospinal fluid of man

The volume of the lumbar sac measured in 4 subjects was found to be 15.5 ml. Exactly 15 ml of lumbar cerebrospinal fluid (L-CSF) was permitted to flow freely out during a lumbar puncture in 20 neurological patients and small samples of the L-CSF were collected in the beginning (sample 1), at the middle (sample 2), and at the end (sample 3) of this procedure either for 5-HIAA or HVA measurement. The concentrations of 5-HIAA and HVA increased in an exponential manner from sample 1 to sample 3. These results indicate that CSF in the lumbar sac is not a homogeneous fluid as is generally believed and that certain rules have to be followed in the sampling of the L-CSF to obtain reproducible biochemical data.

Alkaline shift in lumbar and intracranial CSF in man after 5 days at high altitude.

In six healthy male volunteers at sea level (PB 747-759 Torr), we measured pH and PCO2 in cerebrospinal fluid (CSF), and in arterial and jugular bulb blood; from these data we estimated PCO2 (12) and pH for the intracranial portion of CSF. The measurements were repeated after 5 days in a hypobaric chamber (PB 447 Torr). Both lumbar and intracranial CSF were significantly more alkaline at simulated altitude than at sea level. Decrease in [HCO3-] IN lumbar CSF at altitude was similar to that in blood plasma. Both at sea level and at high altitude, PCO2 measured in the lumbar CSF was higher than that estimated for the intracranial CSF. At altitude, hyperoxia, in comparison with breathing room air, resulted in an increase in intracranial PCO2, and a decrease in the estimated pH in intracranial CSF. With hyperoxia at altitude, alveolar ventilation was significantly higher than during sea-level hyperoxia or normoxia, confirming that a degree of acclimatization had occurred. Changes in cerebral arteriovenous differences in CO2, measured in three subjects, suggest that cerebral blood flow may have been elevated after 5 days at altitude.

Spinal descent of cerebrospinal fluid in man

The descent of radiopharmaceuticals injected within the right lateral ventricle toward and into the spinal subarachnoidal spaces has been followed by scintiphotographic techniques and by computerized flow analysis in a group of "normal" patients. A substantial and rapid downward progression of the albumin-tagged tracer has been observed. This progression is faster than the subarachnoidal ascent toward the convexity of the brain.

Absorption and passage of fat- and water-soluble thiamin derivatives into erythrocytes and cerebrospinal fluid of man

Oral administration of the lipid-soluble allithiamins, thiamin propyl disulfide and thiamin tetrahydrofurfuryl disulfide, caused a significant increase in thiamin activity in whole blood, red blood cells, and cerebrospinal fluid equivalent to that produced by parenteral, water-soluble thiamin hydrochloride and thiamin pyrophosphate. In contrast, oral administration of the water-soluble thiamins did not significantly elevate thiamin activity in biological fluids; this was probably due to their rate-limited intestinal transport. The odor of thiamin propyl disulfide limits its usefulness in multivitamins and food fortification. Thiamin tetrahydrofurfuryl disulfide is odorless and is therefore more useful for such purposes. Orally administered allithiamin vitamers are recommended for prophylaxis and treatment of thiamin deficits because they have the same biological properties as parenterally administered water-soluble thiamins.

Transport of 5-methyltetrahydrofolic acid into the cerebrospinal fluid in man.

1. 5-Methyltetrahydrofolate appeared in the CSF when given intravenously to man. 2. The data suggest considerable circulation of folate between CSF and other body compartments.

