Glutamic acid decarboxylase in cerebrospinal fluid in infancy and childhood. Part I. Glutamic acid decarboxylase activity in cerebrospinal fluid of normal infants and children

Glutamic acid decarboxylase (GAD) activity in the cerebrospinal fluid (CSF) of normal infants (n:14) and children (n:28) was determined by measuring the amount of 14CO2 released from L-[1-14C]-glutamic acid. The mean GAD activity in CSF of infants and children was 5.2 +/- 2.5 pmol CO2 formed/hr/ml. Dividing these subjects into 4 groups according to age, GAD activities in CSF were 5.4 +/- 1.6 pmol CO2 formed/hr/ml in neonates (0-1 m), 3.6 +/- 1.6 pmol CO2 formed/hr/ml in infants (2-12 m), 3.9 +/- 1.1 pmol CO2 formed/hr/ml in young children (2-6 yr) and 7.1 +/- 2.3 pmol CO2 formed/hr/ml in school children (7-16 yr), respectively. In neonates and school children, GAD activities were significantly higher (p less than 0.001) than those in the other age groups. In infants under 6 months of age, a significantly negative correlation between GAD activity in CSF and their ages was recognized (r = -0.52, p less than 0.001). In infants and children ranging from 6 months to 16 years of age, a significantly positive correlation between GAD activity in CSF and their ages was found (r = 0.67, p less than 0.001). These data suggest that high GAD activity in neonates may be due to hypoxia at birth and the activity gradually increases from 6 months to 15 years of age.     

Clinical and immunological significance of neopterin measurement in cerebrospinal fluid in patients with febrile convulsions.

Neopterin is synthesized mainly by monocytes/macrophages and is considered to be a marker for activation of the cellular immune system. It has been reported that cerebrospinal fluid (CSF) neopterin levels are significantly higher in patients with bacterial meningitis than in those with aseptic meningitis or non-pleocytotic CSF. In this study levels of neopterin and interferon-gamma (IFN-gamma) were measured in children with non-pleocytotic CSF. The CSF neopterin levels were significantly higher in patients with typical febrile convulsions (FCs) (15.0 +/- 4.5 nmol/l) than in those with pyrexia without convulsions (6.5 +/- 2.7 nmol/l) or convulsions without pyrexia, namely, epilepsy (4.8 +/- 2.4 nmol/l). The CSF neopterin/serum neopterin ratio (C/S ratio) was also higher in patients with typical FCs (1.54 +/- 0.83) than in those with pyrexia without convulsions (0.32 +/- 0.18) or convulsions without pyrexia (0.77 +/- 0.28). Patients with prolonged FCs tended to have higher CSF neopterin levels than those with typical FCs. There was also a tendency for CSF IFN-gamma levels to be higher in patients with FCs than in those with pyrexia without convulsions or convulsions without pyrexia. The results of the present study suggest that some immune activation in the central nervous system (CNS) compartment may be related to the mechanisms of FCs.     

Low CSF GABA concentration in children with febrile convulsions,untreated epilepsy,and meningitis

In 14 children with epilepsy, 51 with febrile convulsions and 22 with meningitis gamma-aminobutyric acid (GABA) concentrations in lumbar CSF were determined. While the mean for CSF GABA concentrations for all epileptic children was unchanged [144 (range: 73-285) pmol/ml; controls: 148 (range: 90-243) pmol/ml] extraordinarily high GABA levels were found in the CSF of two children on valproate (525 and 557 pmol/ml) and remarkably low GABA concentrations in hitherto untreated epileptic children [109 (range: 67-176) pmol/ml]. Children with febrile convulsions [103 (range: 63-170) pmol/ml] and acute meningitis [105 (range: 65-171) pmol/ml] had significantly decreased CSF GABA concentrations (P less than 0.001 and P less than 0.02 compared with controls). The data indicate that valproate intake increases dramatically the GABA concentrations in the CSF of epileptic children. Furthermore, the study supports the concept that low GABAergic activity within the CNS may be one cause for an increased seizure frequency.     

