Neither seizures nor epilepsy occur in isolation from the rest of the body’s functions. Epilepsy is regularly associated with complex biologic interactions as a result of the seizures themselves, an underlying medical or neurologic disorder, or antiepileptic drug treatment. Epileptic seizures, especially when frequent or in the form of status epilepticus, result in significant physiologic stress to the autonomic nervous system and to the cardiovascular, pulmonary, and endocrine systems. The occurrence of seizures and epileptiform electroencephalographic (EEG) abnormalities is strongly influenced by circadian and ultradian rhythms. In some cases, this is sufficiently distinct that it is included among the features defining some epilepsy syndromes. Antiepileptic drugs can have profound consequences for reproductive health including hormonal effects, fertility, and pregnancy outcomes. Finally, seizures occur frequently with many medical conditions that affect the brain, either as part of a systemic disease process or secondarily as the result of he-patic or renal failure and other causes of metabolic dysfunction. Successful management of patients with epilepsy and seizures must take these broader biologic considerations into account, and that is the purpose of the chapters in this section.

Sleep and epilepsy are intimately related, at multiple levels and in multiple ways, as discussed in two chapters by Dr. Shouse et al. Hippocrates and Aristotle were perhaps the first to write of the occurrence of epileptic seizures during sleep. More modern views linking biologic rhythms, epitomized by the waking–sleep cycle, to epilepsy began to appear in the late 19th and early 20th centuries, both in the French (Echeverria, Fere) and English (Gowers) literature. Several biologic clocks influence the occurrence of epileptic seizures. A number of epileptic syndromes are strongly related to circadian (24-hour) rhythms. Representative examples include both primary generalized epilepsies, such as grand mal seizures upon awakening and juvenile myoclonic epilepsy, and focal epilepsies, such as autosomal dominant frontal lobe epilepsy. EEG epileptiform discharges may be even more entrained to the wake–sleep cycle than clinical events, as illustrated by the phenomenon of continuous spikes and waves during slow-wave sleep and the discharges of benign partial epilepsy with central-midtemporal spikes. Ultradian rhythms (shorter than 24 hours), such as the basic rest–activity cycle (BRAC), interact with the circadian rhythm to further influence the occurrence of both seizures and, especially, interictal discharges at shorter periodicities (e.g., 90 minutes). These effects have been described in both generalized and localization-related epilepsies. Infradian rhythms (longer than 24 hours) characterize the secretory patterns of hormones and hormone-releasing factors; their influence is evident in catamenial epilepsy. Among the exciting discoveries in neuroscience today is a growing understanding of the neurobiologic mechanisms underlying biologic clocks. The master circadian clock involves the suprachiasmatic nuclei of the anterior hypothalamus; other areas of the hypothalamus, such as the orexin-containing cells of the lateral hypothalamus, are specifically important in the sleep–wake cycle. Brainstem mechanisms are central to generation of the BRAC type of ultradian rhythm.

The distribution of ictal events and interictal discharges differs in rapid eye movement (REM) and non-REM stages of sleep, and the effects are different for primary generalized epilepsies and localization-related epilepsies. The effects of sleep and of sleep deprivation on interictal EEG discharges are well known and clinically useful.

The recognition that patients with epilepsy have increased mortality rates has been an important finding. Part of this increase is related to underlying diseases (e.g., brain tumors) or to accidental death (e.g., drowning). In recent years, however, there has been growing awareness that death also occasionally occurs unexpectedly in otherwise healthy people for no apparent reason. Indeed, sudden unexpected death in epilepsy (SUDEP) is now recognized as the most common cause of seizure-related mortality in people with chronic epilepsy. Compared to persons without seizures, the incidence is particularly high in young adults with epilepsy. Early age of onset of epilepsy, frequent generalized tonic–clonic seizures, and intractability appear to be risk factors, and polytherapy may independently add additional risk, at least in adults. Drs. Nashef and Tomson provide a critical analysis of data related to SUDEP, and suggest that SUDEP is a direct consequence of an epileptic seizure, perhaps involving a cardiac mechanism. They conclude with an emphasis on optimizing seizure control and raising considerations that are important in informing patients about the condition.

Drs. Goodman, Stewart, and Drislane review the anatomy of the autonomic nervous system and the many clinical features of seizures (e.g., tachycardia, increased blood pressure, apnea, pupillary changes, sweating, salivation, incontinence, skin flushing or pallor) that indicate autonomic activation. Because the autonomic nervous system is controlled by a central autonomic network that involves the limbic system and lower brainstem, autonomic symptoms and signs are especially common with partial seizures that originate in the mesial temporal
lobe, the cingulate gyrus, and other medial frontal cortical areas. Such autonomic features can occur before, during, or after a seizure. Occasionally, autonomic dysfunction may be life threatening, as in some cases of seizure-related neurogenic pulmonary edema or cardiac arrhythmias. Involvement of neurons that innervate the heart can produce tachyarrhythmias as well as heart block, and this particular manifestation of autonomic dysfunction may be a contributing factor to SUDEP.