Claire M. Lathers

Autonomic Dysfunction in Epilepsy: Characterization of Autonomic Cardiac Neural Discharge Associated with Pentylenetetrazol‐Induced Epileptogenic Activity

Summary: The purpose of this study was to determine if epileptogenic activity is associated with changes in autonomic cardiac neural discharge and the development of arrhythmias. Nine cats, anesthetized with a‐chloralose, received pentylenetetrazol (PTZ), 10, 20, 50, 100, 200, and 2,000 mg/kg, intravenously at 10 min intervals. The following were monitored: neural discharge from 1 to 3 postganglionic cardiac sympathetic branches (8 cats, 17 nerves) and the vagus (7 cats, 8 nerves); the electrocorticogram; blood pressure; heart rate; and lead 11 electrocardiogram. Autonomic dysfunction was manifested by: the observation that autonomic cardiac nerves did not always respond in a predictable manner to changes in blood pressure; the development of a marked increase in variability in mean autonomic cardiac sympathetic and parasympathetic neural discharge; and the fact that the very large increase in the variability of the discharge rate of parasympathetic nerves was seen after PTZ, 50 mg/kg, but did not develop until 100 mg/kg in sympathetic neural discharge. This autonomic imbalance was associated with both interictal and ictal epileptogenic activity. Almost invariably, interictal discharge occurred after PTZ, 10 mg/kg; with higher doses, the duration of ictal activity increased although interictal discharges were present. The altered cardiac autonomic neural discharge was associated with minimal epileptogenic activity in the form of interictal discharges and cardiac arrhythmias which may contribute to sudden unexplained death of the epileptic.

Synchronization of cardiac autonomic neural discharge with epileptogenic activity: the lockstep phenomenon

Autonomic dysfunction has been implicated in the sudden, unexplained deaths which account for 5-17% of mortality in persons with epilepsy. This study was designed to determine if epileptogenic activity is associated with changes in the pattern of autonomic cardiac neural discharge and the development of arrhythmias. Nine cats, anesthetized with alpha-chloralose, received pentylenetetrazol (PTZ) 10, 20, 50, 100, 200 and 2000 mg/kg, i.v. at 10 min intervals. Cardiac postganglionic sympathetic and vagal nerve discharges were correlated with the interictal spikes, brief ictal discharges (bilateral polyspikes less than 10 sec duration), and prolonged ictal discharges (polyspikes lasting greater than 10 sec). Cardiac sympathetic and vagal neural discharges were intermittently synchronized 1:1 with all 3 types of epileptogenic discharge, i.e., the lockstep phenomenon (LSP); at other times the relationship was almost 1:1 LSP was not present during control and did not always persist for the entire interval after each PTZ dose. Five of 8 cats showed LSP in the cardiac sympathetic neural discharge associated with interictal spikes induced by 10 mg/kg PTZ; 3 others exhibited LSP with interictal spikes seen subsequent to ictal discharges. The incidence of LSP was less often associated with cardiac vagal neural discharge (2 of 7 cats). Premature ventricular contractions were sometimes associated with LSP. Abnormal cardiac sympathetic and vagal neural discharge and cardiac arrhythmias were thus associated with subconvulsant (interictal) activity. Therefore, the LSP may be a factor in the mechanism of unexplained death in persons with epilepsy who exhibited no overt seizure activity at the time of demise.

Paroxysmal autonomie dysfunction, epileptogenic activity and sudden death

Abstract Transient abnormalities of autonomie nervous system function are observed during almost every generalized tonic-clonic seizure and include disruptions in blood pressure, cardiac arrhythmias and apnea. An increasing body of literature indicates that epileptogenic discharges, even without accompanying clinical seizure activity, can produce a spectrum of autonomie abnormalities. Marked changes in blood pressure and cardiac rhythm occur in patients paralyzed with neuromuscular blocking agents and subjected to electrical shock or intravenous pentylenetetrazol. Similar changes are observed in patients with focal temporal lobe discharges. There is also experimental evidence suggesting that in addition to the well known effects of generalized seizure discharges, interietai discharges can produce effects upon the cardiovascular system. Neurogenic pulmonary edema may be another autonomie dysfunction associated with seizures. The phenomenon of unexplained sudden death in persons with epilepsy, which accounts for up to 15% of mortality in this group, may be a result of some unexplained irreversible disruption of autonomie homeostasis in the face of all these forces of electrical disorganization. Paradoxically, some persons manifest cardiovascular autonomie dysfunction with consequent seizures which are phenomenologically very similar to those of cerebral origin. It is important to consider performing Holter monitoring in patients with epilepsy of unknown cause and 24 h ambulatory electroencephalograms in patients with unexplained cardiac arrhythmias.

