CHAPTER 19: Seizure Disorders

• 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.

• 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.

• 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.

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

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

• 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.

Had epilepsy never existed, it would have been discovered eight times over the past year by those intent on knocking out mouse genes one at a time.

Noebels, 1996

The many different causes of epilepsy are too numerous to list. Many knockout mice experience spontaneous seizures, and the various forms of human epilepsy that appear to have a genetic basis have been traced to many different genes 19–1. Moreover, as previously mentioned, epilepsy frequently occurs after brain trauma or infection.

Why is the brain predisposed to seizure activity? Because neurons are so extensively and often reciprocally interconnected, it appears that any excitatory activity can propagate and perpetuate itself across a brain or brain circuit. In healthy individuals, inhibitory circuitry generally limits the degree to which any neural activity is propagated, either spatially or temporally. As a result, any condition that upsets the delicate balance between excitation and inhibition is likely to cause a seizure. The sections that follow discuss a few of the many different ways such imbalance can occur.

Genetic Influences

Mutations in more than 50 human genes/loci have been identified in human epilepsy syndromes 19–1. That such a wide variety of gene products can influence seizure susceptibility is not surprising. Ion channels and neurotransmitter receptors influence the excitability of neurons directly; enzymes, which modify neurotransmitter receptors and ion channels, influence neuronal excitability in many ways; DNA-binding proteins influence the repertoire of proteins expressed by neurons, which might in turn affect excitability. These proteins might also influence epileptogenesis in a more complex manner; for example, they might alter developmental processes so that abnormal neural circuits are produced.

A particularly interesting example is autosomal dominant temporal lobe epilepsy, a disorder with onset in adolescence or adulthood associated with mutations in Lgi1. The Lgi1 protein is also associated with an acquired form of epilepsy in which there is an immune-mediated attack on this protein, a component of voltage-gated K⁺ channel complexes, resulting in faciobrachial dystonic seizures. This phenomenon, in which the identification of a novel genetic mutation aids in the identification of an antigen targeted in an autoimmune disorder, or vice versa, is not uncommon.

Neuronal Death, Neurogenesis, and Sprouting: Keys to Epileptogenesis?

In addition to the large number of genetic abnormalities that can lead to epilepsy, trauma, such as a blow to the head, can cause epilepsy in humans as well as in experimental animals. Seizure-inducing trauma is generally associated with discrete anatomic changes, which have been most intensively studied in the hippocampus, a particularly epileptogenic area of the brain. In animal models, seizure-inducing trauma is associated with selective loss of inhibitory interneurons of the dentate hilus, and also with an increase in the number of excitatory dentate granule cell axons (mossy fibers) (Chapter 14). Loss of hilar cells and sprouting of mossy fibers are also a prominent aspect of the pathologic changes observed in human temporal lobe epilepsy.

These observations raise several questions. The loss of hilar inhibitory interneurons is consistent with the imbalance of excitation and inhibition that might be expected to lead to seizures. However, why do hilar interneurons die in greater numbers than excitatory neurons? Moreover, what mechanisms underlie the increased number of mossy fibers, and what are the consequences of this sprouting? An increase in mossy fibers may result from the sprouting of existing dentate granule cells or it may be related to an increase in the total number of these cells. Indeed, the generation of new dentate granule cells, neurogenesis, which occurs at low levels during adulthood, has been found to increase after trauma, as well as after seizures.

The ultimate effects of the increase in mossy fiber density are uncertain. It is possible that mossy fiber sprouting contributes to epileptogenesis by increasing excitatory input to hippocampal circuits. Alternatively, mossy fibers may selectively synapse onto remaining hilar interneurons in an attempt to return the overall level of inhibition to normal. Mossy fiber proliferation may be manipulated by means of pharmacologic and molecular interventions. The NMDA glutamate receptor antagonist MK-801 retards seizure development and mossy fiber sprouting in animal models, as does elimination of the gene for the transcription factor c-Fos. Neurotrophic factors most likely play a role in mossy fiber proliferation, and research into the effects of neurotrophins such as brain-derived neurotrophic factor (BDNF) (Chapter 8) on mossy fiber sprouting has begun to yield interesting results. If mossy fiber sprouting is proven to contribute directly to the development of seizures, these findings could in theory be exploited for therapeutic purposes. The latent period between the time of the insult and the development of epilepsy may provide an ideal therapeutic window for therapies aimed at inhibiting epileptogenesis.

