Cerebrospinal fluid purine metabolites after complex febrile convulsions

Adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and uric acid were determined in cerebrospinal fluid (CSF) of 15 children after complex febrile seizures (CFS) and in 27 after simple febrile seizures (SFS), and compared with those in a control group of 63 children. There was no statistically significant difference between the groups for any of these metabolites, suggesting that CFS and SFS neither significantly disturb the metabolism of nucleotides, nucleosides or bases nor significantly deplete neuron adenosine triphosphate levels.     

Monoamine metabolite levels in cerebrospinal fluid of psychotic women treated with melperone or thiothixene

Summary Psychotic women with schizophrenic symptoms were treated with melperone 100 mg×3 (n=29) or thiothixene 10 mg×3 (n=34) using a double-blind procedure. Before and during treatment, levels of HVA, MOPEG, and 5-HIAA, the major metabolites of DA, NE, and 5-HT, were determined in lumbar cerebrospinal fluid by a mass fragmentographic technique. Both treatments resulted in an elevation of the HVA levels after 2 weeks, thiothixene having a more marked effect. The effect of thiothixene but not of melperone persisted after 4 weeks. Thiothixene did not influence the MOPEG level, but melperone reduced it after 4 weeks of treatment. The 5-HIAA levels were not significantly altered by the drugs. The HVA/MOPEG and the HVA/5-HIAA ratios were highly significantly elevated by both drugs after 2 as well as 4 weeks. Thiothixene induced a significantly greater change of these ratios than melperone. The results supply evidence that thiothixene accelerates central dopamine metabolism in man, presumably by blocking DA receptors. Melperone appears to act similarly, but has an effect which is weaker and/or of shorter duration. During long-term treatment with melperone the receptors develop tolerance to it. The acceleration in DA metabolism declines and the effect of melperone switches instead to central NA metabolism. The results indicate that both drugs cause long-term changes in the activity ratios of central monoamine systems. It is suggested that such changes in several systems rather than single biochemical events may be related to the antipsychotic effects of neuroleptic drugs. This study also demonstrated the versatility of using monoamine metabolite analysis of the CSF as a tool for the quantification of biochemical effects of neuroleptic drugs on the human CNS.A preliminary report of the present study was presented at the VI International Congress of Pharmacology, Helsinki, 1975Financial support was provided by the Swedish Medical Research Council (14X-03560), National Institutes of Mental Health, (MH 27254-01), Bethesda, Maryland, USA, F. Hoffmann-La Roche & Co., Basle, Switzerland, Svenska Sällskapet för Medicinsk Forskning, Karolinska Institutet, AB Ferrosan, Sweden, and Pfizer-Roerig, Sweden.     

Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with senile dementia of Alzheimer type

The possibility of disturbed dopamine and serotonin metabolism in senile dementia of Alzheimer type was studied. The basal concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were studied in 28 patients with senile dementia of Alzheimer type and in 13 controls of similar age with no neurological disease. The concentrations of HVA were significantly reduced in the dementia patients compared to the concentrations of the controls. The values of HVA were also significantly reduced in the most severely demented patients compared to the less severely demented ones. There was a slight but statistically significant decrease in the 5-HIAA levels in the dementia patients compared to the levels of the controls. The 5-HIAA levels were reduced in the most severely demented patients compared to the controls but not when compared with the less severely demented patients.
It is concluded that in severe forms of senile dementia of Alzheimer type, there is a decrease in the levels of HVA and 5-HIAA in CSF which may reflect a decreased turnover of dopamine and serotonin. Patients diagnosed as senile dementia of Alzheimer type, but with less severe symptoms, had levels of HVA and 5-HIAA similar to controls.     

The effect of valproic acid on the 5-hydroxyindoleacetic, homovanillic and lactic acid levels of cerebrospinal fluid

