Seizures and Epilepsy: Overview and Classification

Synonyms, Key Words, and Related Terms: spells, convulsions, attacks Background: Epilepsy is a disorder characterized by the occurrence of at least 2 unprovoked seizures. Seizures are the manifestation of abnormal hypersynchronous discharges of cortical neurons. The clinical signs or symptoms of seizures depend upon the location and extent of the propagation of the discharging cortical neurons. That seizures are a common nonspecific manifestation of neurologic injury and disease should not be surprising, because the main function of the brain is the transmission of electrical impulses. The lifetime likelihood of experiencing at least one epileptic seizure is about 9%, and the lifetime likelihood of being diagnosed as having epilepsy is almost 3%. However, the prevalence of active epilepsy is only 0.8%.

Classification of epileptic seizures
In 1981, the International League Against Epilepsy (ILAE) developed an international classification of epileptic seizures that divides seizures into 2 major classes: partial-onset seizures and generalized-onset seizures. Partial-onset seizures begin in one focal area of the cerebral cortex, while generalized-onset seizures have an onset recorded simultaneously in both cerebral hemispheres. Some seizures are difficult to fit into one particular class, and they are considered as unclassified seizures. Partial-onset seizures Partial-onset seizures are further classified into 3 categories: (1) simple partial seizures, (2) complex partial seizures, and (3) secondarily generalized tonic-clonic seizures. Simple partial seizures: The key defining element of simple partial seizures is the occurrence of a seizure with preservation of consciousness. Many patients with complex partial seizures have an aura warning them of their seizure. An aura is a simple partial seizure. Many kinds of simple partial seizures exist, including sensory, motor, autonomic, and psychic experiences. Essentially, any discrete human experience that involves the cerebral cortex could be a simple partial seizure. The diagnosis is based upon the repeated stereotypic occurrence of the same experience in association with focal electroencephalography (EEG) changes, or the diagnosis is made after a recurrent aura occurs leading to a complex partial seizure or a secondarily generalized seizure. The disappearance of the recurrent clinical phenomena with the use of anticonvulsants is presumptive but not diagnostic evidence for epileptic seizures. The clinical diagnosis is quite difficult, as many stereotypic auras may be induced in areas of the cerebral cortex that are not recorded well by a typical EEG. Only 20-40% of auras have an ictal correlate in the scalp EEG. Simple partial seizures may last a few seconds to a few minutes; by definition, however, if the aura lasts longer than 30 minutes, it is considered simple partial status epilepticus. Complex partial seizures: Consciousness is impaired during a complex partial seizure. In practice, assessing historically whether consciousness was impaired is difficult. The most common way to assess preservation of consciousness is by asking patients whether they were able to recollect the event. In many occasions, patients are able to remember their aura but are unaware that they were briefly unable to respond to the environment. Typically, a complex partial seizure begins with behavioral arrest and is followed by staring, automatisms, and postictal confusion. Frequently, the automatisms consist of chewing, lip smacking, mumbling, and fumbling with the hands. Dystonic posturing of the contralateral upper extremity often is seen when a complex partial seizure originates from the mesial temporal lobe. A typical complex partial seizure lasts about 60-90 seconds and is followed by brief postictal confusion. However, generalized weakness, asthenia, and fatigue may last for a few days. Complex partial seizures of frontal lobe origin may feature bizarre motor behaviors such as bicycling or a fencing posture. They have more prominent motor features than complex partial seizures of temporal lobe onset. The great majority of complex partial seizures have an ictal correlate in the EEG. The presence of normal alpha rhythm during the period of behavioral impairment of consciousness raises the suspicion for nonepileptic seizures. 1

Secondarily generalized seizures: These seizures often begin with an aura that evolves into a complex partial seizure and then into a generalized tonic-clonic seizure. However, a complex partial seizure may evolve into a generalized tonic-clonic seizure, or an aura may evolve into a generalized tonic-clonic seizure without an obvious complex partial seizure. Clinically, classifying a generalized tonic-clonic seizure by history alone as being secondarily generalized (partial onset) or primarily generalized is difficult. In most cases, the more severe a secondarily generalized seizure, the more it is associated with prominent amnesia for the aura. Generalized-onset seizures Generalized-onset seizures are classified into 6 major categories: (1) absence seizures, (2) tonic seizures, (3) clonic seizures, (4) myoclonic seizures, (5) primary generalized tonic-clonic seizures, and (6) atonic seizures. Absence seizures: These are brief episodes of impairment of consciousness with no aura or postictal confusion. They typically last less than 20 seconds and are accompanied by few or no automatisms. Facial automatisms are most frequent, and repetitive blinking is the most common facial automatism. Absence seizures often are precipitated by hyperventilation or photic stimulation. They typically begin during childhood or adolescence but may persist into adulthood. A diagnosis of new-onset absence seizures in adulthood