Massive infantile spasms (MIS), a seizure disorder unique to infants, is considered an age-dependent response of the immature brain to various insults and stressors. The seizures improve with ACTH and glucocorticoids, both major components of the brain-adrenal axis. We hypothesized that CNS levels of these hormones are abnormal in infants with MIS and studied CSF from 14 infants with MIS and 13 age-matched controls by analysis for corticotropin-releasing hormone (CRH), ACTH, cortisol, and interleukin-1-beta. ACTH levels in CSF of patients were significantly lower than those of controls, but differences in cortisol levels between patients and controls were not statistically significant. CRH levels in both groups were similar and fluctuated diurnally. These results indicate an alteration of specific CNS components of the brain-adrenal axis in MIS.

We describe a syndrome of rhythmic coma in children that consists of an invariant, nonreactive, diffuse cortical activity of a specific frequency, such as alpha, beta, spindle, or theta, recorded from a comatose child. We report 11 cases of children who were found to be in rhythmic coma during their acute illnesses. Their ages ranged from 2 to 15 years, and their diagnoses included encephalitis, head trauma, seizures, near drowning, brain tumors, stroke, and metabolic derangements. The specific frequency of the electroencephalographic pattern, ie, alpha, beta, spindle, or theta, did not influence the outcome. The clinical outcome appeared to depend on the primary disease process rather than the electroencephalographic finding. The prognosis of alpha-frequency rhythmic coma as well as of rhythmic coma in general was better in children than in adults. The pathophysiology in children may be similar, ie, the interruption of reticulothalamocortical pathways by metabolic or structural abnormalities, but the expression of this deafferentation may be more varied in the developing brain. Thus, we propose the term rhythmic coma as a unified concept for alpha, beta, spindle, and theta coma in children.

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.

Objective

To compare the efficacy of corticotropin (ACTH) (150 U/m2/day) and prednosone (2 mg/kg/day) given for 2 weeks, in suppressing clinical spasms and hypsarrhythmic electroencephalogram (EEG) in infantile spasms (IS). AACTH and prednisone are standard treatments for IS. ACTH at high doses causes severe dose- and duration-dependent side effects, but may be superior to prednisone, based on retrospective or uncontrolled studies. Blinded prospecive studies have shown equal efficacy of prednisone and low-dose ACTH, and low versus high-dose ACTH.

Design

A prospective, randomized, single-blinded study.

Subjects and methods

Patient population consisted of consecutive infants fulfilling entry criteria, including the presence of clinical spasms, hypsarrhythmia (or variants) during a full sleep cycle video-EEG, and no prior steroid/ACTH treatment. Response required both cessation of spasms and elimination of hypsarrhythmia by the end of the 2-week treatment period, as determined by an investigator "blinded" to treatment. Treatment of responders was tapered off over 12 days; those failing one hormone were crossed-over to the other.

Results

OF 34 eligible infants, 29 were enrolled. Median age of patients was 6 months. Twenty-two infants were "symptomatic" with known or suspected cause, and seven were cryptogenic (two normal). Of 15 infants randomized to ACTH, 13 responded by EEG and clinical criteria (86.6%); Seizures stopped in an additional infant, but EEG remained hypsarrhythmic (considered a failure). Four of the 14 patients given prednisone responded (28.6%,, with complete clinical-EEG correlation), significantly less than with ACTH, (chi2 test).

Conclusions

Using a prospective, randomized approach, a 2-week course of high-dose ACTH is superior to 2 weeks of prednsone for treatment of IS, as assessed by both clinical and EEG criteria.