In this study the cisternal cerebrospinal fluid (CSF) contents of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were sequentially measured in free-moving rats which were administered 50–500 mg·kg⁻¹ valproic acid. Animals receiving 100–500 mg·kg⁻¹ valproic acid showed significant increases in CSF 5-HIAA and HVA content, with maximal accumulation rates of 1.80–2.10 and 0.25–0.30 nmol·ml⁻¹·h⁻¹, repectively, being reached at the 250 mg·kg⁻¹ dose. The combination of valproic acid 500 mg·kg⁻¹ and probenecid 300 mg·kg⁻¹ failed to increase the accumulation rates of 5-HIAA and HVA over those seen with valproic acid 500 mg·kg⁻¹ or probenecid 300 mg·kg⁻¹ alone. This pattern of change indicates that valproic acid and probenecid share a common site of action in blocking the clearance of 5-HIAA and HVA from CSF. The tranquillizer diazepam produced progressive increases in CSF 5-HIAA and HVA content which suggested a similar action to that of valproic acid and probenecid. The anticonvulsants phenytoin and phenobarbital produced selective increases in 5-HIAA, whereas the tranquillizer chlorpromazine produced proportionally larger increases in HVA, changes which seem to indicate a more selective effect of these drugs on the serotonergic or dopaminergic systems, respectively. Valproic acid was associated with increases in CSF lactate which occurred in the absence of similar increases of blood or tissue lactate. This indicated that valproic acid, like probenecid, can inhibit the monocar☐ylic acid transport system which removes lactate from the CSF.     

A long-term follow-up study of cerebrospinal fluid 5-hydroxyindoleacetic acid in delirium

Cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) was determined for elderly delirious patients during the acute stage and after a 1-year follow-up period, and the 5-HIAA levels were compared with age-equivalent controls. As compared with the controls, the 5-HIAA levels were significantly higher at the beginning of the index admission in patients with multi-infarct dementia and patients with no apparent CNS disease. The 5-HIAA levels were also higher in the latter subgroup in the 1-year sampling, but no other differences between delirious patients and controls were observed. The one-way procedure showed no differences between the subgroup means of delirious patients when divided according to the severity of cognitive decline or type of delirium in any of the samples. The 5-HIAA levels measured during the index admission correlated with the length of life after delirium suggesting that serotonergic dysfunction may have prognostic significance in delirious patients.     

5-HIAA in cerebrospinal fluid of patients with status epilepticus

Cerebrospinal fluid concentration of 5-hydroxyindolacetic acid (5-HIAA) was determined in 15 patients soon after recovery from status epilepticus. Similarly, patients with generalised epilepsy and persons without epilepsy, serving as controls, were also studied. The level of 5-HIAA was significantly reduced in all epileptic patients with or without status epilepticus, as compared with the nonepileptic control group. However, there was no statistical difference between patients with status epilepticus and those with generalised epilepsy. Among patients with epilepsy, low 5-HIAA levels in CSF could not be correlated with frequency or severity of seizures, or with antiepileptic drugs. A link between CSF 5-HIAA and susceptibility of humans to epilepsy may indicate a possible future therapeutic approach.     

Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with progressive myoclonus epilepsy

The possibility of disturbed dopamine and serotonin metabolism in the progressive myoclonus epilepsy (PME) occurring in Finland (a type of PME without Lafora bodies) was examined. Both basal concentrations of HVA and 5-HIAA in the CSF and their increase after oral probenecid administration were studied in 19 PME patients and in 19 age- and sex-matched control patients. The control patients had grand mal epilepsy but not myoclonus or ataxia. The basal value of HVA was significantly reduced and that of 5-HIAA was also slightly reduced in the PME patients as compared to the values of the epileptic controls or to those of 26 nonepileptic controls. The concentrations of HVA and 5-HIAA also seemed to correlate with the severity of the PME. The most severely affected patients had generally the lowest values. After oral probenecid this trend was also seen when the increases of HVA and 5-HIAA were expressed per microgram CSF probenecid, i.e. the mildly affected PME group showed higher increases in response to probenecid than the most severely affected PME group. The PME patients had higher probenecid levels in the CSF than the epileptic controls.     

Homovanillic acid and 5-hydroxyindoleacetic acid in lumbar cerebrospinal fluid in children with afebrile and febrile convulsions

The concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in lumbar cerebrospinal fluid (CSF) from five groups of children: (1) afebrile controls (2) febrile controls, (3) children with afebrile convulsions, which included children with established idiopathic epilepsy, (4) children with first febrile convulsions, and (5) children with repeated febrile convulsions. There were no significant differences between the metabolite levels in the five diagnostic groups. The CSF concentrations of 5-HIAA and HVA in these children, with a mean age of 2.5 years, were about twice the levels found in adults.     

