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  A seizure is caused by the abnormal synchronous firing of large ensembles of neurons. Epilepsy refers to any neurologic disorder that is characterized by recurrent seizures.

  
  
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  Seizures can be classified as focal, which indicates that the initial abnormal firing is limited to a specific area in one hemisphere, or generalized, which indicates that a large population of neurons in both hemispheres is involved.

  
  
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  Seizures occur because of a change in the brain’s delicate balance of excitatory and inhibitory synaptic processes. This change can be caused by any number of different brain insults, including tumors, strokes, and head injury as well as developmental abnormalities.

  
  
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  Many forms of epilepsy have a genetic component, although the inheritance of epilepsy is rarely simple.

  
  
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  Most anticonvulsants work by modifying the function of sodium or calcium channels or by enhancing GABA-mediated inhibitory synaptic transmission.

  
  
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  Other known actions of a smaller number of anticonvulsants include potentiation of potassium channels, inhibition of glutamatergic transmission, and poorly defined actions on a synaptic vesicle-associated protein termed synaptic vesicle protein 2A (SV2A).

This chapter is devoted to seizure-related disorders such as epilepsy. Seizures are characterized by uncontrolled firing of sets of neurons in the brain and can have devastating consequences. Seizure disorders are common: approximately 5% to 10% of people will experience at least one seizure in their lifetime. Fortunately, the treatment of seizures has steadily improved with the introduction of safer and more effective anticonvulsant agents.

A seizure is a paroxysmal derangement of cerebral function caused by excessive and generally synchronized activity of a group of neurons. Seizure activity can occur in many different regions of the brain, and its physical manifestations vary according to the region in which it occurs. Thus, the term seizure may refer to a 3-second lapse of consciousness that is barely noticeable to the affected individual or to witnesses of the event. The same term also applies to a “grand mal” tonic–clonic seizure that causes an individual to lose consciousness and contract all muscles of the body followed by a jerking of his or her entire body that is violent enough to result in muscle damage and electrolyte abnormalities.

In many cases a seizure can be traced to a specific insult, such as head trauma, high fever, or alcohol withdrawal. An isolated seizure does not mean that an individual has epilepsy, a disorder defined by an increased propensity for recurring seizures. The traditional clinical definition of epilepsy is the occurrence of two or more unprovoked seizures. In the US population, epilepsy has a prevalence of 1 in 100 and an incidence of 1 in 2000. Inherited vulnerabilities, focal brain injury, or chronic illness can produce lower seizure thresholds in epileptic individuals, who generally require medication to control their seizures.

Because there are many varieties of seizures, there are many types of epilepsy. Patients who visit epilepsy clinics exhibit a wide diversity of symptoms, from grand mal tonic–clonic seizures to seizures that consist of lapses of consciousness and odd behavior such as lip smacking. Patients also vary in terms of seizure control, ranging from those who are well controlled on one antiepileptic drug and have not had a seizure for years to those who have difficulty maintaining employment because of recurrent seizures resistant to treatment with multiple drugs. Accordingly, the impact of seizures on quality of life varies. Some epileptic patients are inconvenienced only by their need for daily medication, whereas others can be nearly incapacitated by their condition. The effectiveness of treatment also can be highly variable. Some types of epilepsy, including juvenile absence epilepsy, are eminently treatable; other types, especially those related to gross developmental disorders, cannot be adequately treated. Moreover, some patients readily tolerate pharmacotherapy, while others experience distressing side effects such as fatigue, forgetfulness, and medical complications.

The treatment of seizures, along with our understanding of their biologic basis, has undergone slow, steady progress during the last few decades. Newer anticonvulsant drugs are improving seizure control and reducing side effects for many patients. The genetic factors that underlie seizure vulnerability are increasingly well understood. Next-generation sequencing technologies have led to a marked increase in the number of genetic mutations associated with human epilepsies. The physiology of certain types of seizures is also slowly being elucidated. As well, the molecular events that contribute to epileptogenesis in previously healthy neuronal tissue are beginning to be discovered. Although epilepsy remains a serious disorder for many, effective treatments continue to be developed.

In a normal, conscious state, the net neuronal activity recorded by an electroencephalogram (EEG) reveals few waves and no large shifts in polarity (Chapter 13). Such activity does not indicate that the brain is quiet; rather it indicates that neuronal activity is asynchronous. To maintain balance, posture, and fine motor control, for example, some cortical motor neurons may fire action potentials while others are hyperpolarized.

