Abstracts

Rationale: Infantile spasms belong to the group of childhood catastrophic epilepsies characterized by (1) the early onset, mostly between 3-12 months of postnatal development, (2) clusters of spasms, (3) interictal EEG hypsarrhythmia, and (4) mental retardation. While the mechanisms underlying infantile spasms still remain poorly understood, responsiveness of this disorder to adrenocorticotropic hormone (ACTH) treatment indicates involvement of the hypothalamic-pituitary-adrenal (HPA) axis in the pathophysiology. We have developed a two-hit model of cryptogenic infantile spasms (Velisek et al., Ann. Neurol., 2007, 61(2):109-119) consisting of prenatal derangement of the HPA axis using betamethasone exposure and postnatal trigger of the spasms with N-methyl-D-aspartic acid (NMDA). The spasms in our model respond to the ACTH treatment. Here we determined whether some other agents used in the treatment of infantile spasms are also effective in the model. Methods: Pregnant Sprague-Dawley dams were exposed to betamethasone (2x 0.4 mg/kg on G15) or saline (as a control) ip injections. The offspring were subjected to NMDA (15 mg/kg ip) on P15 to induce the flexion spasms. We tested the following drugs: (1) Vigabatrin in two different doses: 100 mg/kg and 250 mg/kg i.p. administered 24 hours prior to NMDA trigger. (2) Rapamycin, which is a newly used drug to treat infantile spasms associated with the tuberous sclerosis complex. We studied the effects of rapamycin in a dose of 3 mg/kg i.p. using three different treatment paradigms: Long-term treatment included (1) 8 times (P7-P14) daily injections of rapamycin, and (2) a single injection of rapamycin 24 hours prior to the NMDA trigger, and (3) acute injection of rapamycin 4 hours prior to NMDA seizure testing. Results: Vigabatrin significantly increased the latency to the onset of spasms in the dose of 250 mg/kg. The dose of 100 mg/kg did not affect the development of NMDA-induced spasms. Rapamycin pretreatment significantly decreased the body weight (except the 4-hour paradigm). However, none of the treatments with rapamycin modified the development of NMDA spasms. Conclusions: Efficacy of vigabatrin against the spasms in our double-hit model further supports the validity of the model. Refractoriness of NMDA spasms to the rapamycin treatment suggests that our model corresponds to the cryptogenic spasms since rapamycin treatment may be beneficial only in patients with the diagnosed structural changes (i.e. in symptomatic infantile spasms) such as the presence of tuberous sclerosis.