Elevated 5-S-cysteinyldopamine/homovanillic acid ratio and reduced homovanillic acid in cerebrospinal fluid: possible markers for and potential insights into the pathoetiology of Parkinson's disease

Summary High-performance liquid chromatography with electrochemical detection has been employed to analyze ultrafiltrates of cerebrospinal fluid of Parkinson's Disease (PD) patients and age-matched controls for the dopamine (DA) metabolites homovanillic acid (HVA) and 5-S-cysteinyldopamine (5-S-CyS-DA). The mean level of HVA in the CSF of PD patients, measured 5 days after withdrawal from L-DOPA therapy, was significantly lower than that measured in controls. By contrast, mean levels of 5-S-CyS-DA were not significantly different in the CSF of PD patients taking L-DOPA (PD-LT patients) the same patients 5 days after discontinuing this drug (PD-LW patients) or controls. However, the mean 5-S-CyS-DA/HVA concentration ratio was significantly (p < 0.05) higher in the CSF of PD-LW patients compared to controls. Although the PD patient population employed in this study had been diagnosed with the disease several years previously and had been treated with L-DOPA for prolonged periods of time the results of this study suggest that low CSF levels of HVA and a high 5-S-CyS-DA/HVA ratio together might represent useful markers for early diagnosis of PD. The high 5-S-CyS-DA/HVA ratio observed in the CSF of PD-LW patients also provides support for the hypothesis that the translocation of glutathione or L-cysteine into neuromelanin-pigmented dopaminergic cell bodies in the substantia nigra might represent an early event in the pathogenesis of PD.Abbreviations CSF cerebrospinal fluid - CySH L-cysteine - DA dopamine - DA-o-quinone dopamine-o-quinone - L-DOPA 3,4-dihydroxyphenylalanine - DOPAC 3,4-dihydroxyphenylacetic acid - EPI epinephrine - GSH glutathione - GSSG oxidized glutathione - 5-HIAA 5-hydroxyindole-3-acetic acid - HVA homovanillic acid - HO· hydroxyl radical - HPLC-EC high performance liquid chromatography with electrochemical detection - 5-HT 5-hydroxytryptamine (serotonin) - NE norepinephrine - PD Parkinson's disease - PD-LT Parkinson's disease patients taking L-DOPA therapy - PD-LW Parkinson's disease patients withdrawn from L-DOPA therapy for 5 days - 5-S-CyS-DA 5-S-cysteinyldopamine - 5-S-Glu-DA 5-S-glutathionyldopamine - SN substantia nigra - O ₂· Superoxide radical anion     

Brain-derived neurotrophic factor gene variation influences cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol concentrations in healthy volunteers

Brain-derived neurotrophic factor (BDNF) has been shown to influence monoamine transmitter synthesis, metabolism and release. We investigated possible relationships between four BDNF gene polymorphisms and cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 132). All BDNF polymorphisms (270 C/T, −633 T/A, Val66Met, and 11757 G/C) were associated with MHPG (P < 0.02), but not with 5-HIAA and HVA concentrations. At a second clinical investigation 8–20 years after CSF sampling 30% of the subjects had experienced various psychiatric disorders. Development of a psychiatric disorder was predicted by low 5-HIAA concentrations (P = 0.01). The results suggest that BDNF gene variation participates in regulation of norepinephrine turnover rates in the central nervous system of human subjects.     

5-Hydroxyindoleacetic acid and homovanillic acid in human cerebrospinal fluid below partial and complete spinal subarachnoid block

Concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were investigated by lumbar cerebrospinal fluid (CSF) of 21 patients with partial and total spinal subarachnoid block. HVA levels in CSF below a complete block were significantly lower and 5-HIAA levels were signigicantly higher than controls. Below a partial block, HVA levels were normal; 5-HIAA levels were higher than in patients with complete block. Possible explanations for these findings are discussed.     

Temporal lobe epilepsy – not a consequence of childhood febrile convulsions in Denmark

Temporal lobe epilepsy in particular has been considered a consequence of childhood febrile convulsions. Previous studies have dealt with populations of epileptic children. This retrospective, follow-up study concerns 362 children with a primary diagnosis of febrile convulsions. 4% developed epilepsy. When followed into early adulthood one half of those remitted. The incidence of temporal lobe epilepsy among the non-rermitters did not differ from that of a random population of epileptics.     