Comparative measurements of glucose, beta-hydroxybutyrate, acetoacetate, and insulin in blood and cerebrospinal fluid during starvation

The possibility that altered central nervous system (CNS) metabolism is reflected by changes in the constituents of the cerebrospinal fluid (CSF) was investigated. From eight obese subjects undergoing total starvation for weight reduction, overnight and 21-day fasting specimens of venous blood and lumbar CSF were obtained nearly simultaneously to determine the concentrations of glucose, beta-hydroxybutyrate (β-OHB), acetoacetate (AcAc), and immunoreactive insulin (IRI). After 21 days of starvation, the glucose concentration fell in both blood and CSF. The decrease in blood glucose was greater than the decline in CSF glucose, resulting in a diminished blood-CSF difference. Concentrations of β-OHB and AcAc in blood and CSF were elevated after prolonged fasting, but blood levels exceeded those in CSF, producing an increased blood-CSF ketone body difference. After an overnight and 21-day fast, the IRI levels in CSF were about one-half of the serum levels. These data suggest that metabolic alterations in CNS metabolism during prolonged starvation are reflected in substrate concentrations observed in CSF, and demonstrate that insulin is presented in the CSF of man.

Concentration of ethambutol in cerebrospinal fluid in man as a function of the non-protein-bound drug fraction in serum.

Using a chemical assay method, which had been confirmed by chromatography, the concentration of ethambutol in CSF and serum was determined in 13 patients. Ethambutol entered the CSF, even at low serum concentrations. For serum levels greater than 1 µg/ml, a linear correlation was found between the serum and CSF concentrations. In order to reach therapeutic levels in CSF (more than 1 µg/ml) the serum concentration should be at least 2 µg/ml, corresponding to a daily dose of about 20–30 mg/kg. The serum protein binding of ethambutol varied from 39.3% at a serum level of 0.61 µg/ml, to 8.3% at a serum level of 4.82 µg/ml.

Absence of effect of para-chlorophenylalanine on 5-hydroxyindoleacetic acid in cerebrospinal fluid in man.

The effect of para-chlorophenylalanine (PCPA) on the 5-hydroxy-indoleacetic acid (5-HIAA) content in human cerebrospinal fluid (CSF) has been studied. There was no effect on the CSF-content of 5-HI ...

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

Die individuell-vergleichende Gegenuberstellung des Kreatingehaltes im Serum und Liquor cerebrospinalis bei „Normalpersonen“ und bei Patienten mit neurologischen Erkrankungen zeigte, das fur den Kreatingehalt im Liquor keine gesetzmasige Abhangigkeit von der Hohe des Kreatinspiegels im Plasma besteht. Abgesehen von experimentell erzeugten extremen Erhohungen kann deshalb der Plasmakreatinspiegel bei der Beurteilung der Kreatinkonzentration im Liquor auser 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 erhohten Kreatingehalt im Liquor aufwiesen. Die Bestimmung des Kreatingehaltes im Liquor konnte bei dieser Erkrankung diagnostische Bedeutung gewinnen, wenn sich die hier beobachtete Erhohung des Kreatinspiegels bei einer groseren Anzahl von Patienten bestatigen sollte. Aus den Ergebnissen kann gefolgert werden, das das Kreatin im Liquor zwar primar aus dem peripheren Blut stammt, seine Konzentration jedoch durch Faktoren reguliert wird, die im Bereich des zentralnervosen Parenchyms und seiner Grenzflachen mit dem Blut zu suchen sind und fur eine Homoostase von Kreatin in Liquor, Extracellularflussigkeit und zentralnervosem Gewebe sorgen.

The effect of the administration of cortisol on the levels of cortisol and electrolytes in blood and cerebrospinal fluid in man

In some patients with brain tumor, neurosurgery involving ventricular drainage and ventriculography resulted in an increase in the sodium level in cerebrospinal fluid without any modification of its level in blood. In these patients, the effects of the administration of cortisol on the levels of corticosteroids, sodium, and potassium in blood and cerebrospinal fluid were studied. After the administration of cortisol, the corticosteroid levels in blood and cerebrospinal fluid were markedly increased. When patients had normal levels of sodium in cerebrospinal fluid, cortisol administration did not affect these sodium levels. However, when the sodium level in cerebrospinal fluid was high, the sodium level decreased 2 to 4 hr after the administration of cortisol. In all these patients, the sodium and potassium levels in blood were not influenced by cortisol administration. This finding may have bearing upon the apparent beneficial action of adrenal cortical hormones on cerebral edema following trauma or brain surgery.