Abstracts

Rationale: The risk of sudden unexpected death is a significant burden for people with epilepsy, particularly those who experience drug-resistant tonic clonic seizures. There is a pressing need to model the condition in animals in order to understand the mechanism that underlies the fatal episode, the predisposing factors and potential triggers. The tetanus neurotoxin (TeNT) model of epilepsy in rats develops clusters of randomly occurring seizures over periods of several weeks, without causing status epilepticus at any stage. Using this model we reported last year that seizures were associated with arrhythmias and long lasting postictal tachycardia. Here we present a more detailed analysis of the ECG.Methods: Rats were implanted under isoflurane anaesthesia with Telemetry Research dual biopotential radiotelemeters to record ECG and ECoG (Millar Inc, TX). 2-3 weeks after initial surgery TeNT (2.5 ng in 1 μl) was injected into right ventral hippocampus through a guide cannula. Controls received vehicle solution only. Continuous recordings were made for up to 6 weeks from rats co-housed with non-epileptic buddies. Data were recorded and analyzed using Spike2 software and a Power 1401 signal acquisition system (Cambridge Electronic Design, UK); some analyses also used Matlab routines.Results: Seizures started after 2-7 days, typically lasted 0.5-3.0 minutes and recurred at <15 per day (average incidence ranges from 1 to 11 per day in different rats). Seizures were characterized by periods of cardiac arrhythmia, which sometimes recurred during the postictal period, and also prolonged postictal tachycardias lasting up to 1 hour (typically 8-10 min). Ictal arrhythmias were more prevalent during secondarily generalized Racine 4 and 5 seizures. Ictal sinus bradycardias were more prevalent during non-convulsive seizures. Over the course of the seizure syndrome interictal QT interval increased to 78.5 ± 1.5 ms from 69.8 ± 1.1 ms measured in the same rats before induction of epilepsy. The increase often was associated with changes in the shape of the T component of the ECG waveform (e.g. increased amplitude, inversion and/or duration). During each seizure QT increased further, when the heart was in sinus rhythm between periods of arrhythmia, and this increase could persist for several minutes into the postictal period.Conclusions: The data suggest that the TeNT model undergoes progressive development of neurally-induced pathophysiological changes in the heart. The ictal and postictal increased QT and arrhythmias are consistent with previous reports of centrally-evoked sympathetically-mediated changes long recognized in the physiological literature (e.g. Porter et al, 1962, Am. J. Heart, 64: 815-9; Hockman et al, 1966, Am. J. Heart, 71, 695-700). Cardiac repolarization dysfunction during progression of epilepsy may predispose to development of fatal arrhythmias. Supported by Epilepsy Research UK.