Infantile spasms: hypothesis-driven therapy and pilot human infant experiments using corticotropin-releasing hormone receptor antagonists

Abstract

Background and rationale: Infantile spasms (IS) are an age-specific seizure disorder occurring in 1:2,000 infants and associated with mental retardation in approximately 90% of affected individuals. The costs of IS in terms of loss of lifetime productivity and emotional and financial burdens on families are enormous. It is generally agreed that the seizures associated with IS respond poorly to most conventional anticonvulsants. In addition, in the majority of patients, a treatment course with high-dose corticotropin (ACTH) arrests the seizures completely within days, often without recurrence on discontinuation of the hormone. However, the severe side effects of ACTH require development of better treatments for IS. Based on the rapid, all-or-none and irreversible effects of ACTH and on the established physiological actions of this hormone, it was hypothesized that ACTH eliminated IS via an established neuroendocrine feedback mechanism involving suppression of the age-specific endogenous convulsant neuropeptide corticotropin-releasing hormone (CRH). Indeed, IS typically occur in the setting of injury or insult that activate the CNS stress system, of which CRH is a major component. CRH levels may be elevated in the IS brain, and the neuropeptide is known to cause seizures in infant rats, as well as neuronal death in brain regions involved in learning and memory. If 'excess' CRH is involved in the pathogenesis of IS, then blocking CRH receptors should eliminate both seizures and the excitotoxicity of CRH-receptor-rich neurons subserving learning and memory.

Patients and methods: With FDA approval, alpha-helical CRH, a competitive antagonist of the peptide, was given as a phase I trial to 6 infants with IS who have either failed conventional treatment or who have suffered a recurrence. The study was performed at the Clinical Research Center of the Childrens Hospital, Los Angeles. The effects of alpha-helical CRH on autonomic parameters (blood pressure, pulse, temperature, respiration) were determined. In addition, immediate and short-term effects on ACTH and cortisol and on electrolytes and glucose were examined. The potential efficacy of alpha-helical CRH for IS was studied, using clinical diaries and video EEG.

Results: alpha-Helical CRH, a peptide, did not alter autonomic or biochemical parameters. Blocking peripheral CRH receptors was evident from a transient reduction in plasma ACTH and cortisol. No evidence for the compound's penetration of the blood-brain barrier was found, since no central effects on arousal, activity or seizures and EEG patterns were observed. In addition, a striking resistance of the patients' plasma ACTH to the second infusion of alpha-helical CRH was noted.

Conclusions: Peptide analogs of CRH do not cross the blood-brain barrier, and their effects on peripheral stress hormones are transient and benign. Nonpeptide compouds that reach CNS receptors are required to test the hypothesis that blocking CRH receptors may ameliorate IS and its cognitive consequences.

Fig. 1

The stress-activated neuroendocrine CRH-ACTH-glucocorticoid axis. Stress-conveying signals rapidly activate immediate early genes in CRH-expressing neurons of the central nucleus of the amygdala (ACe) and in the hypothalamic paraventricular nucleus (PVN). Concurrent rapid CRH release from terminals of PVN neurons into the hypothalamic-pituitary-portal system induces ACTH and gluco-corticoid (cortisol) secretion from the pituitary and adrenal, respectively. Glucocorticoids exert a negative feedback on the PVN (directly and via the hippocampus), yet activate CRH gene expression in the amygdala, potentially promoting further CRH release in this region. Continuous and dashed arrows denote established or putative potentiating and inhibitory actions, respectively. Arrows do not imply monosynaptic connections.

Fig. 2

Plasma ACTH levels in 6 infants treated with α-helical CRH. Plasma samples were drawn from an existing intravenous line, minimizing stress to the infants. Pre1 and pre2 indicate levels prior to the first and second CRH antagonist infusions, respectively. Post1 and post2 show values after the infusions. While the expected reduction of ACTH plasma levels upon blocking of CRH receptors in the pituitary is evident after the first infusion, this reduction is absent after the second CRH antagonist administration. Following the second infusion, plasma ACTH levels are actually significantly higher (p = 0.03, paired t test).

Fig. 3

Plasma cortisol levels in 6 infants treated with α-helical CRH. Plasma samples were drawn from an existing intravenous line, minimizing stress to the infants. Pre1 and pre2 indicate levels prior to the first and second CRH antagonist infusion, respectively. Post1 and post2 show values after the infusions.