Along with advances in our understanding of the etiologies of seizure disorders, there has been slow but steady progress in the development of new and safer anticonvulsants. Nevertheless, many individuals with recurrent seizures continue to be treated with anticonvulsant drugs that have been available for many years 19–5.

Almost all anticonvulsants work by directly modifying neuronal excitability through alterations either in ion channels or in the availability of amino acid neurotransmitters. The key to seizure prevention is interference of rapid, synchronized firing of neurons. The ideal anticonvulsant drug must prevent the excessive, synchronized discharges that occur during a seizure without impeding normal neuronal function. Most anticonvulsants can be divided into six general categories according to their mechanisms of action: (1) agents that act on Na⁺ channels, (2) those that act on K⁺ channels, (3) those that act on Ca²⁺ channels, (4) those that affect GABAergic transmission, (5) those that affect glutamatergic transmission, and (6) those that bind to synaptic vesicle protein 2A (SV2A).

Drugs that selectively stabilize the inactive state of Na⁺ channels decrease a nerve’s ability to fire rapid bursts of action potentials (Chapter 2). Drugs that open neuronal voltage-gated K⁺ channels lead to membrane hyperpolarization and decreased neuronal excitability. The activities of drugs that inhibit Ca²⁺ channels were discussed earlier in this chapter; inhibitors of T-type Ca²⁺ channels are especially effective against generalized absence seizures. Drugs that enhance inhibitory GABAergic transmission are able to increase GABA availability or to enhance the effect of GABA on GABA receptors. Drugs that decrease glutamatergic transmission via effects on the NMDA receptor inhibit an important factor in the initiation and propagation of seizures. The mechanism underlying the antiepileptic effects of SV2A-binding drugs remains unknown.

Drugs That Enhance Na⁺ Channel Inactivation

Phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, topiramate, zonisamide, rufinamide, lacosamide, and felbamate all enhance Na⁺ channel inactivation, although some of these substances produce additional effects that may contribute to their anticonvulsant activity. Because these drugs bind to and stabilize Na⁺ channels that are inactivated, their binding is dependent on the opening of Na⁺ channels, which leads to the inactivated state. Stabilization of the inactivated state of the voltage-gated Na⁺ channel has the ultimate effect of reducing sustained high-frequency firing of action potentials 19–6. Drugs with this mechanism act specifically on rapidly firing neurons, and the ability of neurons to fire one or a few action potentials is little affected.

Valproate is another use-dependent Na⁺ channel blocker, although it is weaker in this regard than drugs such as phenytoin and carbamazepine. However, valproate exerts other effects as well. It also is a Ca²⁺ channel blocker, and, based on the results of many studies, it may be able to increase levels of GABA in the brain, albeit via as yet unknown mechanisms. In addition, valproate is a nonselective inhibitor of histone deacetylases (Chapter 4); however, there is no evidence to connect valproate’s anticonvulsant properties to this action.

Interestingly, several of these anticonvulsant agents, particularly valproate and lamotrigine, are used clinically in the treatment of bipolar disorder. The mechanism by which these drugs exert such mood-stabilizing effects is a matter of considerable debate (Chapter 17).

Drugs That Enhance Inhibitory GABAergic Transmission

Benzodiazepines and barbiturates bind to distinct sites on the GABA_A receptor and increase the receptor’s affinity for GABA, thereby increasing its chloride conductance (19–7; see Chapter 5). These agents, such as phenobarbital, are not as frequently prescribed for epilepsy as they once were. They often produce unwanted sedative effects in patients, who may complain of tiredness, forgetfulness, and confusion. Benzodiazepines (eg, diazepam, midazolam) are used, however, for the emergency treatment of status epilepticus, a sustained, unrelenting seizure that can be life-threatening if left untreated. Moreover, patients are subject to rapid tolerance to the anticonvulsant effects of benzodiazepines with repeated administration. However, several newer anticonvulsants, some of which (eg, topiramate—which is also a Na⁺ blocker) work at GABAergic synapses as well, may be more effective and better tolerated.

