Abstracts

Rationale: Previous animal models of chemoconvulsant-induced status epilepticus have demonstrated age-specific developmental changes in behavioral correlates of seizure activity and subsequent neuronal damage. However, because of technical challenges obtaining EEG recordings in pre-weaned animals, our knowledge of electrical activity during chemoconvulsant-induced status epilepticus in pups younger than postnatal day 12 (P12) is limited. We examined the electrographic seizure activity and resultant acute neuronal damage in two different models of chemoconvulsant-induced status epilepticus. Methods: Sprague Dawley rat pups were implanted with a miniature wireless telemetry device, and status epilepticus was induced at 7, 14, or 21 days of age with either lithium-pilocarpine (LiPC) or diisopropylfluorophosphate (DFP). For LiPC treatment, rats were given an intraperitoneal injection of pilocarpine (50 mg/kg) with pretreatment of LiCl (127 mg/kg). For DFP treatment, rats received 0.026 mg/kg pyridostigmine bromide (i.p.) and following 30 min, 4.5 mg/kg DFP (s.c.). One min after DFP delivery, 0.2mg/kg atropine sulfate was administered (i.p). Status epilepticus was monitored for at least 4 h with continuous video-EEG recordings. After 24 h, brain tissue was examined with Fluoro-Jade B, a marker for degenerating neurons. Results: LiPC provoked prolonged seizure activity that could be observed by both electrographic recording and clinical behavior. At P7, discontinuous, rhythmic polyspike and sharp-wave activity was observed. At P14 and P21, the seizure activity was larger in amplitude with sustained spike-and-wave activity, similar to activity in adult rats. In DFP-treated rats, electrographic seizure activity appeared less severe, compared to age-matched LiPC-treated rats. In LiPC-treated rats at P7, behavioral correlates of seizures consisted of myoclonic jerks, single-limb clonus, and behavioral arrest. In older rats, rearing with loss of posture (Racine scale 4-5) consistently correlated with initiation of electrographic activity. By contrast, DFP-treated rats had myoclonic jerks and tonic stiffening, but also whole-body tremors and head bobbing that poorly correlated with electrographic recordings. Rarely did these rats progress to clear tonic-clonic (Racine scale 3-5) activity. Histological studies with Fluoro-Jade B showed more neurodegeneration with older ages in both treatment groups, although the most neuronal damage was seen in LiPC-treated rats. Conclusions: Both LiPC- and DFP-induced status epileticus results in age-specific patterns of acute seizure activity and neuronal degeneration, which increases in severity as a function of age. In terms of seizure amplitude, duration, behavioral correlates, and neuronal damage, DFP caused less robust seizure activity and brain damage compared to LiPC at all ages. Neuronal degeneration in DFP-treated rats was more closely correlated with electrographic seizure activity than with behavioral measures, thus confirming the importance of EEG monitoring compared to analyses of behavior alone.