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Purpose: The molecular mechanisms that lead to long-term consequences of infantile spasms (IS) are poorly understood. Insulin-like growth factor-1 (IGF-1) is regulated by insults that might be stressful to the brain, and is crucial for early brain development. The aim of the present study was to correlate cerebrospinal fluid (CSF) levels of IGF-1 with antecedent insults and cognitive outcome., Methods: We studied CSF IGF-1 and the adrenocorticotropic hormone (ACTH) concentrations in infants with idiopathic IS (IIS), symptomatic IS (SIS), and controls., Results: Infants with IIS had CSF IGF-1 concentrations similar to those of the control children, but children with SIS had markedly low CSF IGF-1 concentrations. In addition, CSF ACTH concentrations were significantly lower in the children with SIS than in those with IIS. High CSF IGF-1 concentrations were associated with an idiopathic etiology, absence of early (pre- or perinatal) insults or stress, normal brain imaging studies, good response to ACTH therapy, and favorable cognitive outcome. Low CSF IGF-1 concentrations were associated with low CSF ACTH concentrations, a history of early insults or stress, cerebral atrophy, poor response to therapy, and poor cognitive outcome., Discussion: In children with IS, insults or stress in early life may affect the synthesis of IGF-1, which might play a role in the reduction of certain cognitive functions.

Purpose: To compare the levels of brain nitric oxide production in patients with PEHO or PEHO-like syndrome and in controls with other neurologic disease., Methods: Nitric oxide metabolites, nitrates, and nitrites (NNx), were measured in the cerebrospinal fluid (CSF) of children with PEHO syndrome or PEHO-like syndrome, and in controls with other neurologic diseases., Results: The NNx levels were markedly higher in both PEHO (mean, 48 microM; p < 0.001) and PEHO-like (22 microM; p < 0.003) patients as compared with the controls (6 microM), but did not correlate with age or with brain atrophy or CSF levels of insulin-like growth factor-1 (IGF-1)., Conclusions: Our findings suggest that in PEHO syndrome, production of nitric oxide is markedly increased, suggesting that nitric oxide is involved in the pathologic phenomena (i.e., seizures and neurodegeneration) of the disease.

Purpose: In patients with progressive encephalopathy, hypsarrhythmia, and optic atrophy (PEHO) syndrome, the pathophysiology underlying early progressive cerebellar and brainstem degeneration and severe epilepsy is unknown. Because insulin-like growth factor (IGF)-1 has been shown significantly to promote survival of cerebellar neurons, we wanted to see if the IGF system played a role in the pathogenesis of cerebellar atrophy., Methods: We used a sensitive enzyme immunoassay kit for measuring cerebrospinal fluid (CSF) IGF-1 and insulin-like growth-binding protein (IGFBP)-3 in four groups of patients: PEHO syndrome patients (eight), PEHO-like patients (seven), age-matched controls (31), and patients with other types of cerebellar atrophy (11)., Results: Patients with PEHO syndrome and those with other progressive, degenerative cerebellar diseases had lower levels of CSF IGF-1 than the controls with other neurologic diseases. The CSF IGF-1 also allowed us to differentiate the "true" PEHO patients from the "PEHO-like" patients (those with similar clinical symptoms but without the typical neuroophthalmologic or neuroradiologic findings). The concentrations of IGFBP-3 did not significantly differ in any of the patient or control groups studied., Conclusions: CSF IGF-1 levels might be used as a marker of the degeneration of neurons in specific areas.

In view of the therapeutic efficacy of adrenocorticotropic hormone (ACTH) in the treatment of infantile spasms (IS) with hypsarrhythmia, we studied the cerebrospinal fluid (CSF) levels of ACTH in 15 children (4-10 months) affected by IS with hypsarrhythmia (eight cryptogenic forms, seven secondary to perinatal distress) and in age-matched controls. Lumbar puncture was performed in all but one case before any kind of treatment. In another case, CSF was collected 3 weeks after a spontaneous remission. Both ACTH and beta-endorphin (beta-EP), the other peptide related to the same precursor (proopiomelanocortin), were measured by specific radioimmunoassay after gel chromatography. While beta-EP levels were unchanged in the two groups of patients, ACTH concentrations of cryptogenic (3.75 +/- 2.40 fmol/ml, Mean +/- SD p less than 0.05) and secondary (6.36 +/- 3.70, NS) forms were lower than in controls (10.90 +/- 5.79). On the other hand, ACTH was higher in the case studied after therapy (9.0) and in the case presenting a spontaneous clinical and EEG remission (15.0). These data indicate that in children affected by IS with hypsarrhythmia (mainly of cryptogenic type), CSF levels of ACTH are lower, while levels of beta-EP remain normal. It would therefore appear that central ACTH content may play a possible role in the pathogenesis of IS with hypsarrhythmia.

Profiles of free amino acids in cerebrospinal fluid (CSF) were determined by high-performance liquid chromatography for 20 nonneurologic control patients and 12 patients with infantile spasms. Statistical comparisons showed significantly elevated levels of lysine (p less than 0.001) and the excitatory neurotransmitter, glutamate, (p less than 0.01) for the infantile spasms group as compared to the nonneurologic control group. When the infantile spasms patients were subdivided according to the presence or absence of etiologic associations, highly elevated amino acid levels were observed only in CSF from patients of the symptomatic subgroup. The idiopathic subgroup showed levels of free amino acids that were not statistically different from those of the nonneurologic control group. These results indicate that while abnormalities of amino acid metabolism often accompany infantile spasms, no specific pattern of the major free amino acids in CSF appears to be directly related to this seizure disorder. Elevated levels of the excitatory amino acids, aspartate and glutamate, do not necessarily accompany infantile spasms, and in this study were only observed in symptomatic patients.

To determine the role of noradrenaline, dopamine, and serotonin in the brain of patients with infantile spasms, levels of respective major metabolites in cerebrospinal fluid were examined. Homovanillic acid levels were significantly increased in these patients, while 3-methoxy-4-hydroxyphenylethylene glycol and 5-hydroxyindoleacetic acid were not significantly altered, as compared with controls. In patients with febrile convulsion and status epilepticus who were examined during or within a few hours after convulsions the same phenomenon was evident. The increased level of dopamine metabolite was closely related to the occurrrence of convulsions and is considered to be a secondary phenomenon.