is incorrect in the vast majority of cases. Often, those adult patients have complex partial seizures with relatively minor automatisms. In children, absence seizures often are unrecognized until a child develops a generalized tonic-clonic seizure and is brought to medical attention. A sudden decreased performance in school grades or overall attention is a subtle manifestation of frequent absence seizures. The classic ictal EEG correlate of absence seizures consists of 3.5-Hz generalized spike and slow wave complexes. A significant inherited predisposition for typical childhood absence seizures exists, as demonstrated by twin studies. The EEG abnormality may persist into adulthood despite the absence of further clinical seizures. However, the electroencephalographic discharges in adults occur less often, are less well formed, and are of lesser amplitude than those recorded in affected children. Myoclonic seizures: This seizure type consists of brief, arrhythmic, jerking, motor movements that last less than a second. Myoclonic seizures often cluster within a few minutes. If they evolve into rhythmic jerking movements, they are classified as evolving into a clonic seizure. Myoclonus is not always epileptic in origin. For example, the myoclonic jerks during phase I of sleep are normal “release” phenomena. The classic ictal correlate of myoclonic seizures in the EEG consists of fast polyspike and slow wave complexes. Clonic seizures: This seizure type consists of rhythmic, motor, jerking movements with impairment of consciousness. Clonic seizures also could have a focal origin with or without impairment of consciousness. The focal seizures are classified as simple or complex partial seizures. Typically, generalized clonic seizures simultaneously involve the upper and lower extremities. The ictal EEG correlate consists of bilateral rhythmic epileptiform discharges. Tonic seizures: This seizure type consists of sudden-onset tonic extension or flexion of the head, trunk, and/or extremities for several seconds. Typically, these seizures occur in relation to drowsiness, shortly after falling asleep, or just after awakening. They often are associated with other neurologic abnormalities. The ictal correlate of tonic seizures in the EEG includes an electrodecremental response, which is a high-frequency electrographic discharge in the beta frequency (also known as "beta buzz") with a relatively low amplitude compared to the background rhythm and may evolve into slow spike-and-wave complexes or diffuse polyspikes. Tonic-clonic seizures: This seizure type commonly is referred to as "grand mal" seizures. They consist of several motor behaviors including generalized tonic extension of the extremities lasting for few seconds followed by clonic rhythmic movements and prolonged postictal confusion. Clinically, the only behavioral difference between these seizures and secondarily generalized tonic-clonic seizures is that these seizures lack an aura. However, the aura preceding the secondarily generalized seizure often is forgotten because of postictal amnesia. The ictal correlate of generalized tonic-clonic seizures consists of generalized (bilateral) spike or polyspike and slow wave complexes. Often these epileptiform discharges have higher amplitude in the frontal regions.

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Atonic seizures: This seizure type occurs in people with significant neurologic abnormalities. These seizures consist of brief loss of postural tone, often resulting in falls and injuries. The ictal EEG correlate is similar to abnormalities observed in tonic seizures. Unclassified seizures Each seizure type is classified by its clinical and EEG manifestations. Occasionally, classifying seizures is difficult despite videotape review of the data. Classification of epileptic syndromes Epileptic seizures are symptoms of neurologic dysfunction and are but one manifestation of many neurologic diseases. Like any other syndrome in medicine, an epileptic syndrome is a group of signs and symptoms that share a common pathogenesis, prognosis, and response to treatment. International classification of epilepsies and epileptic syndromes In 1989, the ILAE developed a classification of epileptic syndromes. At the present time, a task force is revising this syndromatic classification. The current system comprises 2 major categories: localization-related syndromes and generalized-onset syndromes. Ideally, physicians would classify the seizures of their patients using the classification for seizure types, and if possible, make a syndromatic diagnosis. Localization-related epilepsies and syndromes • Idiopathic with age-related onset • Benign childhood epilepsy with centrotemporal spikes • Childhood epilepsy with occipital paroxysms • Symptomatic Generalized epilepsies and syndromes • Idiopathic with age-related onset • Benign neonatal familial convulsions • Benign neonatal convulsions • Benign myoclonic epilepsy of infancy • Childhood absence epilepsy (pyknolepsy) • Juvenile absence epilepsy • Juvenile myoclonic epilepsy • Epilepsy with grand mal seizures on awakening • Idiopathic and/or symptomatic infantile spasms • Lennox-Gastaut syndrome • Epilepsy with myoclonic astatic seizures • Epilepsy with myoclonic absences • Symptomatic These epileptic syndromes are described in various articles of this electronic journal. Historical background Epileptic seizures have been recognized for several millennia. One of the earliest descriptions of a secondarily generalized tonic-clonic seizure was recorded over 3000 years ago in Mesopotamia. The seizure was attributed to the god of the moon. Epileptic seizures were described in several ancient cultures, including China, Egypt, and India. An ancient Egyptian papyrus described a