Cardiac neural discharge and epileptogenic activity in the cat: An animal model for unexplained death

This study developed an animal model to explore the hypothesis that altered autonomic function may be one cause for unexplained sudden epileptic deaths. After alpha-chloralose anesthesia, 9 cats received a tracheostomy and a thoracotomy. Intravenous gallamine was used to paralyze the cats. Blood pressure, arterial blood gases, electrocardiogram, and rectal temperature were monitored. Simultaneous monitoring of the neural discharge in postganglionic cardiac sympathetic branches and the vagus nerve was combined with a bilateral craniectomy and electrocorticography. Pentylenetetrazol was given intravenously at 10 min intervals in 10, 20, 50, 100, 200, and 2000 mg/kg doses. Epileptiform discharges were categorized as a prolonged ictal (duration of 10 sec or more), brief ictal (duration of less than 10 sec mixed with suppression), and interictal spike activity. The two types of ictal activity were quantified by duration in seconds for the 10 min interval after each dose of pentylenetetrazol; the number of interictal spikes/min was determined for each minute of the entire experiment. This study developed a model which quantified the degree of epileptiform activity and correlated it with changes in cardiovascular function and autonomic cardiac neural discharge. An imbalance within and between sympathetic and parasympathetic cardiac neural discharges was found, as was a significant disruption of the physiological relationships between heart rate and blood pressure. Frequent and varied electrocardiogram abnormalities occurred. All of the above changes occurred during minimal (interictal) subconvulsant as well as during maximal (ictal) convulsant epileptogenic activity.

Review of Autonomic Dysfunction, Cardiac Arrhythmias, and Epileptogenic Activity

Similarities in autonomic dysfunction associated with arrhythmias and death in animal models for digitalis toxicity, myocardial infarction, psychotropic toxicity, and epileptogenic activity are reviewed. When intravenous (IV) pentylenetetrazol was given to anesthetized cats, autonomic dysfunction was associated with both interictal and ictal epileptogenic activity. The autonomic dysfunction was manifested by the fact that autonomic cardiac nerves did not always respond in a predictable manner to changes in blood pressure, the development of a marked increase in variability in mean autonomic cardiac nerve discharge, and the appearance of a very large increase in the variability of the discharge rate of parasympathetic nerves first and then secondly in sympathetic discharge. The altered autonomic cardiac nerve discharge was associated with interictal epileptogenic activity and arrhythmia, which may contribute to sudden unexplained death in patients with epilepsy. Since phenobarbital (20 mg/kg, IV 60 min prior to pentylenetetrazol) exhibited anticonvulsant, but not antiarrhythmic and neural depressant activity, phenobarbital does not appear to be the ideal agent to prevent the autonomic dysfunction associated with epileptogenic activity in this animal model.

Cocaine-induced seizures, arrhythmias and sudden death

T he earliest cocaine use has been dated to AD 600, as suggested by the presence of coca leaves in the tombs of Indian mummies.1 Unfortunately, cocaine use has become even more predominant in modern society. Of the estimated 22 to 30 million Americans who have used cocaine, about 5 million individuals use it regularly.2 The rising increase in cocaine abuse may be attributed partly to the widespread misconception that cocaine is a benign, nonaddicting substance.3 In addition, most of the information published on cocaine effects is limited. Until recently, documented reports on the systemic effects of cocaine have been sparse, anecdotal, and often controversial.4-6 It is known, nevertheless, that cocaine has the potential to precipitate life-threatening cardiac events.2 Thus, although the pathogenesis of cardiotoxicity of cocaine is not well defined,2 reported data have associated cocaine use with tachycardia, systemic hypertension, ventricular arrhythmia, acute myocardial infarction, seizures, and sudden death.7-9

Intraosseous diazepam suppression of pentylenetetrazol-induced epileptogenic activity in pigs