Vigabatrin, a relatively new anticonvulsant medication, is a synthetic structural analogue of GABA that acts as a specific inhibitor of GABA transaminase, an enzyme critical to the breakdown of GABA in the nerve terminal (Chapter 5). As might be expected, patients who take vigabatrin have increased levels of GABA in their cerebrospinal fluid. This is consistent with the model that vigabatrin may exert its anticonvulsant action by increasing the overall availability of GABA.

Tiagabine is an inhibitor of the plasma membrane GABA transporter that removes released GABA from the synaptic space and returns it to the nerve terminal for recycling or catabolism (Chapter 5). By inhibiting the GABA transporter, tiagabine most likely acts to increase the time that GABA remains in the synaptic cleft after its release. In hippocampal CA1 cells, tiagabine increases the duration of inhibitory postsynaptic currents—an action that is consistent with its ability to produce a prolonged effect of GABA at inhibitory synapses.

Drugs With Other Actions

Gabapentin and the related drug pregabalin are GABA analogues; however, they are now believed to act primarily via GABA-independent mechanisms. As discussed in Chapter 11, both drugs bind to the α₂δ subunit of voltage-dependent Ca²⁺ channels and thereby regulate the trafficking of the channels and perhaps other proteins to synaptic membranes. This mechanism likely explains the ability of the drugs to decrease the release of glutamate and other neurotransmitters at nerve terminals. The drugs are also reported to increase GABA levels at synapses, but the underlying mechanisms are not known. Gabapentin and pregabalin are used widely in the treatment of chronic pain syndromes (Chapter 11).

Levetiracetam is a member of a family of cyclic derivatives of GABA (eg, piracetam) that were originally promoted as so-called nootropic agents to enhance cognitive function. While this effect of the drugs is weak at best, levetiracetam is approved for the treatment of several forms of epilepsy and has become a commonly used first-line agent for many neurologists over past fifteen years. The mechanism of action of levetiracetam is unknown; it is proposed to bind to SV2A, whose role in synaptic vesicle exocytosis is poorly defined.

Recent years have seen renewed interest in the development of K⁺ channel potentiators—drugs that promote the probability of channel opening. Such drugs in theory would reduce the excitability of neurons and potentially exert anticonvulsant effects. One such drug, retigabine (also known as ezogabine), was approved recently for the treatment of partial seizures. Retigabine acts selectively on KCNQ (Kv7) channels (Chapter 2). Drugs with related actions, for example, flutirpine, are being evaluated for treatment of chronic pain syndromes.

Rhyme and Reason: Determining the Appropriate Drug

Clinical trials and experience, rather than an understanding of the pathophysiology of epilepsy and the mechanisms of action of anticonvulsant medications, have provided the best guidelines for determining the medication that is most effective in controlling each type of seizure. Valproate, for example, is effective in controlling primary generalized epilepsy of the absence, myoclonic, or tonic–clonic type, and is less effective in the treatment of partial seizures, for which phenytoin and carbamazepine are the drugs of choice. As previously mentioned, the T-channel blocker ethosuximide is most useful in treating generalized absence seizures; this finding is consistent with what is known about the processes that underlie this type of seizure.

In general, agents that are effective in controlling partial seizures appear to produce relatively effective use-dependent Na⁺ channel blockade compared with drugs that are most useful for treating generalized seizures. Conversely, drugs effective in controlling generalized seizures tend to be better Ca²⁺ channel blockers 19–8.

We look forward to a day when the pathophysiology underlying a particular seizure disorder will more accurately guide the use of drugs with specific mechanisms of action and greater tolerability.