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Infantile spasms: hypothesis-driven therapy and pilot human infant experiments using corticotropin-releasing hormone
T Z Baram1, W G Mitchell, K Brunson
1Department of Anatomy/Neurobiology, University of California at Irvine, CA 92697-4475, USA. tallie@uci.edu
Insights
Alpha-helical CRH, a peptide, did not effectively treat infantile spasms (IS) because it cannot cross the blood-brain barrier. Further research with nonpeptide compounds is needed to block central CRH receptors for potential IS treatment.
Area of Science:
- Neuroendocrinology
- Pediatric Neurology
- Pharmacology
Background:
- Infantile spasms (IS) are a severe infant seizure disorder often leading to mental retardation.
- Current treatments like ACTH have significant side effects, necessitating novel therapeutic approaches.
- The corticotropin-releasing hormone (CRH) system is implicated in IS pathogenesis, suggesting CRH receptor blockade as a potential treatment.
Purpose of the Study:
- To evaluate the safety and efficacy of alpha-helical CRH, a CRH receptor antagonist, in infants with IS.
- To investigate the effects of peripheral CRH receptor blockade on autonomic and biochemical parameters.
- To determine if CRH receptor blockade can ameliorate IS and associated cognitive deficits.
Main Methods:
- A Phase I trial administering alpha-helical CRH to 6 infants with IS who failed conventional therapy.
- Monitoring of autonomic parameters (blood pressure, pulse, temperature, respiration).
- Assessing effects on ACTH, cortisol, electrolytes, and glucose; clinical diaries and video EEG used for efficacy evaluation.
Main Results:
- Alpha-helical CRH did not alter autonomic or biochemical parameters.
- Transient reduction in plasma ACTH and cortisol indicated peripheral CRH receptor blockade.
- No central effects were observed, suggesting the peptide did not cross the blood-brain barrier; resistance to repeat infusion noted.
Conclusions:
- Peptide CRH analogs do not effectively cross the blood-brain barrier to impact central CRH receptors.
- Peripheral effects on stress hormones are transient and benign.
- Nonpeptide compounds capable of CNS penetration are required to test the hypothesis of CRH receptor blockade for IS treatment.
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.