seizure in a man who had experienced prior head trauma. Hippocrates wrote the first book about epilepsy almost 2500 years ago. He rejected ideas regarding the divine etiology of epilepsy and concluded that it was caused by an excess of phlegm that caused abnormal brain consistency. Hippocratic teachings were forgotten, and divine etiologies again dominated beliefs about epileptic seizures during medieval times. Even at the turn of the last century, excessive masturbation was considered a cause of epilepsy. This hypothesis is credited as leading to the use of the first effective anticonvulsants, bromides. The modern era on the investigation of the etiology of epilepsy began with the work of Fritsch, Hitzig, Ferrier, and Caton in the 1870s. They recorded and evoked epileptic seizures in the cerebral cortex of animals. In 1929, Berger discovered that electrical brain signals could be recorded from the human head with scalp electrodes; this discovery led to the use of EEG to study and classify epileptic seizures. Gibbs, Lennox, Penfield, and Jasper further advanced the understanding of epilepsy and developed the system of the 2 major classes of epileptic seizures 3

currently in use. An excellent historical review of seizures and epilepsy, written by E. Goldensohn, was published recently in the journal Epilepsia commemorating the 50th anniversary of the creation of the American Epilepsy Society. Pathophysiology: Seizures are a paroxysmal manifestation of the electrical properties of the cerebral cortex. A seizure results when a sudden imbalance occurs between the excitatory and inhibitory forces within the network of cortical neurons in favor of a sudden-onset net excitation. If the affected cortical network is located in the visual cortex, the clinical manifestation would be visual phenomena. Other affected areas of primary cortex give rise to sensory, gustatory, or motor manifestations. The pathophysiology of partial-onset seizures differs from the mechanisms underlying generalized-onset seizures. Overall, cellular excitability is increased, but the mechanisms of synchronization appear to differ significantly and thus should be discussed separately. Partial-onset seizures The clinical neurophysiological hallmark of partial-onset seizures is the focal interictal epileptiform spike or sharp wave. The cellular neurophysiological correlate of an interictal epileptiform discharge in single cortical neurons is the paroxysmal depolarization shift (PDS). The PDS is characterized by a prolonged calcium-dependent depolarization that results in multiple sodiummediated action potentials during the depolarization phase, and it is followed by a prominent after hypolarization, which is a hyperpolarized membrane potential beyond the baseline resting potential. Calcium-dependent potassium channels mostly mediate the afterhyperpolarization. When multiple neurons fire PDSs in a synchronous manner, the extracellular field recording would show an interictal spike. If the number of discharging neurons is over several million, they usually can be recorded with scalp EEG electrodes. Calculations show that the interictal spikes need to spread to about 6 cm2 of cerebral cortex before they can be detected with scalp electrodes. Several factors may be associated with the transition from an interictal spike to an epileptic seizure. When any of the mechanisms that underlie an acute seizure become a permanent alteration, patients are assumed to then develop a propensity for recurrent seizures (ie, epilepsy). Mechanisms leading to decreased inhibition Defective GABA-A inhibition Gamma-butyric acid (GABA) is the main inhibiting neurotransmitter in the brain. GABA binds to 2 major classes of receptors: GABA-A and GABA-B. GABA-A receptors are coupled to chloride channels, and they are one of the main targets modulated by the anticonvulsants that are currently available. The reversal potential of chloride is about -70mV. The contribution of chloride channels during resting potential in neurons is minimal because at the typical resting potential, which is near -70mV, no significant electromotive force exists for net chloride flux. However, chloride currents become more important at more depolarized membrane potentials. These channels make it more difficult to achieve the threshold membrane potential necessary for an action potential. Their influence in the neuronal membrane potential increases, as the neurons become more depolarized via summation of the excitatory postsynaptic potentials (EPSPs). Properties of the chloride channels associated with the GABA-A receptor often are modulated clinically using benzodiazepines (eg, diazepam, lorazepam, clonazepam), barbiturates (eg, phenobarbital, pentobarbital), or the anticonvulsive drug topiramate. Benzodiazepines increase the frequency of openings of chloride channels, while barbiturates increase the duration of openings of these channels. Topiramate increases the frequency of channel openings but binds to a site that is different than the benzodiazepine receptor site. Individual chloride channels appear to be modulated by either benzodiazepines or barbiturates but not both. Whether combining topiramate with either class of agents would increase chloride currents is unknown. Alterations in the normal state of the chloride channels described above result in increased membrane permeability and conductance of chloride ions. In the end, the behavior of all individual chloride channels sum up to form a large chloride-mediated hyperpolarizing current that counterbalances the depolarizing currents created by summation of EPSPs induced by activation of the excitatory input. The EPSPs are the main form of communication between neurons, and they are mediated by the release of the excitatory amino acid glutamate from the presynaptic element. The effect of the 4

