Cerebrospinal fluid GABA levels in children with infantile spasms

The mean CSF GABA level in 22 children with infantile spasms was significantly lower than in 35 controls. There was no significant difference between the CSF GABA levels in untreated children and those treated with anticonvulsants, or between uncontrolled and temporarily controlled patients. After treatment with ACTH, CSF GABA levels were lower than before treatment, and seizures disappeared. Brain GABAergic neuronal function may be disturbed in children with infantile spasms, but the decreased CSF GABA level does not directly correlate with the seizures of infantile spasms.     

Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid.

Concentrations of HVA, 5-HIAA, ascorbic acid, and uric acid in the lumbar and cisternal cerebrospinal fluid (CSF) were measured in psychiatric and neurologically impaired patients. The concentration of HVA is 6.1 times and of 5-HIAA 2.7 times higher in cisternal than in lumbar samples, the cisternal level of uric acid is half that of the lumbar region, but no significant differences were found in ascorbic acid concentrations. Correlation between lumbar and cisternal metabolite concentrations is high for 5-HIAA and ascorbic acid, and is less for HVA and uric acid. In cisternal CSF there is a significant correlation between levels of HVA-5-HIAA, 5-HIAA-ascorbic acid, and 5-HIAA-uric acid. These correlations disappear in lumbar CSF. These findings indicate that extrapolations to cisternal neurotransmitter metabolite concentration from lumbar measures are unwarranted for HVA, but not for 5-HIAA.     

Relationship between platelet MAO activity and concentrations of 5-HIAA and HVA in cerebrospinal fluid in chronic pain patients

Summary Platelet monoamine oxidase (MAO) activity and concentrations of 5-HIAA and HVA in the cerebrospinal fluid (CSF) were estimated in a series of 54 chronic pain patients. Platelet MAO activity was found to correlate, positively to CSF concentrations of 5-HIAA and HVA, which had been adjusted in order to eliminate the influence of age and body height. However, only the correlation with 5-HIAA reached a significant level. When partial correlations were sought, only the positive correlation between platelet MAO activity and CSF 5-HIAA remained. The results support the notion that platelet MAO ia a biological marker for some trait dependent property of the central serotonergic system.Supported in part by grants from the Swedish Medical Research Council (grants No. 166, 4145 and 5740).     

Lactic dehydrogenase isoenzyme in cerebrospinal fluid of children with infantile spasms

Increased levels of lactic dehydrogenase (LDH) in cerebrospinal fluid (CSF) have been reported in association with several intracranial pathologies. We studied LDH isoenzymes in the CSF of children with infantile spasms. CSF samples collected from 12 patients (aged 4-9 months) with infantile spasms were analyzed for total LDH isoenzymes activity, and were compared to samples from 15 normal children. Mean total LDH activity in the CSF was 34.62 +/- 6.52 U/l. Patients with infantile spasms had a lower LDH-1 percentage and higher LDH-3 percentage; the differences from the control group were statistically significant (p < 0.01). LDH-4 and LDH-5 had similar values in both groups. Infantile spasm is apparently associated with a distinct LDH isoenzyme pattern in the CSF. More studies are needed to confirm the rise in LDH-2, LDH-3 and to determine the optimum time of analysis.     

Isoniazid effects on choreiform movement and on GABA, HVA and 5-HIAA in CSF

Isoniazid was administered in 4-week open trial in patients with choreiform movement. Gamma-aminobutyric acid (GABA), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in CSF were measured before and after treatment. Isoniazid did not improve choreiform movement. CSF GABA levels were significantly increased after treatment, but HVA and 5-HIAA levels were not significantly altered. The findings suggest that isoniazid influenced brain GABA metabolism but did not influence dopamine and serotonin metabolism in patients with chorieform movement.     

CT and ACTH treatment in infantile spasms

Computed tomography of 8 cases with West's syndrome before, during and after ACTH treatment are reported. The scans, performed at the third week of therapy, showed consistent widening of the sulci, cisterns and ventricles in all the patients. Of these, 2 patients underwent ICP monitoring which showed higher than normal values. A return to the normal ICP values in association with the disappearance of the CT findings was observed in both cases. It is concluded that widening of the sulci, cisterns and ventricles are not findings of atrophy, but a condition of initial communicating hydrocephalus, which is in accordance with the hypotheses of Riikonen and Lyen.     