Intravenous access for the administration of antiepileptic drugs can be both time-consuming and difficult in an actively seizing infant. We conducted a study to examine the intraosseous route as an alternate means of vascular access for the administration of diazepam in a pentylenetetrazol-seizure model in pigs. Epileptogenic activity was induced with pentylenetetrazol 100 mg/kg in 15 domestic swine that had undergone craniotomies for electrocortical recording. Diazepam (0.1 mg/kg) was administered IV (n = 5) or intraosseously (n = 5); control animals received no drug (n = 5). Epileptogenic activity was suppressed below control levels within one minute in the IV group and within two minutes in the intraosseous group. A two-way analysis of variance did not show a significant difference between the IV and intraosseous routes; however, both were significantly different when compared to the control. There also was no significant difference in plasma diazepam levels between the two groups at one, two, five, ten, 15, and 20 minutes. Our study demonstrated that the intraosseous route is a rapid and effective alternative for diazepam administration.

Regional distribution of myocardial β-adrenoceptors in the cat

Abstract The purpose of this study was to delineate the distribution of β-adrenoceptor density in the cat heart, with an emphasis on areas within the left ventricle. β-Adrenoceptor densities, determined for hearts obtained from five cats, were not significantly different in the left and rights atria, i.e. 47.6 ± 7.2 and 32.8 ± 7.5 fmol/mg protein, respectively. β-Adrenoceptor densities for the septum and right ventricle were 105.4 ± 15.0 and 65.0 ± 14.0 fmol/mg protein, respectively. The β-adrenoceptor density for the proximal distribution of the left anterior descending artery LV1, distal distribution of the left anterior descending artery LV2 and posterior wall of the left ventricle LV3 were: 81.3 ± 11.5, 145.1 ± 20.8 and 165.4 ± 35.8 fmol/mg protein, respectively. Thus, the distribution of the β-adrenoceptor densities was greatest in the apex of the left ventricle. The data suggest that there are regional differences in the β-adrenoceptor densities among the areas of the heart and within the left ventricle. These differences may be related to functional differences.

Neural mechanisms in cardiac arrhythmias associated with epileptogenic activity: The effect of phenobarbital in the cat

Sudden unexplained death accounts for 5-17% of mortality in epileptic persons; autonomic dysfunction is thought to be a contributing factor. This paper describes the effect of phenobarbital (PB) pretreatment (20 mg/kg, i.v.) one hour prior to pentylenetetrazol (PTZ) 10, 20, 50, 100, 200, and 2000 mg/kg, i.v. given at ten minute intervals on autonomic parameters in the cat. PB depressed heart rate, blood pressure, and postganglionic cardiac sympathetic neural discharge, but did not significantly alter vagal discharge. PB shifted the peak duration of interictal activity from a lower to a higher dose of PTZ without affecting the average duration across doses. PB also significantly diminished the increases in heart rate and blood pressure induced by PTZ but altered neither the occurrence of arrhythmias nor the changes in cardiac autonomic neural discharge. Thus, PB appears to prevent only some forms of autonomic dysfunction associated with epileptogenic activity in this model.

Psychoactive Agents, Seizure Production, and Sudden Death in Epilepsy

Major tranquilizers as well as antidepressant agents have been associated with clinical seizures in patients administered these agents. The incidence of such seizures is generally low when these drugs are administered in therapeutic doses. However, administration of large doses of these agents has been associated with many cases of convulsion production. The effects that these drugs have on animal models of epilepsy have been examined. It appears that the phenothiazines act as convulsant agents at lower doses, whereas, at higher doses, they act as anticonvulsant drugs. Antidepressants, on the other hand, appear to exert an anticonvulsant effect at low doses and convulsant effects at high doses. The mechanism by which these agents alter the seizure threshold is not yet known. Clinically, drugs of lower seizure production potential should be substituted for those drugs with greater potential in treating epileptic patients for psychiatric ailments. The problem of sudden death in epileptic patients is one that must be confronted. Sudden death has most frequently been attributed to autonomic dysfunction and cardiac arrhythmia in these patients. The contribution of stress in sudden death production also must be taken into account. In addition, some psychoactive agents have been associated with sudden death as well as cardiac arrhythmia and seizure production. Thus, in light of the possible additivity of the factors involved in the production of sudden death, the administration of a psychoactive agent to an epileptic patient should be approached with caution. Those agents that do not alter cardiac rhythm or seizure threshold should be administered if a psychoactive agent is deemed necessary for the management of psychiatric illness in the epileptic patient.