release of glutamate in the postsynaptic neuron is mediated by 3 main receptors: N-methyl-Daspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/ kainate, and metabotropic, which are coupled via different mechanisms to several depolarizing channels. They are tempered by the inhibitory postsynaptic potentials (IPSPs), which are mediated mainly by release of GABA in the synaptic cleft with postsynaptic activation of GABA-A receptors. All channels in the nervous system (and essentially any living organism) appear to be subject to modulation via several mechanisms such as phosphorylation, possibly by a change in the tridimensional conformation of a protein within the channel. The chloride channel has several phosphorylation sites, one of which appears to be modulated by topiramate. The phosphorylation of this channel induces a change in normal electrophysiological behavior, with more frequent channel openings but only for certain types of chloride channels. Each channel has a multimeric structure with several subunits of different types. Chloride channels are no exception; they have a pentameric structure. The subunits are molecularly related but different proteins. The heterogeneity of electrophysiological responses of different GABA-A receptors is due to different combinations of the subunits. In mammals, at least 6 different alpha subunits and 3 different types of beta and gamma subunits exist for the GABA-A receptor complex. A complete GABA-A receptor complex (which in this specific case is the chloride channel itself) is formed with two alpha, two beta, and one gamma subunits. The number of possible combinations of the known subunits is almost 1000; thus, theoretically, over 1000 receptor types may exist. In practice, however, only about 20 of those combinations have been found in the normal mammalian brain. Thus, some epilepsies may be due to mutations or lack of expression of 1) the different GABA-A receptor complex subunits, 2) the molecules that govern their assemble, or 3) the molecules that modulate their electrical properties. For example, hippocampal pyramidal neurons might not be able to assemble alpha 5/beta 3/gamma 3 receptors because of deletion of chromosome 15 (ie, Angelman syndrome). Changes in the distribution of GABA-A receptor complex subunits have been demonstrated experimentally in several animal models of partial-onset epilepsy such as electrical kindling, chemical kindling, and the pilocarpine model. In the last model, decreases in the concentration of mRNA for the alpha 5 subunit of the surviving interneurons have been reported in the CA1 region of the rat hippocampus (Houser & Esclapez, 1996). Defective GABA-B inhibition The GABA-B receptor is coupled to potassium channels, forming a current that has a relatively long duration of action compared to the chloride current evoked by activation of the GABA-A receptor. Because of the long duration of action, alterations in the GABA-B receptor are thought to possibly play a major role in the transition between the interictal abnormality and a partial-onset seizure. The molecular structure of the GABA-B receptor complex consists of 2 subunits with 7 transmembrane domains each. Coupling to the potassium channel is mediated by a G protein, a second messenger system, which explains the latency and long duration of the response. In many cases, GABA-B receptors are located in the presynaptic element of an excitatory projection. Thus, release of GABA from the interneuron terminal inhibits the postsynaptic neuron via 2 mechanisms: 1) directly, by inducing an IPSP, which is mediated typically by a GABA-A chloride current, and 2) indirectly, by inhibiting the release of excitatory neurotransmitter in the presynaptic afferent projection, typically with a GABAB potassium current. Once again, alterations or mutations in the different subunits, or in the molecules that regulate their function, might affect seizure threshold or a propensity for recurrent seizures. Defective activation of GABA neurons GABA neurons are activated via feedforward and feedback projections by excitatory neurons. These 2 types of inhibition in a neuronal network are defined on the basis of time of activation of the GABAergic neuron relative to that of the principal neuron output of the network, such as the hippocampal pyramidal CA1 cell. In feedforward inhibition, GABAergic cells receive a collateral projection from the main afferent projection that activates the CA1 neurons, namely the Schaffer collateral axons from the CA3 pyramidal neurons. This feedforward projection activates the soma of GABAergic neurons prior to, or simultaneously with, activation of the apical dendrites of the CA1 pyramidal neurons. 5

Activation of the GABAergic neurons results in an IPSP that inhibits the soma or axon hillock of the CA1 pyramidal neurons almost simultaneously with the passive propagation of the excitatory potential (ie, EPSP) from the apical dendrites to the axon hillock. In this manner, the feedforward projection primes the inhibitory system in a manner that allows it to inhibit the pyramidal cell’s depolarization and firing of an action potential. Feedback inhibition is another system that allows the GABAergic cells to control repetitive firing in principal neurons such as pyramidal cells and to inhibit the surrounding pyramidal cells. Recurrent collaterals from the pyramidal neurons activate the GABAergic neurons once the pyramidal neurons have fired an action potential once. In the past few years, experimental evidence has indicated that some other kind of interneuron might be a gate between the principal neurons and the GABAergic neurons. In the dentate gyrus, the mossy cells of the hilar polymorphic region appear to