At the onset of a seizure, the EEG reveals characteristic changes 19–1. Events that may include dramatic upward and downward shifts of polarity begin to appear. Such events indicate that a large number of neurons are firing and repolarizing in synchrony; the summation of their activity produces a noticeable effect on the EEG recording. This type of synchrony can be accompanied by abnormalities in movement, sensation, or consciousness. If synchronous firing occurs in cortical motor neurons, for example, twitching and jerking of affected body parts may replace the fine gradations of muscle activity needed to maintain balance, posture, and smooth, controlled motion. When synchrony occurs in other brain regions, the result may be strange sensations, such as the perception of a particular odor, confusion, or the loss of consciousness.

What causes this change from normal neuronal activity to abnormal synchronized firing of large ensembles of neurons? Many factors can set the stage for a seizure. Abnormal synchronized activity often arises from a particular area in the brain, referred to as a seizure focus. Brain imaging and EEGs can be used to identify seizure foci, which may be associated with areas of neuronal maldevelopment, degeneration, or a structural abnormality such as a tumor 19–2. A decrease in the overall level of inhibitory transmission in the brain also can precipitate a seizure. Such decreases can occur after the administration of γ-aminobutyric acid (GABA) antagonists, or during withdrawal from repeated exposure to GABA agonists such as alcohol or benzodiazepines (Chapter 5). Moreover, events that do not cause seizures in most people, such as hyperventilation or flashing lights, may precipitate seizures in vulnerable individuals.

Although the exact chain of events that trigger individual seizures may be poorly understood, the tendency of neurons to fire in synchrony is related to their extensive interconnectedness. Neurons in different regions of the brain, as well as those within single regions, often have extensive reciprocal connections with one another; for example, glutamatergic neurons in the thalamus project to glutamatergic neurons in the cortex, which in turn project to the thalamus. After they emerge, waves of activity can become self-sustaining and can even propagate from one region of the brain to another.

Seizures can be broadly categorized as focal (partial) or generalized. As their name suggests, focal seizures are characterized by clinical and EEG changes that indicate an initial activation of neurons in a relatively small, discrete region of the brain, whereas generalized seizures are characterized by involvement of both hemispheres and widespread neuronal activation. These two broad classifications comprise dozens of subtypes of seizures that have distinct clinical manifestations and involve particular brain regions (see the section “Selected Reading”).

Seizure classification aids in the selection of optimal treatment regimens. However, one individual can undergo multiple seizures of varying types; indeed, a single seizure event can involve more than one type of seizure. Focal seizures, for example, commonly evolve into a generalized seizure as activity spreads from the seizure focus to other areas of the brain. The identification of seizure type and progression also helps to determine an optimal treatment regimen 19–1.

As previously mentioned, the clinical manifestations of focal seizures reflect the region of brain in which they occur; for example, a focal seizure in sensory cortex may produce an odd sensory experience, such as a noxious smell or a clicking sound. Other types of focal seizures include aphasic/phonatory, somatosensory, and adversive seizures. Aphasic/phonatory seizures result in a sudden inability to speak, write, or read. Related seizure foci often are found in the temporal, inferior frontal, or inferior parietal cortex. Somatosensory seizures cause paresthesias often referred to as “pins and needles,” or hot or cold sensations, with corresponding seizure foci often found in somatosensory cortex. Adversive seizures result in sudden movements of the head and eyes to the contralateral side of the seizure focus, and related foci often are found in the frontal lobe or precentral gyrus.

Focal motor seizures are characterized by clonic twitching of the contralateral muscles consequent to a localized epileptic discharge from the motor cortex. The muscles involved depend on the affected area of the brain. The motor activity can be moderate (inconspicuous twitching) or extreme (massive jerking of the affected muscles) (see 19–1). Focal motor seizures can spread from the focus to neighboring areas of motor cortex. For example, the seizure may spread from one twitching area of the body to the next until the entire half of the body shows clonic activity (Jacksonian march). Focal motor seizures also may progress into full-blown generalized tonic–clonic (grand mal) seizures.

Complex partial seizures are focal seizures characterized by an impairment of consciousness and can arise from virtually any area of cortex that subserves a complex function such as speech, emotion, or memory. These seizures can produce a variety of effects, including auditory or visual hallucinations, feelings of familiarity (déjà vu) or strangeness (jamais vu), or automatisms such as lip smacking or chewing motions. Although complex partial seizures involve impaired consciousness, the affected individual often continues to interact with the environment, in ways that are sometimes bizarre 19–2.

The behaviors and experiences that occur during a complex partial seizure are usually initiated in higher-level association cortices, which may explain why resulting behaviors are complex, including automatisms, rather than gross, for example, tonic–clonic movements of an appendage. The involvement of high-level auditory and visual association cortices most likely explains the occurrence of hallucinations during some complex partial seizures. The temporal lobe is a particularly common focus for complex partial seizures. Temporal lobe epilepsy is often associated with complex partial seizures involving aphasia and sensations of jamais vu or déjà vu. The hippocampus, which is critical for learning and memory (Chapter 14), is believed to be the source of many temporal lobe epilepsies that in some cases are associated with mesial temporal sclerosis, pathology associated with neuronal cell death, gliosis, atrophy of the hippocampus, and reorganization of dentate granule cell axons.

