Autonomic consequences of kainic acid–induced limbic cortical seizures in rats: Peripheral autonomic nerve activity, acute cardiovascular changes, and death

Abstract

SUMMARYPurpose: Autonomic consequences of seizures are common, but can be severe. We sought to define changes in autonomic activity from limbic cortical seizures and their impact on the heart. Methods: We studied kainic acid (KA)-induced seizures in urethane-anesthetized rats using peripheral nerve, blood pressure (BP), and ECG recordings and echocardiography. Results: Seizures were associated with massive increases in parasympathetic (vagus nerves) and sympathetic (cervical sympathetic ganglion >renal nerve >splanchnic nerve) activity. Seizureassociated activity increases were greater than activity changes induced by nitroprusside or phenylephrine (each producing BP changes of >50 mmHg). Increases in c-fos expression were found in both sympathetic and parasympathetic medullary regions (as well as hypothalamic areas). Baroreceptor reflex function (tested with nitroprusside and phenylephrine) was impaired during seizures. Finally, a significant fraction of the animals died and the mechanism of death was defined through ECG, BP, and echocardiographic measures to be profound cardiac dilatation and bradyarrhythmia leading to hypoperfusion of the brain and ultimately hypoperfusion of the heart. Cardiovascular changes occur within seconds (or less) of autonomic nerve activity changes and death by these mechanisms takes minutes. Discussion: We propose that the massive parasympathetic and sympathetic outflow that occurs during a seizure gets compounded by respiratory distress (driving both autonomic nervous system divisions in the same direction) causing mechanical dysfunction, slowing the heart, and hypoperfusing the brain. KEY WORDS: Autonomic nervous system, Limbic cortex, Cardiac arrhythmia, Cardiac dilatation.Seizure-induced autonomic dysfunction can have serious clinical consequences (Devinsky, 2004; Goodman et al., 2008). Focal simple partial seizures may produce flushing, sweating, and piloerection (Baumgartner et al., 2001), while complex partial seizures produce a broader spectrum of autonomic signs, including changes in heart rate and rhythm, blood pressure, gastrointestinal moti- (Wilder-Smith, 1992;Lathers et al., 1998;Locatelli et al., 1999;Nei et al., 2000;Baumgartner et al., 2001). Generalized tonic-clonic seizures may be associated with severe increases in blood pressure and changes in heart rate and conduction, such as complete nodal block (Schraeder & Lathers, 1989). In some individuals, however, seizures may trigger more ominous autonomic derangements such as marked bradycardia or asystole (Smith-Demps & Jagoda, 1998;Cheung & Hachinski, 2000;Mameli et al., 2001). The causes of death in epilepsy are suspected to involve cardiovascular or respiratory dysfunction provoked by seizures (Liedholm & Gudjonsson, 1992;Smith-Demps & Jagoda, 1998;Cheung & Hachinski, 2000;Langan, 2000;Mameli et al., 2001;Tinuper et al., 2001). 983 Autonomic Consequences of Limbic Seizures in RatsAnimal experimentation has replicated features of human epilepsy and autonomic dysfunction (reviewed in (Lathers & Schraeder, 2006))....

Cardiac Repolarization Indices in Epilepsy Patients

“…Left insular cortex stimulation in rats caused degrees of heart block [27], resembling findings from an intraoperative study of epilepsy surgery patients [28, 29]. In our own model, arrhythmias during kainic acid-induced limbic cortical seizures were episodes of bradyarrhythmia [30]. The mechanism of death in our animals that displayed either discrete limbic seizures or periods of limbic status epilepticus was a seizure-driven episode of autonomic overactivity that must be compounded by a condition of respiratory distress to ensure death.…”

Progressive development of cardiomyopathy following altered autonomic activity in status epilepticus

“…A 2008 study by Sakamoto et al (62) indicated that seizure induction by KA administration in a rat decreased ejection fraction and increased left ventricular diastolic diameter; however, the study did not deliver any information on incidence, extent, or time course of left ventricular dysfunction. Elevated sympathetic stimulation and catecholamine levels have been reported to produce left ventricular dilation, elevated enddiastolic pressure, decreased wall thickness, and reduced ejection fraction (30).…”

“…In contrast to earlier studies (3,4,38,46,47,62), this investigation used implantable transmitters in con-scious (nonanesthetized) animals to simultaneously assess cardiac function and encephalographic activity during and following seizure activity. Using an adaptation of a previously validated protocol of excitotoxic seizure induction (73), intrahippocampal KA administration was employed to produce seizures while excluding any direct systemic effects of the excitotoxin.…”

Inhibition of microglial activation with minocycline at the intrathecal level attenuates sympathoexcitatory and proarrhythmogenic changes in rats with chronic temporal lobe epilepsy

“…Cardiovascular autonomic dysfunction with profound arrhythmogenic effects, including prolongation of QT interval, QT dispersion, "T"-wave inversion, and tachycardia or bradycardia, are major risks for SUDEP in humans and animals with spontaneous recurrent seizures (Opherk et al, 2002;Sakamoto et al, 2008;Metcalf et al, 2009;Brotherstone et al, 2010;Powell et al, 2014b;Eastaugh et al, 2015;Lamberts et al, 2015). Activated microglia are present in post-SE rats (Shapiro et al, 2008), and during chronic periods of epilepsy in humans (Beach et al, 1995) and animals (Shapiro et al, 2008).…”