gate the inhibitory tone and activate GABAergic neurons. The mossy cells receive both feedback and feedforward activation, which they convey to the GABAergic neurons. However, in certain circumstances they appear highly vulnerable to seizure-related neuron loss. Once some of the mossy cells are lost, the activation of the GABAergic neurons is impaired (Sloviter, 1999). Synaptic reorganization is a form of brain plasticity induced by neuronal loss. Formation of new circuits that include excitatory and inhibitory cells has been demonstrated in several animal models and in humans with intractable temporal lobe epilepsy. Insufficient sprouting that attempts restoring inhibition might alter the balance between excitatory and inhibitory tone in the neural network. Defective intracellular buffering of calcium Recurrent seizures induced with a variety of methods result in a pattern of interneuron loss in the hilar polymorphic region in rodents, with striking loss of the neurons that lack calcium-binding proteins parvalbumin and calbidin. In rat hippocampal slices, these interneurons demonstrate progressive inability to maintain a hyperpolarized resting membrane potential; eventually, they die. An experiment that used microelectrodes containing the calcium chelator BAPTA demonstrated reversal of the deterioration in the membrane potential as the calcium chelator was allowed to diffuse in the interneuron, demonstrating the critical role of adequate concentrations of calciumbinding proteins (Scharfman and Schwartzkroin, 1989). A postulated factor that contributes to medical intractability in some patients may contribute to the abnormally low concentrations of these protein or even to their dysfunction. The end result is the premature loss of interneurons, altering inhibitory control over the local neuronal network in favor of net excitation. This may explain, for example, why 2 patients who experience a similar event such as a simple febrile convulsion exhibit remarkably dissimilar outcomes; one may develop completely normally and the other develop intractable partial-onset epilepsy a few years later. Mechanisms leading to increased excitation Increased activation of NMDA receptors Glutamate is the major excitatory neurotransmitter in the brain. The release of glutamate causes an EPSP in the postsynaptic neuron via activation of glutaminergic receptors AMPA/kainate, NMDA, and the metabotropic receptor. Fast neurotransmission is achieved with the first 2 types. The metabotropic receptor alters cellular excitability via a second messenger system with later onset but longer duration. The major functional difference between the 2 fast receptor types is that the AMPA/kainate receptor opens channels that primarily allow passage of monovalent cations (ie, sodium and potassium), whereas the NMDA type is coupled to channels that also allow passage of divalent cations (ie, calcium). Calcium is a catalyst for many intracellular reactions that lead to changes in phosphorylation and gene expression. Thus, it is in itself a second messenger system. NMDA receptors generally are assumed to be associated with learning and memory. The activation of NMDA receptors is increased in several animal models of epilepsy such as kindling, kainic acid status, pilocarpine, and other animal models. Some patients with epilepsy may have an inherited predisposition for faster or longer-lasting activation of NMDA channels, resulting in alteration of seizure threshold. Other possible alterations include the ability of intracellular proteins to buffer calcium, resulting in a higher vulnerability of neurons from any kind of injury that otherwise would not have resulted in neuronal death. 6

Increased synchrony between neurons due to ephaptic interactions Electrical fields created by synchronous activation of pyramidal neurons in laminar structures such as the hippocampus may increase further the excitability of neighboring neurons by nonsynaptic (ie, ephaptic) interactions. Other possible nonsynaptic interactions include electrotonic interactions due to the presence of gap junctions or changes in extracellular ionic concentrations of potassium and calcium. Increased synchrony and/or activation due to recurrent excitatory collaterals Neuropathologic studies of patients with intractable partial-onset epilepsy have revealed frequent abnormalities in the limbic system, particularly within the hippocampal formation. A common lesion is hippocampal sclerosis, which consists of a pattern of gliosis and neuronal loss primarily in the hilar polymorphic region and CA1 pyramidal region with relative sparing of the CA2 pyramidal region and an intermediate lesion in the CA3 pyramidal region and dentate granule cells. Prominent hippocampal sclerosis is found in about two thirds of patients with intractable temporal lobe epilepsy. Experimentally, animal models of status epilepticus are able to reproduce this pattern of injury; however, animals that experienced more than 100 brief convulsions induced by kindling seizures also demonstrated a similar pattern (Cavazos et al, 1994). A more subtle, but apparently more common, situation is the presence of mossy fiber sprouting (Sutula et al, 1988). Mossy fibers are the axons of the dentate granule cells and typically project into the hilar polymorphic region and the CA3 pyramidal neurons. As neurons in the hilar polymorphic region are lost, their feedback projection into the dentate granule cells also degenerates. Denervation due to loss of the hilar projection induces sprouting of the neighboring mossy fiber axons. The net consequence of this phenomenon is formation of recurrent excitatory collaterals, increasing the net excitatory drive of dentate granule neurons. The mechanisms discussed here may coexist in different