Abstracts

Rationale: The primary goal of this study was to evaluate the effectiveness of ACTH in abolishing epileptic spasms in the TTX animal model. Secondly, we hoped to provide insights into the role circulating corticosteroids play in spasm cessation by comparing the ACTH dose response relationships for spasm suppression to ACTH-induced corticosterone release from the adrenal glands. Methods: To induce spasms, TTX was chronically infused into the neocortex via osmotic mini pumps beginning on postnatal day 11 or 12.  ACTH dosages between 8 and 32 IU/kg/day were divided into 2 equal daily injections.  After weaning, animals were treated for 10 days at each dose.  A drug titration protocol was used and comparisons were made to injections of a vehicle gel. Video/EEG recordings (24/7) were used to monitor the drug’s effects on spasms and hypsarrhythmia.  Recordings were continuous for up to 2 months and TTX-infused control rats were monitored for the same period of time.  In separate experiments, the same dosages of ACTH were given to rats and 1 hour later plasma was collected and assayed for corticosterone. Results: ACTH was ineffective at dosages of 8 and 16 IU/kg/day but eliminated spasms in 66% of animals treated with 32 IU/kg/day.  In rats that had hypsarrhythmia during baseline recordings, ACTH eliminated this abnormal interictal EEG pattern in all rats that became seizure-free.  Plasma corticosterone levels increased linearly with increasing dosages of ACTH and this stood in sharp contrast to the sigmoid-like dose-response curve for decreases in spasm counts.   Conclusions: Results further validate the TTX model as relevant for the study of infantile spasms.  The model should also be useful for investigating how ACTH acts to eliminate seizures and hypsarrhythmia.  Dose response results suggest that either very high concentrations of circulating corticosteroids are required to abolish spasms or ACTH acts through a different mechanism. Funding: This work was funded by an Investigator Initiated Study Grant from Mallinckrodt Pharmaceuticals.  Our work on infantile spasms is also supported by The Infanttile Spasms Initiative of CURE and NINDS.