Brain function estimated from the ratio of glutamine to homocarnosine levels in cerebrospinal fluid

The ratio of glutamine to homocarnosine (G/H ratio) in CSF of children with meningeal pathology or convulsions was measured and the following results were obtained. 1. The mean G/H ratio of normal subjects was 83.0 +/- 41.4. 2. The mean G/H ratios of the patients with bacterial meningitis and meningeal leukemia were 115.9 +/- 81.9 and 115.2 +/- 49.2, respectively. Significant differences were found between those in normal subjects and these diseases. 3. The mean G/H ratio of the patients with viral meningitis was 80.0 +/- 35.1 and no significant difference was found between normal subjects and these patients. 4. The mean G/H ratios in the patients with controlled versus uncontrolled epilepsy were 130.9 +/- 67.1 and 74.8 +/- 49.4, respectively. A significant difference was found between normal subjects and the patients with controlled epilepsy. 5. The mean G/H ratio in the patients with febrile convulsions was 46.5 +/- 6.3. A significant difference was found between normal subjects and these patients. These data suggest that a high G/H ratio in CSF may indicate the excited state of the brain.     

Plasma and cerebrospinal fluid gamma-aminobutyric acid in neurological disorders.

In 49 patients with various neurological disorders plasma and CSF gamma-aminobutyric acid (GABA) concentrations were determined by radioreceptor assay. The CSF GABA concentration of 127 +/- 47 pmol/ml (range: 65-275; n = 52) was independent of the age, the sex and the intake of various drugs including benzodiazepines, baclofen and antidepressants. Patients with diverse neurological disorders such as multiple sclerosis, ischaemic strokes, intracranial tumour and polyneuropathies had similar CSF GABA levels. The mean plasma GABA concentration was 309 +/- 79 pmol/ml (range: 179-498; n = 44). The correlation between the GABA concentrations of CSF and plasma was very poor (r = 0.18; n = 44). Therefore plasma GABA is not a suitable indicator for CSF GABA.     

Vasopressin in the cerebrospinal fluid of febrile children with or without seizures

Immaturity in water and electrolyte balance in the brain has been considered to increase the susceptibility of young animals and children to febrile convulsions (FCs). Arginine-vasopressin (AVP) is involved in the regulation of several centrally mediated events such as modulation of fever and the ease with which water permeates into and out of the brain. To evaluate the possible role of AVP in the control of water balance and susceptibility to convulsions during fever we measured the AVP concentration in the cerebrospinal fluid (CSF) and plasma of febrile children with or without convulsions. The febrile population consisted of 47 children, of whom 29 experienced seizures during fever. Seven children with epileptic symptoms and 18 children without seizures were included as nonfebrile controls. The CSF AVP concentration in febrile children without seizures and in nonfebrile convulsive children was significantly lower (0.60 ± 0.07 pmol / 1, mean ± SEM,P < 0.01 and 0.65 ± 0.19 pmol/l,P < 0.05, respectively) than in nonfebrile children without convulsions (0.83 ± 0.06 pmol/1). However, the levels of CSF AVP were not significantly different in children with FCs (0.71 ± 0.06 pmol/1) compared with other groups. CSF AVP correlated with the CSF osmolality (r = 0.33, P = 0.02). No statistical differences in plasma AVP levels between the groups could be found. The present data provide support for the hypothesis of synchronous regulation of osmolality and AVP concentration in CSF. During fever the concentration of CSF AVP was lower in nonconvulsive children compared with nonfebrile nonconvulsive children. CSF AVP levels were not affected in febrile children by convulsions.     

Neopterin and interferon-gamma in serum and cerebrospinal fluid of patients with HIV-associated neurologic disease