combinations to cause partial-onset seizures. If the mechanisms leading to a net increased excitability become permanent alterations, patients may experience pharmacologically intractable partial-onset epilepsy. Currently available medications were developed in acute models of convulsions and clinically are most effective at blocking propagation of a seizure. Further understanding of the mechanisms that permanently increase net excitability may lead to development of true “antiepileptic” drugs that alter the natural history of epilepsy. Generalized-onset seizures The best-understood example of the pathophysiological mechanisms of generalized seizures is the thalamocortical interactions that may underlie typical absence seizures. The thalamocortical circuit has normal oscillatory rhythms with periods of relatively increased excitation and periods of relatively increased inhibition. It generates the oscillations seen, for example, in sleep spindles. The circuitry includes the pyramidal neurons of the neocortex, the thalamic relay neurons, and the neurons in the nucleus reticularis of the thalamus (NRT). Alterations in the thalamocortical rhythms may result in primarily generalized-onset seizures. The thalamic relay neurons receive ascending inputs from spinal cord and project to the neocortical pyramidal neurons. The circuitry has prominent regulation by cholinergic pathways from the forebrain and the ascending serotonergic, noradrenergic, and cholinergic brainstem pathways (McCormick, 1992). The thalamic relay neurons are capable of having oscillations in the resting membrane potential, which result in a higher-than-normal probability of synchronous activation of the neocortical pyramidal neuron during the period of depolarization and a significantly lower probability of activating the neocortex during the relative period of hyperpolarization. The key to the presence of these oscillations is the presence of transient low-threshold calcium channels, also known as Tcalcium current. In experimental animals, the activity of thalamic relay neurons is controlled by inhibitory inputs from NRT. The NRT neurons are inhibitory and contain GABA as their main neurotransmitter. They regulate the activation of the T-calcium channels in thalamic relay neurons because those channels need to be de-inactivated in order to open transitorily. T-calcium channels have 3 functional states: open, closed, and inactivated. Calcium enters the cells when the T-calcium channels are open. Immediately after closing, the channel is unable to open again until it reaches a state of inactivation. The thalamic relay neurons have GABA-B receptors in the cell body and receive tonic activation by GABA release from the NRT projection to the thalamic relay neuron. The result is a hyperpolarization that switches the T-calcium channels 7

away from the inactive state, permitting the synchronous opening of a large population of the Tcalcium channels every 100 milliseconds or so. Several animal models of absence seizures, such as lethargic mice, demonstrate that GABA-B receptor antagonists suppress absence seizures, while GABA-B agonists worsen these seizures (Hosford et al, 1992). The anticonvulsants that prevent absence seizures, such as valproic acid and ethosuximide, suppress the T-calcium current, blocking its channels. One clinical problem that has been observed is that some anticonvulsants that increase GABA levels, such as gabapentin, tiagabine, and vigabatrin, are associated with exacerbation of absence seizures. Increased GABA level is thought to allow a higher degree of synchronization of the thalamocortical circuit and to permit a larger pool of T-calcium channels to be available for activation. Frequency: • The lifetime likelihood of experiencing at least one epileptic seizure (febrile or nonfebrile) is about 9%, and the lifetime likelihood of being diagnosed as having epilepsy is almost 3%. However, the prevalence of active epilepsy is only 0.8%. It was demonstrated that the incidence per year of new cases of epilepsy (recurrent nonfebrile seizures), is about 100 per 100,000 persons aged 0-1 year, 40 per 100,000 persons aged 39-40 years, and 140 per 100,000 persons aged 79-80 years. By the age of 75 years, the cumulative incidence of epilepsy is 3,400 per 100,000 men (3.4%) and 2,800 per 100,000 women (2.8%). • Internationally: Studies in several countries have shown incidence and prevalence of seizures equel. In some countries, parasitic infections account for the increased incidence of seizures and epilepsy. Mortality/Morbidity: • Mortality: Seizures are a cause of death in a very small proportion of individuals with this medical condition. Most of the deaths are accidental due to impairment of consciousness. However, sudden unexpected death in epilepsy (SUDEP) may occur even when patients are resting in a protected environment such as a bed with rail guards. The incidence of SUDEP is quite low, being 2.3 times higher than the incidence of sudden death in the general population. The mechanism of death in SUDEP is controversial, but suggestions include cardiac arrhythmias, pulmonary edema, and suffocation during an epileptic seizure with impairment of consciousness. The risk of SUDEP is higher in people with uncontrolled seizures and probably in people with poor compliance. The higher risk of SUDEP than sudden death in the general population is accounted for mostly by people with long-standing partial-onset epilepsy. The risk is even higher for people with uncontrolled secondarily generalized tonic-clonic seizures. Physicians should try to educate regarding seizure precautions. Most accidents occur while patients have impairment of consciousness. This is one of the rationales for restrictions on driving, swimming, and working or recreation