Abstracts

Rationale: Infantile spasms (IS), a catastrophic, age-dependent epilepsy, are provoked by numerous etiologies and are abolished by high doses of ACTH. However, how these many etiologies induce the spasms, and why IS respond to the stress hormone ACTH is unclear. We previously found that children with IS have abnormal stress-hormoned levels in CSF (Baram et al., 1992, 1995), and that in rodents, ACTH suppressed brain levels of the stress hormone CRH (Brunson et al.,2001). CRH expression is increased in several brain regions by severe stress, and induces seizures in immature rodents (Baram and Hatalski, 1998). Taken together, these finding predict that early life stress (perhaps a common denominator of developmental problems associated with IS) will increase brain excitability and result in spontaneous IS via CRH-mediated mechanisms. Methods: To test this hypothesis, we induced chronic stress in neonatal rats on postnatal (P) day 2-9, using a simulated poverty paradigm (limiting maternal nesting material; Brunson et al., 2005). Rats (n = 12) were implanted with hippocampal or amygdala electrodes on P11-15, and video-EEG obtained between days P14-P36. Unstressed, normally reared control rats (n = 5) underwent the same video-EEG procedures. Results: Abnormal flexion spasms, singly and in clusters, were observed in 5/12 stressed rats and in none of the controls. These commenced on postnatal day 16 and disappeared by day 35. One additional stressed rat developed two limbic seizures that generalized. EEG correlates of the spontaneous flexion spasms were obscured by cable artefact (in 3), and consisted of a spike followed by voltage attenuation (in 2). Additional abnormal myoclonic events, associated with spike / attenuation on EEG, were noted throughout the recording period in 6/12 rats. Conclusions: EEG in otherwise normal rats. These finding support the idea that a common denominator of the many IS etiologies is activation of the brain s stress system, and increased expression and release of CRH, an excitatory neuropeptide that causes seizures. In this scenario, the mechanism of action of ACTH in ameliorating IS, includes suppression of CRH expression, as shown in rodents (Brunson et al., 2001). Stress-induced spontaneous spasms in infant rats reproduces many of the features of idiopathic/ cryptogenic infantile spasms and should provide a useful model for mechanistic and therapeutic studies. Supported by NIH NS 28912 and a gift from Questcor.