We measured the levels of interferon-gamma (IFN-gamma) and neopterin in the serum and cerebrospinal fluid of 121 human immunodeficiency virus-seropositive (HIV+) and 62-seronegative (HIV-) individuals evaluated for neurologic disease. CSF levels of IFN-gamma and serum and CSF levels of neopterin were higher in HIV+ than in HIV- individuals. Patients with HIV- related meningitis and with opportunistic CNS infections had higher serum neopterin levels than HIV+ asymptomatic individuals. CSF levels of IFN-gamma were slightly higher in CSF of HIV+ individuals in all groups (0.31 +/- 0.03 U/ml) than in HIV- individuals (0.12 +/- 0.03). CSF levels of neopterin were similar in HIV+ asymptomatic individuals (6.9 +/- 0.7 nmol/l) and HIV- individuals (5.9 +/- 1.1), but were elevated in those HIV-infected individuals with neurologic disease, particularly patients with HIV-associated meningitis (72.1 +/- 13.3 nmol/l), opportunistic CNS infections (36 +/- 9.1), and inflammatory demyelinating polyneuropathies (32.4 +/- 17.2). Levels of neopterin correlated positively with levels of soluble interleukin 2 receptor and soluble CD8, 2 additional indicators of immune activation. In the absence of neurologic disease, levels of IFN-gamma and neopterin in both serum and CSF were stable for up to 4 years after seroconversion. These data suggest that increased CSF neopterin is associated with HIV-associated neurologic disease.     

Beta-2-microglobulin and ferritin in cerebrospinal fluid for evaluation of patients with meningitis of different etiologies.

To determine whether or not the beta-2-microglobulin (beta2-m) and/or ferritin levels in cerebrospinal fluid (CSF) can be used as markers for the differential diagnosis of meningitis and determination of the response to treatment, 122 subjects with etiologically well-characterized diagnoses were classified into three groups: bacterial meningitis (n = 5; mean age +/- SD. 1.0+/-1.0 year), viral meningitis (n = 39; 5.9+/-3.8 years), and a non-meningitis group (n = 78; 5.2+/-4.9 years). The levels of beta2-m and ferritin in CSF were determined by means of a latex photometric immunoassay. The statistical significance of the data was analyzed with the Mann Whitney U-test. A receiver operating characteristic curve was used to evaluate the diagnostic accuracy of each prediction marker. This study indicated that (1) the levels of beta2-m and ferritin in CSF were related with age in the non-meningitis group: subjects of up to 5 months of age exhibited higher concentrations of these proteins than ones of above 6 months of age (beta2-m, 1.89+/-1.13 vs. 0.84+/-0.65 mg/l. P < 0.01; ferritin, 2.97+/-2.04 vs. 1.81+/-1.34 microg/l, P = 0.09); (2) the beta2-m level was significantly higher in the CSF of patients with viral meningitis than in ones without meningitis (2.41+/-1.23 vs. 0.84+/-0.65 mg/l, P < 0.01): the best cut-off value was 1.2 mg/l (3) the ferritin level was significantly higher in the CSF of patients with bacterial meningitis than in ones with viral meningitis (43.24+/-39.49 vs. 6.81+/-7.41 microg/l, P < (.01): the best cut-off value was 7.5 microg/l; and (4) sequential measurement of the CSF ferritin level was of value for determination of the response to antibiotic treatment for bacterial meningitis. These results only apply to patients of greater than 6 months of age. beta2-m and ferritin in the CSF can be used as an ancillary tool for diagnostic guidance in the acute phase of meningitis and determination of the response to treatment for bacterial meningitis.     

Arginine vasopressin concentrations in the cerebrospinal fluid of children

Cerebrospinal fluid (CSF) arginine vasopressin (AVP) levels are reported in a group of 22 children (median age 24 months) investigated for possible bacterial meningitis and subsequently found not to be suffering from this disease. The mean CSF AVP concentration was 0.80±0.33 pg/ml. The results obtained in patients suffering from febrile convulsions (mean 0.71 pg/ml), other convulsive disorders (mean 0.80 pg/ml) and miscellaneous infectious disease (mean 0.85 pg/ml) did not differ significantly from one another. Our findings confirm the presence of AVP in the CSF of children and provide reference values for further investigations into the functions of CSF AVP in children.     