at great heights. Treatment with anticonvulsants decreases the likelihood of an accidental seizure-related death. • Morbidity: Trauma is not uncommon among people with generalized tonic-clonic seizures. Tongue, facial, and limb lacerations; ecchymosis; and abrasions often develop as a result of the repeated tonic-clonic movements, which injure body parts. Atonic seizures also are associated with frequent facial and neck injuries. Worldwide, burns are the most common serious injury associated with epileptic seizures. History: The diagnosis of epileptic seizures is made by analysis of a detailed clinical history and confirmed by ancillary tests. Typically, the best provider of adequate history is an observer of repeated events. However, the patient also provides invaluable details about the presence of an aura, preservation of consciousness, and the postictal state. A key feature of epileptic seizures is their stereotypic nature. • Key questions that help clarify the seizure type include the following: • Was any warning noted before the spell? If so, what kind of warning occurred? • What did the patient do during the spell? • Was the patient able to relate to the environment during the spell and/or does the patient have recollection of the spell? 8

• How did the patient feel after the spell? How long did it take for the patient to get back to baseline condition? • How long did the spell last? • How frequent do the spells occur? • Are any precipitants associated with the spells? • Has the patient shown any response to therapy for the spells? Physical: The clinical diagnosis of seizures is based on the history obtained from the patient and, most importantly, the observers. The physical examination helps in the diagnosis of specific epileptic syndromes that involve abnormal physical findings, such as dermatologic abnormalities. Causes: Epileptic seizures are only one manifestation of neurologic or metabolic diseases. Epileptic seizures have multiple causes, including a genetic predisposition for certain seizures, head trauma, stroke, brain tumors, alcohol or drug withdrawal, and other conditions. Epilepsy is a medical condition with recurrent unprovoked seizures. Thus, repeated seizures due to alcohol withdrawal are not epilepsy. The causes for most epileptic syndromes are described in several articles of this journal. Cardioembolic Stroke Confusional States and Acute Memory Disorders Febrile Seizures First Seizure in Adulthood: Diagnosis and Treatment First Seizure: Pediatric Perspective Frontal Lobe Epilepsy Idiopathic Orthostatic Hypotension and other Autonomic Failure Syndromes Migraine Headache [Seizure, Pseudo] /NEURO/topic0.htm Somnambulism (Sleep Walking) Transient Global Amnesia Other Problems to be Considered: Syncope (eg, cardiac arrhythmia, vasovagal syncope, dysautonomia) Metabolic conditions (eg, hypoglycemia) Migraine (eg, migrainous aura, migraine equivalent) Vascular conditions (eg, transient ischemic attacks) Sleep disorder (eg, cataplexy, narcolepsy, night terror) Movement disorder (eg, paroxysmal dyskinesia) GI conditions (eg, esophageal reflux in neonates and infants) Psychiatric conditions (eg, conversion, panic attacks, breath-holding spells, malingering, secondary gain) Lab Studies: • Prolactin levels obtained shortly after a seizure have been used to help assess the etiology of a spell. However, prolactin levels are considerably variable when associated with epileptic seizures. Imaging Studies: • The 2 studies that need to be performed after a seizure are neuroimaging (eg, brain MRI, head CT scan) and EEG. • Neuroimaging • A neuroimaging study, such as brain MRI or head CT scan, provides evidence about structural abnormalities that could be the cause for a seizure. • If the patient has a normal neurologic examination and is back to the usual baseline (eg, cognitive, motor), the preferred study is a brain MRI because it has a much higher resolution to detect subtle abnormalities. • Brain MRI studies with additional, thin-slice, coronal cuts using fast spin echo (FSE) or inversion recovery (IR) sequences from the presumed region of 9

epileptogenic aura are quite useful to assess cortical lesions, which may be amenable to potentially curative surgery. Note that not every brain MRI study provides the same quality of information. • Tests: • Electroencephalogram • Interictal epileptiform discharges or focal abnormalities strengthen the diagnosis and provide some help in determining the prognosis. • Although the criterion standard for diagnosis and classification of epileptic seizures includes the interpretation of a sleep-deprived EEG, the clinical history remains the cornerstone for the diagnosis of epileptic seizures. • Video-EEG monitoring might be needed to establish a definitive diagnosis of spells with impairment of consciousness. This test can rule out an epileptic etiology with a high degree of confidence if the patient has demonstrable impairment of consciousness during the spell in question. Video-EEG monitoring also is used to characterize the seizure type and epileptic syndrome for optimization of pharmacologic treatment and for presurgical workup. Procedures: • Lumbar puncture for cerebrospinal fluid (CSF) examination has a role in the obtunded patient or in patients in whom meningitis or encephalitis is suspected. Histologic Findings: Multiple pathophysiological causes for epileptic seizures exist. Some epileptic syndromes have very specific histopathological abnormalities. For further discussion, refer to articles on specific epileptic syndromes. Medical Care: The goal of treatment is to make the patient seizure free without adverse effects. This goal is achieved in over 60% of people who require treatment with anticonvulsants. Unfortunately, many people experience adverse