Generalized seizures are those that involve multiple, bilateral areas of the brain. The exact cause of most generalized seizures is unknown. Although a focal seizure can spread or generalize, there are many instances in which the entire cortex seems to give rise to seizure activity all at once. Many generalized seizures are associated with developmental disorders.

Tonic seizures are characterized by an extension of the extremities and a rigid stretching of the body. These attacks are common in children with Lennox–Gastaut syndrome. This syndrome is characterized by a slow spike-and-wave complex on EEG recordings, impaired cognitive function, and multiple types of seizures, including atonic drop attacks. Lennox–Gastaut syndrome typically becomes evident between 1 and 10 years of age, and often is refractory to anticonvulsant medications. The disorder has been associated with brain malformations, hypoxic–ischemic brain injury, encephalitis, meningitis, and tuberous sclerosis. Hereditary factors are also likely to play a role in the acquisition of this syndrome, as a family history of epilepsy is evident in 3% to 27% of cases.

Atonic seizures are accompanied by a sudden loss of muscle tone, which is sometimes preceded by a myoclonic jerk; if standing, the affected individual typically falls to the ground. These attacks generally last only a few seconds, and do not involve a loss of consciousness. A patient generally recovers immediately after an atonic seizure; however, a risk of injury is present during the fall, and many affected individuals must wear protective gear such as helmets to prevent fall-related injuries. Clonic seizures involve repetitive muscle twitching; such attacks can last as long as 1 minute. Myoclonic seizures are rapid involuntary muscle contractions; the term myoclonic is used to denote a single twitch event, which is distinct from repetitive, or clonic, twitching.

Generalized tonic–clonic (grand mal) seizures are associated with immediate loss of consciousness and orderly sequences of motor activity. This activity comprises distinct tonic phases (arms in semiflexion and legs extended) that are followed by a clonic phase (full-body spasms with intermittent relaxations). EEGs exhibit massive fast spiking during the tonic phase and bursts of polyspikes interrupted by slow waves during the clonic phase. Such seizures are frequently preceded by focal seizures.

Generalized absence seizures, or petit mal seizures, are characterized by a brief lapse of consciousness (approximately 10 seconds or less) accompanied by an EEG recording of a spike-and-wave discharge of approximately 3 Hz 19–3. The earliest clinical description of a generalized absence seizure appeared in 1705 in a report by a French physician: “At the approach of an attack the patient would sit down in a chair, eyes open, and would remain there immobile and would not afterward remember falling into this state. If she had begun to talk and the attack interrupted her, she took it up again at precisely the point at which she stopped and she believed she had talked continuously.” Although this description gives the essence of an absence seizure, additional phenomena such as mild atonia, automatisms, and mild tonic or clonic components may occur in some patients. The 3-Hz spike-and-wave pattern that accompanies an absence seizure reflects a widespread phase-locked oscillation between excitation (spike) and inhibition (wave) in mutually connected thalamocortical neuronal networks.

The activity of a group of neurons in the nucleus reticularis thalami (NRT) is particularly important for determining the behavior of thalamocortical networks and therefore the occurrence of absence seizures. GABAergic neurons of the NRT project densely to one another and to almost all thalamic relay nuclei. They also receive excitatory, glutamatergic inputs from the collaterals of both thalamocortical axons and corticothalamic axons 19–4. During periods of reduced conscious awareness, NRT neurons exhibit firing in rhythmic bursts, whereas during alert wakefulness, they exhibit tonic single-spike firing. The cellular event that is responsible for the rhythmic burst firing mode of NRT neurons is the low-threshold (T-type) Ca²⁺ spike (Chapter 2). What causes this type of rhythmic firing during absence seizures is unclear, but the role of T-type channels elegantly explains the actions of ethosuximide, the drug of choice in the treatment of absence seizures. At clinically relevant concentrations, ethosuximide diminishes T-channel currents in NRT neurons; it is believed that this action quells the 3-Hz spike-and-wave activity that characterizes the absence seizure. Interestingly, absence seizures are among the few types of seizure that can actually be made worse by the administration of GABA agonists. Drugs that promote GABAergic transmission such as vigabatrin may enhance the ability of NRT neurons to adopt rhythmic firing mode by enhancing their hyperpolarization, which leads to greater activation of T channels when the cells are subsequently depolarized.