Activin A concentrations in human cerebrospinal fluid are age-dependent and elevated in meningitis

OBJECTIVE: Activin A, and its binding protein, follistatin (FS), are expressed in the central nervous system (CNS). We have previously shown elevated concentrations of FS in the cerebrospinal fluid (CSF) of patients with meningitis and increased concentrations of activin A in the CSF of rabbits with bacterial meningitis. METHODS: We measured CSF and serum concentrations of activin A and FS in normal subjects and in patients with various neurological diseases using previously validated immunoassays specific for activin A or FS. RESULTS: In healthy persons, serum concentrations of both activin A and FS were age-dependent. In CSF, concentrations of activin A ranged from 0.03 to 0.33 ng/ml and were strongly correlated with age in both sexes, whereas FS CSF concentrations were below the assay detection limit in most of the patients. Activin A concentrations in CSF of patients with various neurological diseases, including meningitis, chronic inflammatory CNS diseases, neurodegenerative diseases, tumors in the CNS, cerebral ischemia, intracerebral/subarachnoid hemorrhages, subdural hemorrhages and epileptic seizures, were compared with age- and sex-matched control patients. The comparisons revealed significantly elevated concentrations of activin A in patients with meningitis (P=0.017). Serum concentrations of activin A or FS were not affected by any of the neurological diseases examined. CONCLUSIONS: Our results show for the first time that in normal subjects concentrations of activin A in CSF are correlated with age, and furthermore, that activin A CSF concentrations are elevated in patients with meningitis. The latter underlines a role for activin A in acute inflammatory processes within the CNS.     

5-Hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid of children with febrile convulsions.

5-Hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured by high-performance liquid chromatography (HPLC) in lumbar cerebrospinal fluid (CSF) obtained from febrile children subdivided according to the presence or absence of convulsions. Lumbar puncture was made either early (mean time 2 h) or late (3-6 days) after the febrile convulsion. The level of 5-HIAA was significantly decreased in children early and late after the febrile convulsion as compared with the convulsion-free group, but the HVA level was reduced only early after the febrile convulsion. These results support the hypothesis that a decrease in CSF 5-HIAA may be a biologic marker of susceptibility to convulsions and indicate that the transient decrease in HVA is a secondary phenomenon related to occurrence of convulsions.     

Transcranial Doppler in infantile cerebrospinal fluid disorders: clinical validity

The present study was designed to investigate a possible relationship between transcranial Doppler sonography (TCD) parameters with infantile hydrocephalus and other types of cerebrospinal fluid (CSF) abnonnalities, i.e. arrested hydrocephalus and essential ventriculomegaly. TCD parameters in the major arteries of the circle of Willis were studied in hydrocephalic children (n = 12) before and after insertion of a ventricular shunt device. It was correlated with TCD parameters of children with CSF disorders (n = 13), in whom no surgery was performed. Also, TCD parameters were assessed in control cases (n = 10). Mean values for medial cerebral artery (MCA) flow velocities were higher in the essential ventriculomegaly (75.38 +/- 4.1) and in the control group (73.93 +/- 3.4) compared with hydrocephalic children (64.13 +/- 5.3). All hydrocephalic children had a higher mean MCA pulsatility index (RI) (1.08 +/- 0.13) and resistance index (RI) (0.64 +/- 0.17) values than the essential ventriculomegaly group (PI: 1.03 +/- 0.48; RI: 0.63 +/- 0.13) and the control group (PI: 0.84 +/- 0.32; RI: 0.57 +/- 0.23). Analysis of all TCD parameters disclosed its usefulness only after a particular and thorough evaluation of the TCD results with special emphasis in the clinical correlation of every case.     

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.     