effects while being treated to prevent seizures, and some people are refractory to medical therapy. Monotherapy is important because it decreases the likelihood of adverse effects and avoids drug interactions. In addition, monotherapy may be cheaper, as many of the anticonvulsants have hepatic enzyme–inducing properties that decrease the serum level of the concomitant drug, thus increasing the required dose of the concomitant drug. People with seizures experience psychosocial adjustments after their diagnosis; therefore, social/vocational rehabilitation may be needed. Many physicians underestimate the consequences that epilepsy may have on patients. Patients with epilepsy may live in fear of experiencing the next seizure and may be unable to drive or work at heights. • Special situations in which treatment is needed • The mainstay of therapy for people with recurrent unprovoked seizures is the use of anticonvulsants. If a patient has had more than one seizure, administration of an anticonvulsant is recommended. On the other hand, the standard of care for the treatment of a single unprovoked seizure is avoidance of typical precipitants, such as alcohol and sleep deprivation; no anticonvulsants are recommended unless the patient has risk factors for recurrence. • Studies have shown that the risk of recurrence in the 2 years following a first unprovoked seizure range from 15-70% depending upon several factors. The 3 main factors that have been discovered as risk factors for recurrence are abnormal brain MRI, abnormal sleep-deprived EEG, and partial-onset seizure. • The abnormal brain MRI refers to a possible substrate for an epileptogenic zone and, thus, most often a brain injury that led to epilepsy is in cortical and limbic regions. Diffuse abnormalities, such as hydrocephalus, might increase the risk by injuring the cerebral cortex. • An abnormal sleep-deprived EEG could include any or several of the following abnormalities: epileptiform discharges, focal slowing, diffuse background slowing, and intermittent diffuse intermixed slowing. The presence of epileptiform abnormalities and focal slowing are associated with a higher risk of seizure recurrence than the latter 2 abnormalities. Nevertheless, the risk of recurrence for a 10

person who had one generalized tonic-clonic seizure with a normal EEG, normal brain MRI, and no evidence of focal onset is about 15%. On the other hand, if all risk factors are present, the risk of seizure recurrence is approximately 80%. The first patient would not be treated and the second would be treated. The big unresolved question is what to do with people who have one abnormality with risk factors in the range of 30-50%. • When the authors have a patient who has one abnormality with risk factors in the range of 30-50%, they talk to the patient and discuss the possibilities, including risk of seizure recurrence, risk of toxic effects from taking the anticonvulsant, and benefits of avoiding another seizure. The authors also discuss seizure precautions, including not driving for a specific period of time. Treatment with anticonvulsants does not alter the natural history of seizure recurrence; it only masks the risk for the duration of treatment. • The FIRST Group Study, published in 1993 in Neurology, randomized 397 patients who had a unprovoked, generalized tonic-clonic first seizure to take a conventional anticonvulsant (ie, carbamazepine, phenobarbital, phenytoin, valproic acid) or no treatment. About 18% of treated patients experienced a seizure recurrence in 1 year, as compared to 39% of untreated patients. Thus, patients must be told that anticonvulsants reduce the chances of having another seizure but that anticonvulsants do not totally stop seizures from recurring. Treatment with anticonvulsants: The mainstay of treatment is anticonvulsant medication. The seizure type and the specific epileptic syndrome play some role in the selection of anticonvulsants, probably because of different pathophysiological mechanisms. Mechanisms of action of anticonvulsants can be divided into 5 large groups, including (1) blockers of repetitive activation of sodium channel, (2) GABA enhancers, (3) glutamate modulators, (4) T-calcium channel blockers, and (5) carbonic anhydrase inhibitors. Some anticonvulsants have multiple mechanisms of action (eg, lamotrigine, topiramate, valproic acid), and some have only one known mechanism of action (eg, phenytoin, carbamazepine, ethosuximide). • Absence seizures: If only absence seizures are present, most neurologists treat with ethosuximide. If absence seizures are present with other seizure types, such as generalized tonic-clonic seizures or myoclonic seizures, the choices are valproic acid, lamotrigine, and topiramate. Do not use carbamazepine or tiagabine as they might exacerbate absence seizures. • Tonic/atonic seizures: Typically, tonic or atonic seizures indicate significant brain injury. The Lennox-Gastaut syndrome is one common example of tonic seizures. The Lennox-Gastaut syndrome is best treated with broad-spectrum drugs, such as valproic acid, lamotrigine, topiramate, or felbamate. Clinical trials of levetiracetam and zonisamide are being conducted. • Myoclonic seizures: This seizure type has a bimodal distribution. Myoclonic epilepsies of infancy usually have a poor prognosis; however, in late childhood and adolescence, the syndrome of juvenile myoclonic epilepsy (JME) is often the cause of myoclonic seizures. Typically, JME is a benign process that is treated easily but has a high recurrence rate (approximately 80%) after discontinuation of anticonvulsants. The best medications for JME and myoclonic seizures include valproic acid, lamotrigine, and topiramate. Some anecdotal evidence suggests that zonisamide might be helpful in JME. • