Abstracts

IS (infantile spasms) are an age specific epileptic disorder characterized by recurrent spasms, arrest or regression of psychomotor development and specific ictal and interictal EEG patterns. Children with IS are recognized to have a very poor long-term prognosis even when treated with the currently best available drugs (ACTH and vigabatrin). Because IS have such debilitating effects, it is important to develop innovative treatments to stop the seizures and the developmental regression. This will require the identification of a model system to study the pathophysiological mechanisms. The goal of this study is to create a rat model of IS., Rat pups were injected with a combination of doxorubicin (DOX, in the right lateral venticle) and lipopolysaccharide (LPS, into the right, central-parietal, forebrain region) at postnatal day (P) 3, followed by an i.p. injection of p-chlorophenylalanine (PCPA) at P5. LPS and DOX were given to induce diffuse damage to cortical and subcortical structures including white matter, whereas PCPA was given to reduce brain serotonin levels. The behaviors of the pups were then video-monitored once a day for 45 minutes from P5-12. EEGs were recorded from the left hippocampus in 3 additional pups that developed spasms. A separate group of experimental and non-injected control pups underwent behavioral testing to assess surface righting, open field activity and negative geotaxis., Recurrent seizures resembling spasms were first observed at P7 in 60% and at P9 in 70% of the pups (n=10). The spasms were characterized by the abrupt onset of flexion of the trunk with extension of the limbs at the height of the spasm. In two pups, extension spasms were also observed. Four pups with spasms survived to P12. No spasms were observed at this age. Two of these pups developed limbic seizures upon cessation of the spasms. The three pups that did not develop spasms died by P9. The EEG recorded in pups with spasms showed ictal discharges that were time-locked with the spasms. The ictal discharges were characterized by a high amplitude, slow sharp wave with overriding fast polyspike activity that resembled an electrodecremental response seen in humans with IS. Experimental pups had a worse performance in all three behavioral tests compared to controls (two-way ANOVA, p[lt]0.05). In the open field and negative geotaxis assessments, the differences between the groups were greater after P7 at the time of maximal expression of the spasms (p[lt]0.05)., These preliminary results indicate that we may have developed the first chronic animal model of symptomatic IS. Further development, characterization and validation of the model will lead to better strategies to treat this catastrophic condition.,