Human cerebrospinal fluid somatostatin in neurologic disease

Concentrations of somatostatin-like immunoreactivity (SLI) were examined in human cerebrospinal fluid (CSF). To validate the assay it was shown that CSF which had been run over a somatostatin immunoaffinity column showed no interference with binding of synthetic standards. Reversed phase HPLC showed that the immunoreactive material coeluted with SS14 and SS28 as well as a higher molecular weight precursor. Concentrations of human CSF SLI were stable at both room temperature and 4 degrees C for up to 72 h while repeated freezing and thawing resulted in a significant loss of immunoreactive material after the 3rd repetition. In normal control patients less than 55 years of age, CSF SLI was 54.7 +/- 1.9 pg/ml, while in those older than 55 CSF SLI was 56.2 +/- 2.2 pg/ml. Febrile infants had significantly higher levels (75.4 +/- 7.3) pg/ml. CSF SLI was normal in patients with aseptic meningitis (54.4 +/- 3.4 pg/ml), suggesting that increased CSF protein and white cell counts do not affect concentrations. Concentrations of CSF SLI were significantly increased in intervertebral disc disease (65.1 +/- 5.6 pg/ml), intrinsic spinal cord pathology (101.0 +/- 23.9 pg/ml), central nervous system tumors (78.0 +/- 7.8 pg/ml) and acute cortical damage of varied etiology (277.8 +/- 81.6 pg/ml). Patients with pseudotumor cerebri had concentrations of 43.2 +/- 2.5 pg/ml. Concentrations of CSF SLI were significantly reduced (P less than 0.01) in multiple sclerosis (38.8 +/- 5.5 pg/ml) and old cortical pathology (23.2 +/- 3.9 pg/ml). Serial CSF analysis in patients with acute CNS lesions, suggest that CSF SLI may be a neurochemical marker of acute pathology, as the initially elevated levels fell to or below normal with resolution of the pathologic process.     

Elevated cerebrospinal fluid vasopressin in motor neuron disease.

CSF vasopressin levels were significantly elevated in eight patients with motor neuron disease (2.5 +/- 0.4 pmol/l) compared with controls (0.7 +/- 0.1 pmol/l). CSF oxytocin and plasma vasopressin concentrations were similar in the two groups. This finding may be a primary part of the disease process or an epiphenomenon related to increased autonomic and descending pathway activity secondary to abnormal function and/or loss of anterior horn cells.     

Cerebrospinal fluid somatostatin levels in febrile seizures and epilepsy in children

We analysed the level of cerebrospinal fluid (CSF) somatostatin in children with febrile seizures and epilepsy. In the febrile seizure group (n = 23), the somatostatin level was 83.9 +/- 11.2 pg/ml, which was significantly higher than that of age-matched controls. CSF samples obtained within 3 h of the last seizure had higher somatostatin levels (106.1 +/- 12.4 pg/ml;n = 14) than did the CSF obtained after 3 h (49.4 +/- 15.6 pg/ml;n = 9). The mean somatostatin level in the epilepsy group was 35.3 +/- 4.3 pg/ml (n = 34), and was distributed as follows: 27.6 +/- 3.6 pg/ml in the idiopathic generalized epilepsy group (n = 16), 44.0 +/- 9.4 pg/ml in the symptomatic generalized epilepsy group (n = 13), and 37.2 +/- 10.1 pg/ml in the partial epilepsy group (n = 5). The levels in each group were significantly higher than those in age-matched controls. Somatostatin is a hypothalamic tetradecapeptide with excitatory effects on neurons in children with febrile seizures and epilepsy. The finding that patients with convulsive disease had elevated levels of CSF somatostatin suggests that somatostatin release is somehow related to seizure activity. It remains to be determined whether this is due to increased release from over-active excitatory neurons or leakage from damaged or anoxic neurons, secondary to seizure activity.     

The studies of melatonin values in the cerebrospinal fluid of hydrocephalic patients

The changes in daytime levels of melatonin (MLT) in the cerebrospinal fluid (CSF) of twenty seven hydrocephalic patients were studied by the high-performance liquid chromatography (HPLC) method. Patients comprised three with congenital hydrocephalus (spina bifida 1, Chiari type II malformation 2), four post-meningitic hydrocephalus, fifteen brain tumors (chiasmal germinoma 3; malignant glioma of frontal 3, and temporal lobes 1; germinoma 1, teratoma 2, yolk sac tumor 1, epidermoid 1 in pineal region) and five cases of normal pressure hydrocephalus. CSF was collected between 0930 and 1030 h through puncture of the flushing device of shunt system or the lateral ventricle. The lowest value of MLT detected by HPLC was 15 pg/ml. Melatonin values were higher in patients aged under 10 years than over 20 years in the absence of meningitis or tumor in the pineal region. Even at ages over 15 years, higher CSF MLT values were obtained in the patients with meningitis or tumors in the pineal region. These results suggest that the inflammation or invasion of tumor into the pineal gland may stimulate the secretion of MLT by the pineal gland. However, lower MLT values were obtained in all patients over 40 years old. For these reasons, if one may use the changes of MLT values in CSF as a tumor marker or for determination of the treatment modality, time of CSF collection, age of patient, location or character of the tumor and presence of meningitis should be given due consideration. Also, the presence or absence of the rhythmical changes of melatonin values in a day following circadian rhythm are very important in determination of the treatment modality.     

