Acute and chronic autonomic and cardiac consequences of epileptic seizures in a rat model.

Abstract

The effects of seizures on the autonomic nervous system can be severe. Cardiac consequences of seizures in epileptic patients range from mild sinus arrhythmias and repolarization abnormalities to life-threatening conditions such as cardiac asystole. Previous work from our laboratory has shown that urethane anesthetized rats experience dramatic increases in sympathetic and parasympathetic nervous system activity during kainic acid-induced seizures, before seizure-related death. Our studies in rats, consistent with other studies in sheep and cats, showed that autonomic activity driven acutely by seizures can be compounded by hypoxemia to cause severe bradycardia and death. However, published findings on chronic cardiac damage from seizures in rats suggest that epileptic hearts undergo changes that make them more susceptible to ventricular fibrillation (VF), and data from humans suggests that epilepsy is a risk factor for VF. I sought to define acute specific patterns of autonomic over-activation during seizures and test the hypothesis that chronic autonomic and cardiac changes associated with epilepsy alter susceptibility to VF.

I addressed this hypothesis with three aims: 1) Establish whether acute seizures in rats produce stereotypical changes in autonomic activity and heart rate. 2) Evaluate which specific pattern(s) of autonomic activation and hypoxemia can produce VF in normal rats. 3) Evaluate whether recurrent seizures produce changes in autonomic function, cardiac conduction, and left ventricular morphology that affect the susceptibility of epileptic rats to an autonomic/hypoxemia-induced VF.

I found that: 1) Acute seizures produced increases in cervical sympathetic and vagus nerve activity that were associated with increases or decreases in heart rate. Activity in both divisions of the autonomic nervous system increased during seizures as compared to baseline. Tachycardia or bradycardia depended on the changes in sympathetic and parasympathetic activity relative to each other. Seizures that caused a drastic reduction in heart rate led to cessation of seizure activity and dramatic decreases in autonomic activity. The persistence of sympathetic activity during this vulnerable period was necessary to prevent seizure-induced death. 2) Sympathetic derangements could be manipulated in normal rats with beta-adrenergic agonists/antagonists, and parasympathetic activity could be precisely controlled in timing and magnitude with bilateral vagotomy with/without vagus nerve stimulation. Dead space tubing applied over an endotracheal tube allowed for control of hypoxemia. In manipulating this triad of variables, I found that I could induce spontaneous entry into VF, but only with bilateral vagotomy, high-dose systemic isoproterenol, and moderately severe hypoxemia. 3) The chronic epilepsy state in rats was associated with increased sympathetic and decreased parasympathetic tone in heart rate variability analyses, abnormal cardiac repolarization in QT dispersion measurements, and eccentric hypertrophy in histological studies. While systolic dysfunction by echocardiography was observed in this state after acute seizures, the left ventricular changes were found to be protective against autonomic/hypoxemia-induced ventricular fibrillation, as higher doses of isoproterenol were necessary to induce VF in epileptics as compared to age-matched controls.

These data show that autonomic derangements are evident during most seizures, but spontaneous entry in VF was never observed in relation to seizure activity. Whereas we identified a specific pattern of autonomic activation and hypoxemia to evoke VF, the precise combination of autonomic derangements and hypoxemia to induce VF are even more difficult to attain in epileptic animals. The data are consistent with our original findings that rats die of seizures through severe bradycardia.