Paul Schraeder

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.

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.

Stress and sudden death

Cardiac patients, psychiatric patients, and certain ethnic groups experiencing acute stressful circumstances are at risk for unexpected sudden death. Although stress is associated with changes in autonomic neural function, its role as a potential risk factor for sudden unexpected death in epilepsy (SUDEP) is not known. The association of epilepsy with cardiac abnormalities, such as neurogenic arrhythmias and microscopic perivascular and interstitial fibrosis, and with depression and anxiety indicates that emotional stress should be evaluated as a potential risk factor for SUDEP. The impact of adverse emotional states on the autonomic control of cardiac rhythm is a known important factor leading to cardiac dysrhythmias in humans and other species. The interaction between emotional factors and the arrythmogenic potential of epileptiform discharges and the possibility of benefit from stress management intervention need to be investigated.

The mystery of sudden death: Mechanisms for risks

This review addresses the possible overlapping mechanisms that may apply to the risk of sudden unexpected death occurring in epilepsy and in cardiac disease. It explores the interaction between the central and peripheral autonomic nervous systems and the cardiopulmonary systems. Included is a discussion of the potential interactive role of genetically determined subtle cardiac risk factors for arrhythmias with a predisposition for seizure-related cardiac arrhythmias. We address the possible mechanisms that are operant in producing both epileptogenic and cardiogenic arrhythmias. Finally, we speculate about potential preventive measures to minimize the risk of both sudden unexpected death in epilepsy and sudden cardiac death.

Seizure Disorders Following Periodic Lateralized Epileptiform Discharges

Summary: We reviewed 3,436 EEGs and found 24 patients with periodic lateralized epileptiform discharges (PLEDS). The etiology was unknown in 7, cerebrovascular occlusion in 7, tumor in 3, intracerebral hematoma in 2, and subdural hematoma, neonatal asphyxia, electrolyte imbalance, subarachnoid hemorrhage, and hypoglycemia in each of the remaining cases. We were successful in contacting 18 patients and/or their families for follow‐up. Twenty of the 24 patients with PLEDS had seizures. Seven had focal motor alone, 10 had focal motor with secondary generalization, and 3 had generalized seizures without any observed focal features. Four patients had no seizures. Twelve patients had their first seizure at the time PLEDS were found. Fifteen adults and 3 infants were reevaluated. Only 1 adult was functionally independent. The 3 infants evidenced developmental delay. Six adults had seizures prior to the observation of PLEDS, and 5 (83%) of them reported seizures after hospitalization. Nine of the 15 adults had their first seizure associated with PLEDS, 6 of whom (67%) also reported seizures after hospitalization. In 9 patients with serial EEGs during their hospitalization, PLEDS disappeared within 22 days. We concluded that most patients with PLEDS and concomitant seizures continue having seizures after hospitalization and need antiepileptic medication.

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.

Coroner and medical examiner documentation of sudden unexplained deaths in epilepsy

BACKGROUND Prevalence data for sudden unexplained death in epilepsy (SUDEP) are hampered by its underuse as a final diagnosis on death certificates in appropriate cases. Few data exist about how coroners (COs) and medical examiners (MEs) in the United States use the diagnosis of SUDEP. METHODS A survey instrument that addressed demographics, professional background, annual cases of epilepsy, seizure history, percentage of post-mortem examinations, cause of death, and use of SUDEP as a diagnosis was sent to all COs and MEs in the United States. Unadjusted comparisons between categorical variables used chi2 tests. A multiple regression model examined the odds of respondents considering SUDEP to be a valid diagnosis. RESULTS Of 2995 surveys, 80.7% went to COs and 19.3% to MEs. The response rate was 15.9% for COs and 21.8% for MEs. Acknowledgment of SUDEP as a valid entity was greatest among pathologists (83.5%) versus other physicians and non-physicians (P< .001) and correlated with higher autopsy rates and seeing more cases of epilepsy. In actual practice, SUDEP was not used routinely as a death certificate diagnosis in most cases with no cause of death found at autopsy by any group in the survey regardless of title, educational background, location, autopsy rate, or number of seizure cases seen annually. CONCLUSIONS SUDEP appears to be an underused final diagnosis by COs and MEs throughout the United States. There is a need to educate officials at all levels about this diagnosis in persons who have epilepsy with no other cause of death.

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.

Effect of Phenobarbital Pretreatment on Cardiac Neural Discharge and Pentylenetetrazol-Induced Epileptogenic Activity in the Cat

The effect of phenobarbital on autonomic function associated with ictal discharges and interictal spikes (IS) was examined. Phenobarbital (20 mg/kg, i.v.) was infused over 10 min; 1 h later, pentylenetetrazol (PTZ) 10, 20, 50, 100, 200, and 2,000 mg/kg was given intravenously at 10-min intervals. 10 mg/kg PTZ produced IS in only 3 of 9 phenobarbital-pretreated cats; when used alone, 10 mg/kg of PTZ produced IS in 8 of 9 cats. Ictal discharges first appeared at 20 mg/kg PTZ in 6 of 9 phenobarbital-pretreated cats; all 9 cats receiving only PTZ exhibited ictal discharges after 20 mg/kg. Phenobarbital pretreatment depressed heart rate, blood pressure and postganglionic cardiac sympathetic neural discharge. Maximal ictal discharges in the cats pretreated with phenobarbital occurred with 100 mg/kg PTZ. This discharge was associated with a 10 mm Hg increase in blood pressure and a slight decrease in heart rate, followed by a subsequent return to baseline. The concurrent sympathetic neural discharge increased. When maximal ictal discharges occurred in the cats receiving PTZ alone, blood pressure, heart rate, and sympathetic neural discharge increased significantly. Cardiac vagal neural discharge was not altered after PTZ even in phenobarbital-pretreated cats. Although phenobarbital suppressed PTZ-induced epileptogenic activity and the associated changes in blood pressure and heart rate, a X2 test indicated no significant difference in the incidence of arrhythmias between the two groups. Since phenobarbital did not prevent the changes in cardiac neural discharge and the arrhythmias associated with epileptogenic activity, its effectiveness in decreasing autonomic dysfunction is questionable.