Prolactin levels in cerebrospinal fluid of patients with infantile spasms

Infantile spasms are an age-related epileptic syndrome of infancy and are characterized by the combination of clusters of epileptic spasms and specific electroencephalographic findings. The etiology and the pathogenesis of the disease is still unclear. Prolactin has been thought to be specifically related to epileptic seizures. To investigate the possible mechanism of prolactin secretion in infantile spasms cerebrospinal fluid prolactin levels were examined. Fifteen patients with infantile spasms (10 females and five males), 3-16 months of age, were evaluated and compared with age- and sex-matched control subject. Cerebrospinal fluid samples for prolactin were obtained before and after treatment. The mean prolactin levels in the cerebrospinal fluid of the patients before therapy (3.25 +/- 1.48 ng/mL) was higher than the control group (2.38 +/- 0.89 ng/mL), and the difference between the two groups was statistically significant (P < 0.001). The mean prolactin level in the cerebrospinal fluid of the patients after therapy (4.69 +/- 1.47 ng/mL) was demonstrated to be higher than the mean prolactin level before therapy (3.25 +/- 1.48 ng/mL) and the difference between the two groups was statistically significant (P = 0.037). Elevation of cerebrospinal fluid prolactin levels before and after treatment in patients with infantile spasms provided evidence that the cerebrospinal fluid prolactin level is related with neuronal injury.     

Spinal reflexes and the concentrations of 5-HIAA, MHPG, and HVA in lumbar cereborspinal fluid after spinal lesions in man.

Descending bulbospinal pathways that employ specific neurotransmitter substances are known to be capable of modulating segmental reflex activity in the experimental animal. To determine whether this might also occur in man correlations have been sought between the activity in spinal reflex pathways and the lumbar cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA), 3 methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) in 12 patients with complete or virtually complete spinal lesions. The concentrations of 5-HIAA and MHPG in lumbar CSF ARE REDUCED AFTER COMPLETE OR VIRTUALLY COMPLETE SPINAL LESIONS IN MAN. This may occur within 18 days of the lesion. MHPG concentrations appear to be inversely related to the level of the lesion. The HVA concentration in lumbar CSF is reduced when there is obstruction of the CSF pathways. No relationship could be demonstrated between the concentrations of 5-HIAA or MHPG in lumbar CSF and the activity in the spinal monosynaptic pathway (estimated from the proportion of the motoneurone pool activated by the Achilles tendon reflex or H reflex) or the activity of a spinal inhibitory mechanism (estimated by the degree of vibratory inhibition of the monosynaptic reflex). Patients with a tonic vibration reflex (TVR) tended to have higher MHPG levels. There appeared to be an association between low CSF HVA and enhanced vibratory inhibition of the monosynaptic reflex in the nine patients whose spinal lesions were complete.     

CSF 5-HIAA and HVA concentrations in elderly depressed patients who attempted suicide.

CSF findings distinguished 12 elderly depressed patients who attempted suicide from nine depressed patients who did not and from seven normal control subjects. Psychosocial factors and measures of psychopathology did not differentiate suicidal from nonsuicidal patients. Biochemical factors may be important in evaluating suicide risk in the elderly.     

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.     

Hypothalamo-pituitary-adrenal function in infantile spasms: effects of ACTH therapy

The metyrapone test was used to study the hypothalamo-pituitary-adrenal function in ten children with infantile spasms, before and after ACTH treatment. The hypothalamo-pituitary-adrenal response was normal before ACTH treatment in almost all children. After ACTH, the responses of two children were suggestive of a diminished pituitary reserve; three were suggestive of decreased adrenal as well as decreased pituitary reserve, and one suggested either adrenal hyperplasia with normal pituitary reserve, or appropriate response to a developing medical stress. We suggest that, in children being treated with ACTH, the dosage of ACTH should be gradually tapered, AM cortisol levels should be monitored, and high-dose steroids should be included when treating medical stress.     

