Pathophysiology of massive infantile spasms: perspective on the putative role of the brain adrenal axis

Abstract

Massive infantile spasms are an age-specific seizure syndrome of infancy. Uniquely, the spasms respond to hormonal manipulation using adrenocorticotropic hormone (ACTH) or glucocorticoids. A hypothesis explaining the efficacy of hormonal therapy, age-specificity, multiple causative factors, and spontaneous resolution of infantile spasms is presented. Corticotropin-releasing hormone (CRH), an excitant neuropeptide suppressed by ACTH/steroids, is implicated. Evidence for the age-specific convulsant properties of CRH is presented, and a putative scenario in which a stress-induced enhancement of endogenous CRH-mediated seizures is discussed. Clinical testing of the CRH-excess theory and its therapeutic implications are suggested.

Fig 1

Schematic of the interactions among the components of the corticotropin-releasing hormone-adrenocorticotropic hormone-glucocorticoid loop. Arrows denote increased synthesis and secretion. Blunt-ended lines denote a suppression of synthesis, release, or both. Broken line implies a putative effect.

Fig 2

Graphic illustration of the ontogeny of corticotropin-releasing hormone mRNA (CRH-mRNA) in the hypothalamic paraventricular nucleus in the rat (from {34}). Superimposed is a quantitative analysis of the ontogeny of CRH receptors in rat brain (from {35}, with permission). The top panel demonstrates the observed data. The bottom panel shows the hypothetical effect of stress during late gestation on CRH-mRNA. Birth occurs on the 21st day of gestation. Shaded area = unoccupied CRH receptors.