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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.

West syndrome is a strictly age-limited encephalopathy of early infancy with unknown pathogenesis. It is often progressive, leading to mental retardation. Neurotrophic factors are important for the regulation of neuronal survival and differentiation, and their expression is influenced by hormones. Levels of beta-nerve growth factor in the cerebrospinal fluid were examined by two-site enzyme-linked immunosorbent assay method. Human antigen was used as a standard. We present data on largely normal levels of nerve growth factor in the cerebrospinal fluid of infants with cryptogenic etiology, but low or negligible levels in infants with symptomatic etiology, and very high levels in infants with symptomatic postinfectious etiology. Treatment with ACTH led to a greater increase in patients with a good response than in those with a poor response. Low nerve growth factor in patients with symptomatic infantile spasms possibly reflects massive neuronal death. The regression seen in these infants and their poor response to ACTH therapy may be due in part to lack of growth factors supporting neuron survival. This study, previously only demonstrated in animal models, is the first to depict nerve growth factor gene activity in humans as modulated by steroids.

Infantile spasms respond to ACTH, and levels of the hormone in cerebrospinal fluid of untreated infants with this disorder were found to be lower than in age-matched controls. In this study we analyzed cerebrospinal fluid cortisol and ACTH using improved immunoassays in a larger cohort of infants with infantile spasms. Analysis of 20 patients and 15 age-matched controls revealed significantly lower levels of both ACTH and cortisol in the cerebrospinal fluid. These data, combined with the efficacy of ACTH and glucocorticoids for infantile spasms, support an involvement of the brain-adrenal-axis in this disorder.

The efficacy of thyrotropin-releasing hormone in children with intractable epilepsy was investigated and changes in cerebrospinal fluid monoamine metabolites were analyzed. The 18 patients had either West syndrome (12 patients) or Lennox-Gastaut syndrome (6 patients), which was intractable to antiepileptic drug therapy and to adrenocorticotrophic hormone. Thyrotropin-releasing hormone-tartrate was administered for 4 weeks. Before and after the thyrotropin-releasing hormone administration, cerebrospinal fluid was collected and analyzed for 5-hydroxyindoleacetic acid, kynurenine, homovanillic acid, and 3-methoxy-4-hydroxyphenyl glycol. The patients were classified into 3 groups, based on seizure frequency and electroencephalographic effects: cessation of seizures and seizure discharges (very effective; group A), reduction of seizures and/or seizure discharges (effective; group B), and no changes in frequency of seizures or discharges (not effective; group C). There were 6 patients in group A, 3 in group B, and 9 in group C. There were no significant differences in monoamine metabolites before and after the thyrotropin-releasing hormone therapy. A trial of thyrotropin-releasing hormone for the treatment of intractable epilepsy is warranted and further study is required on the mechanism of the antiepileptic action of thyrotropin-releasing hormone.

Cerebrospinal fluid (CSF) from 8 patients with symptomatic infantile spasms was collected before specific treatment for infantile spasms. The concentration of CSF kynurenic acid (KYA) and 3-hydroxykynurenine (3-OHKY) in infantile spasms was analyzed by high-performance liquid chromatography and compared with CSF KYA from 10 age-matched controls. The levels of CSF KYA were significantly lower in infantile spasm patients compared to controls (P < .05). In contrast, the levels of CSF 3-OHKY were significantly higher in infantile spasm patients than in controls (P < .05). These findings suggest that the presence of seizures in infantile spasms is associated with altered metabolism of 3-OHKY. The possibility that seizures may be related to increased or decreased production of certain kynurenine metabolites is discussed.

One ml of cerebrospinal fluid (CSF) from each patient with West syndrome and patients from disease control groups were analyzed separately by highly sensitive thin-layer chromatography/enzyme-immunostaining method. The levels (mean +/- S.D.) of GM1, GD1a, sum of GD1b, GT1b, and GQ1b, and total gangliotetraose-series gangliosides in West syndrome patients (n = 14) and in an age-matched control group (n = 14) were as follows: 11.6 +/- 7.8 and 30.9 +/- 12.3 ng/ml CSF, 51.5 +/- 23.2 and 91.7 +/- 41.2 ng/ml CSF, 129.6 +/- 57.6 and 195.9 +/- 123.6 ng/ml CSF, and 192.7 +/- 78.6 and 318.4 +/- 131.6 ng/ml CSF, respectively. The differences were statistically significant except for the sum of GD1b, GT1b, and GQ1b (by 2 sample t test). Because they are abundant in the outer surface of neuronal plasma membranes, gangliosides may play an important role in the transformation of a neuroblast into a functionally mature neuron. Low levels of CSF gangliotetraose-series gangliosides, especially GM1 and GD1a, in patients with West syndrome may suggest a maturation disturbance of the brain from an early developmental stage.

Cerebrospinal fluid from 8 patients with infantile spasms (mean age: 6.1 months) was collected before treatment. The concentration of cerebrospinal fluid tryptophan metabolites was analyzed using high-performance liquid chromatography and compared to metabolite concentrations in cerebrospinal fluid from 20 age-matched controls (mean age: 5.8 months). The levels of cerebrospinal fluid serotonin, 5-hydroxyindoleacetic acid, and kynurenine were significantly lower in infantile spasm patients compared to controls (P less than .05). In contrast, the levels of cerebrospinal fluid 3-hydroxykynurenine were significantly higher in infantile spasm patients than in controls (P less than .05). There were no significant differences in the levels of cerebrospinal fluid tryptophan and 5-hydroxytryptophan. Although the study population was small, these findings suggest that the presence of seizures in infantile spasms is associated with a decrease in serotonergic metabolites which, in turn, may indicate a decrease in serotonergic activity, altered clearance of these metabolites, or altered turnover in the direction of 3-hydroxykynurenine. The perturbance caused by increased 3-hydroxykynurenine and decreased kynurenine in the homeostatic balance between these 2 tryptophan metabolites could further contribute to the pathogenesis of infantile spasms.

Cerebrospinal fluid (CSF) from 7 patients with infantile spasms (mean age: 6.7 months) was collected before and after treatment with adrenocorticotropic hormone (ACTH). The concentration of neurotransmitter metabolites was analyzed using high-performance liquid chromatography and compared to the metabolite concentration in the CSF from 7 age-matched controls (mean age: 6.1 months). Pretreatment levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid, 3-methoxy-4-hydroxyphenyl glycol (MHPG), and kynurenine were significantly lower in infantile spasm patients compared to controls. Following treatment, marked increases in 5-HIAA and decreases in kynurenine levels were observed in the CSF of the 5 infants whose seizures were eliminated or reduced by ACTH. In the 2 nonresponders 5-HIAA levels decreased. The level of MHPG was reduced slightly in 5 infants, including the 2 nonresponders, and was increased in 2 responders. CSF homovanillic acid levels increased in 4 infantile spasm infants and decreased in 3 following ACTH. These data demonstrate that the presence of seizures in infantile spasms is associated with a significant decrease in serotonergic activity and that elimination of seizures by ACTH is accompanied by increased serotonin turnover. The simultaneous increase of 5-HIAA and decrease of kynurenine, an alternate metabolite of tryptophan, suggests an underlying disturbance of tryptophan metabolism in infantile spasms. The possibility that elimination of seizures by ACTH may be related to decreased production of certain kynurenine metabolites, particularly quinolinic acid, is discussed.