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 role of the maternal environment in the development of hypertension in spontaneously hypertensive (SHR) rats was evaluated using the technique of reciprocal cross fostering. Litters of SHR and Wistar-Kyoto (WKY) normotensive pups were either reared by their natural mothers, in fostered to mothers of the same strain, or cross fostered to mothers of the opposite strain shortly after birth. Litters were weaned at 21 days of age, at which time all pups were weighed. At 18-20 wk of age, resting mean arterial blood pressures (MAP) and heart rates were determined for male subjects from the six groups (2 strains X 3 rearing conditions) via an indwelling tail artery catheter. At weaning, SHR animals weighed less than WKY animals. SHRs fostered to WKY mothers were significantly heavier than control SHRs, and WKYs fostered to SHR mothers were significantly lighter than WKY controls at weaning. These body weight differences were also evident in adulthood. Cross fostering SHR pups to normotensive WKY mothers resulted in a dramatic reduction in resting MAP measured in adulthood. Conversely, cross fostering WKY pups to SHR mothers had no measurable effect on adult resting MAP. We propose that an interaction between characteristics of the SHR maternal environment and a genetic susceptibility in SHR pups is essential in triggering the full expression of the hypertensive phenotype in this animal model of human essential hypertension.

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Low doses (50-200 pg or 3.1-12.4 fmol) of interleukin 1 (IL-1) infused into the brain of rats produced rapid suppression of various cellular immune responses in peripheral lymphocytes of rats. Fifteen minutes after infusion of purified IL-1f into the lateral ventricle, natural killer cell activity, response to phytohemagglutinin stimulation, and interleukin 2 production were markedly suppressed in lymphocytes isolated from blood and spleen. These effects were due to infusion of IL-1 into brain since they did not occur when IL-1 was infused into the cisterna magna (essentially posterior to brain) or was injected intraperitoneafly. Effects of IL-1 in brain could be blocked by simultaneous infusion of a-melanocytestimulating hormone, which is known to block the biological actions of IL-1. To stimulate release of endogenous IL-1 in brain, lipopolysaccharide was infused; this produced similar effects as IL-1, and these effects also were blocked by amelanocyte-stimulating hormone. At longer intervals after infusion of IL-1 and lipopolysaccharide (3, 6, and 24 hr), immune responses returned to baseline or remained suppressed; i.e., "rebound" immunopotentiation did not occur. Finally, IL-1 infusion suppressed cellular immune responses in adrenalectomized animals, thereby showing that the effects of central IL-1 on peripheral cellular immune responses were, at least in part, independent of the stimulatory effect of IL-1 on secretion of adrenal hormones. These results indicate a link from brain to peripheral immune responses by means of action of a cytokine acting in the brain.Interleukin 1 (IL-1), a cytokine originally detected in macrophages, now has been shown to have biological effects when introduced into the brain as well as peripherally. Infusion of IL-1 into the brain induces fever (1) and slow wave sleep (2, 3) and activates the hypothalamic-pituitary axis by increasing the secretion of corticotropin-releasing factor and adrenocorticotrophic hormone (4-7). IL-1 is produced in vitro by cells found in brain, such as astrocytes and microglia (8,9), and IL-1 has been detected in brain following brain injury (10)(11)(12). Recently, it has been reported that IL-1 is distributed in the brain in such a manner as to suggest that it functions as a neuromodulator or neurotransmitter (13,14 6398The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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Intracerebroventicular (i.c.v.)