The response to ACTH is determined early in the treatment of infantile spasms

Although adrenocorticotropic hormone is the most commonly used treatment for infantile spasms in the United States, the optimal regimen for this indication is not known. The purpose of this study was to elucidate the optimal adrenocorticotropic hormone treatment duration. We conducted a retrospective chart review of response to adrenocorticotropic hormone among all patients with infantile spasms managed at our institution from January 2009 to September 2013. Treatment response was defined as clinical remission for greater than or equal to 28 days starting at any point within the adrenocorticotropic hormone course and remission of hypsarrhythmia (or definite EEG improvement if hypsarrhythmia was absent at baseline). For responders, the diagnostic and post‐treatment EEG tracings were reviewed. Electroclinical remission was achieved in 21 of 39 patients (54%) receiving adrenocorticotropic hormone, including 11/25 (44%) receiving a long course (typically 12 weeks) and 10/14 (71%) receiving a short course (typically four weeks). The mean time to clinical remission was 5.8 days (median: 5 days; range: 1–20 days). Only one patient responded beyond two weeks of treatment. This study provides Class IV evidence that among patients with infantile spasms, the response to adrenocorticotropic hormone is most often determined early in the treatment course. Given the importance of rapid remission, clinicians should consider adding or changing treatment if infantile spasms do not resolve within two weeks of adrenocorticotropic hormone initiation. Further study is needed to determine the optimal adrenocorticotropic hormone regimen for infantile spasms.     

The relationship between GABA concentrations in brain and cerebrospinal fluid

GABA concentrations in cerebrospinal fluid (CSF) and brain of rats and cats were determined before and after intraperitoneal injection of three drugs that increase brain GABA levels. GABA exists in the CSF in two forms: free and conjugated GABA. In the CSF of untreated animals, there is very little free GABA (65 ± 12pmol/ml) but considerable amounts of conjugated GABA (2885 ± 100pmol/ml). After IP administration of γ-vinyl GABA to rats, CSF concentrations of both free and conjugated GABA rise in a dose-dependent manner. There is an exponential correlation (r = 0.92, P < 0.001) between rat whole brain GABA concentrations and free GABA in the CSF. Concentrations of brain GABA and conjugated CSF GABA are linearly correlated (r = 0.84, P < 0.001). γ-Acetylenic GABA has qualitatively similar effects to γ-vinyl GABA. Treatment with ethanolamine-O-sulfate i.p. at a dose not affecting brain GABA concentrations markedly increases serum GABA, leaves conjugated CSF GABA unchanged and significantly elevates free GABA in the CSF.These findings suggest that total CSF GABA concentrations are related primarily to brain GABA levels and are minimally affected by the changes in the peripheral GABA concentrations. Determination of the levels of free and conjugated GABA in the CSF may be useful for the estimation of brain GABA concentration in patients on therapy intended to alter brain GABA levels.     

Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels in the cerebrospinal fluid from the lateral ventricle of patients with brain tumors

In patients with supratentorial tumours and posterior fossa tumours or in the third ventricle the concentrations of HVA and 5-HIAA were determined in the cerebrospinal fluid from the lateral ventricle. A significantly greater concentration of HVA and 5-HIAA was found in the patients with considerable hydrocephalus caused by occlusion of the third ventricle, aqueduct or fourth ventricle as compared with the cases of supratentorial tumours and with cases of moderate hydrocephalus and partial block of fluid outflow caused by third ventricle tumorous or posterior fossa tumours.     

Decrease of GABA in the cerebrospinal fluid of patients with progressive myoclonus epilepsy and its correlation with the decrease of 5HIAA and HVA

The degenerative type of progressive myoclonus epilepsy (PME) is a hereditary disease with grand mal seizures, stimulus sensitive myoclonus, characteristic EEG and mental deterioration in the late stage. GABAergic antiepileptic drugs are the most effective ones in this disease, with an unknown etiology. In this study, the GABA concentration in the CSF of 15 PME patients was measured and compared with values of sex- and age-matched epileptic controls. It was correlated with the concentrations of 5HIAA and HVA in the CSF, which were determined earlier from the same patients. The GABA concentration in the PME patients was statistically significantly decreased, to about 75% of that of the epileptic controls. It correlated with HVA and 5HIAA concentrations in the PME patients, but not in the epileptic controls. It is unknown whether these findings are related to the primary cause of PME or whether they are only secondary, owing to a loss of respective neurons or synapses.