Reduced brain delivery of homovanillic acid to cerebrospinal fluid during human aging

BACKGROUND: Markers of human brain dopamine metabolism are reported to decline with age. However, the cerebrospinal fluid (CSF) concentration of homovanillic acid (HVA), a major dopamine metabolite, is reported to not change or to increase in elderly individuals. OBJECTIVE: To estimate the rate of delivery of HVA from the brain to CSF, taking into account the HVA concentration gradient in the spinal subarachnoid space and CSF flow. METHODS: Homovanillic acid concentrations were measured in 5 serial 6-mL aliquots of CSF removed from the L3-4 or L4-5 interspaces of 7 healthy young (mean +/- SD age, 28.7 +/- 4.6 years) subjects and 7 healthy elderly (mean +/- SD age, 77.1 +/- 6.3 years) subjects. Cisterna magna HVA concentrations were estimated from the slopes of the HVA concentrations along the spinal subarachnoid space. The products of cisternal HVA concentrations and published values for CSF flow were used to estimate lower limits for brain delivery of HVA to CSF, according to the Fick principle. RESULTS: The mean +/- SD HVA concentration in the initial lumbar CSF sample in the young subjects, 116 +/- 66 pmol/mL, did not differ significantly from 140 +/- 86 pmol/mL in the elderly subjects. Estimated cisternal HVA concentrations equaled 704 and 640 pmol/mL, respectively, in the young and elderly subjects. Multiplying these concentrations by CSF flow rates of 591 and 294 mL/d, respectively, gave lower limits for rates of delivery of HVA from the brain to CSF. These rates equaled 416 and 175 nmol/d, respectively. CONCLUSION: A 50% decline in the lower limit for the rate of HVA delivery from the brain to CSF in elderly individuals is consistent with other evidence that brain dopaminergic neurotransmission declines with age.     

Diagnostic value of elastase-α1-proteinase inhibitor in cerebrospinal fluid

In this report we introduce CSF Elastase-alpha 1-Proteinase inhibitor as a valuable indicator for differentiating bacterial meningitis from aseptic meningitis and other neurological disorders. All patients (n = 26) with bacterial meningitis had increased CSF concentrations of E-alpha 1-PI above the range of normal (range of reference values: 0.0-2.3 micrograms/l, n = 79; bacterial meningitis: 30-3490 micrograms/l, n = 26). Concentrations of E-alpha 1-PI in bacterial meningitis were significantly elevated when compared with those in aseptic meningitis (0.0-194 micrograms/l, n = 37), polyneuropathy (0-23 micrograms/l, n = 24) and cerebrovascular attack (0-23.2 micrograms/l, n = 17).     

Dosage of lactate in the cerebrospinal fluid in infectious diseases of the central nervous system.

This paper analyzes the diagnosis aid of the dosage of lactate in the cerebrospinal fluid (CSF) in infectious diseases of the central nervous system (CNS). We analyzed prospectively 130 samples of CSF of 116 patients with diagnoses of infectious processes in the CNS. The 130 samples of CSF were divided into five groups: 28 samples of the control group, 40 of bacterial meningitis, 22 of viral meningitis, 16 of fungal meningitis and 24 of patients presenting acquired immune deficiency syndrome (AIDS). The concentration of lactate in the CSF was elevated in the group of patients with bacterial meningitis (average = 46.2 mg/dL), fungal meningitis (average = 27.3 mg/dL) and in the AIDS group (average = 23.5 mg/dL). In the control group and viral meningitis group the lactate content in the CSF presented the reference rates according to the employed method. The lactate dosage in the CSF presented a negative correlation with glycorrhachia and positive correlation with the cellularity and total proteins of the CSF. We conclude that the lactate dosage in the CSF, although unspecific, helps to distinguish the infectious processes of the CNS.