Summary:Purpose: The present study was conducted to determine the rate of sudden unexplained death in epilepsy (SUDEP) in a well-defined cohort of patients included in the lamotrigine (LTG) clinical development database.Methods: A panel of scientists experienced in the area of SUDEP was assembled and provided with case summaries on all deaths (n = 45) reported during the initial clinical development of LTG. The panel developed a set of criteria for classifying cases as SUDEP (definite or highly probable), possible SUDEP, or non-SUDEP. This classification algorithm was then applied to the LTG cases, and SUDEP rates were calculated using patient-years of exposure as the denominator.Results: At the time of the study, 4,700 patients (5,747 patient-years of exposure) were included in the worldwide LTG clinical trials database. In this ccihort, 45 deaths were reported.Eighteen were judged by the panel to be SUDEP, 6 were defined as possible SUDEP, 20 were judged to be due to other causes (non-SUDEP), and 1 lacked sufficient data from which to make a classification. The overall SUDEP rate (definite/ highly probable SUDEP and possible SUDEP combined) was calculated to be 3.5 in 1,000 patient-years of exposure to LTG.Conclusions: The rate of SUDEP in this cohort of patients was comparable to the rate that would be expected in young adults with severe epilepsy (the subgroup of patients believed to be at highest risk of SUDEP). The data suggest that the rate of SUDEP in the LTG clinical development program is a function of the clinical trial population and is unrelated to drug treatment. Key Words: Sudden unexplained death in epilepsy-Refractory epilepsy-Partial seizures-Lamotrigine.Sudden unexplained death in epilepsy (SUDEP) is a significant cause of mortality among persons with epilepsy (1-13). Although SUDEP has been reported since the turn of the century (14), the incidence and pathophysiology of this phenomenon are not well understood (8,15). SUDEP is, by definition, a diagnosis of exclusion, which is assigned when no obvious cause, such as trauma, infection, hemorrhage, pulmonary embolism, or myocardial infarct, can be determined and the death occurs in a person with epilepsy who was previously in good health. Such deaths are generally, although not always, unwitnessed, and autopsy is generally required for conclusive categorization (8).

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 alpha-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 II 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.

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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 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.

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