Cerebrospinal fluid homovanillic acid patterns during neuroleptic treatment

Twenty-four psychotic patients were studied at two points during continuous neuroleptic treatment. Thirteen patients showed a tolerance pattern with respect to cerebrospinal fluid homovanillic acid following probenecid while 11 showed a nontolerance pattern. Patients who developed tolerance had significantly fewer symptoms and Parkinsonian side effects at approximately the fifth week of treatment.     

Comparative evaluation of 5-HIAA (5-hydroxy indoleacetic acid) and HVA (homovanillic acid) in infantile hydrocephalus

Background Infantile hydrocephalus is a common congenital problem. Functional and behavioral disturbances associated with hydrocephalus may be due to altered neurotransmitters in the brain. The role of neurotransmitters has been established in various psychiatric and neurological conditions. Therefore, we decided to study the role of 5-hydroxy indoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF) of hydrocephalic patients as diagnostic and prognostic marker. Materials and methods Ventricular CSF samples were taken from hydrocephalic patients peroperatively and at days 7 & 30. Control CSF samples were taken from nonhydrocephalic patients operated for other conditions. Samples were analyzed for 5-HIAA and HVA, and results were obtained accordingly. Results Values of 5-HIAA and HVA showed a highly significant decrease after shunt insertion. No significant difference in values of 5-HIAA and HVA were observed in relation to age and duration of disease. The CSF ventriculo-lumbar gradient for both 5-HIAA and HVA done in six patients was statistically significant only in the noncommunicating group. Conclusion Both the neurotransmitter metabolites 5-HIAA and HVA are found to be significantly high in the hydrocephalus, but 5-HIAA is a more sensitive parameter. These markers levels decrease after shunt insertion. Thus, estimation of these metabolites could be valuable markers for its diagnosis and follow-up.     

儿童精神分裂症患者脑脊液中氨基酸神经递质的测定

目的　探讨儿童精神分裂症可能的发病机制。方法　采用反向高效液相色谱法 ,测定16例儿童精神分裂症患儿 (患儿组 )和 11例患阑尾炎的患儿 (对照组 )脑脊液 (CSF)中谷氨酸、天门冬氨酸 (兴奋性氨基酸 )和甘氨酸 (抑制性氨基酸 )的浓度并进行比较。结果　患儿组CSF中谷氨酸为(9 7± 3 1) μmol L ,甘氨酸为 (9 1± 3 7) μmol L ,低于对照组 [分别为 (41 9± 2 2 3) μmol L和 (16 1±11 8) μmol L],而天门冬氨酸含量两组差异无显著性。 结论　儿童精神分裂症的发病机制中可能有氨基酸神经递质的参与。     

Amino acid transport across the human blood-CSF barrier. An evaluation graph for amino acid concentrations in cerebrospinal fluid

The correlation of cerebrospinal fluid (CSF)/serum concentration quotients was used as a method for identification of amino acids which are transported by a common carrier system across the blood-CSF barrier. Isoleucine, leucine, valine, phenylalanine, tyrosine and lysine were found to compete for the same carrier system. This group of amino acids in man was found to be different from the system described as a neutral amino acid carrier at the blood-brain barrier in rats. In man, methionine and tryptophan do not compete with the other neutral amino acids for the same carrier system. In contrast, lysine as a basic amino acid is found to be correlated with the same transport system as the five neutral amino acids. A graph for the evaluation of pathological amino acid concentrations in CSF is presented. Patients with a blood-CSF barrier dysfunction for proteins showed partly normal, partly increased, CSF/serum concentration quotients for the amino acids. Hydroxyproline could be identified as a constituent of the amino acid pool in CSF. For proline and hydroxyproline a special control system has to be suggested because of their smaller biological variance in CSF than in blood. Contrary to the other amino acids proline and hydroxyproline have a smaller biological variation in CSF than in serum.     

Cerebrospinal fluid homovanillic acid and 5-hydroxy-indoleacetic acid in adults with attention deficit disorder, residual type

Following the hypothesis that attention deficit disorder in adults (attention deficit disorder, residual type; ADD, RT), as well as in children, is associated with decreased central dopaminergic activity, the authors measured lumbar cerebrospinal fluid monoamine metabolites in a group of adults with ADD, RT and matched control subjects. Patients were then entered into a double-blind, placebo-controlled trial of methylphenidate. It was predicted that the patients would have lower levels of homovanillic acid (HVA), the major dopamine metabolite in humans. Patients who had a significant response to methylphenidate showed a trend in this direction. Nonresponding patients had significantly higher levels of HVA than controls.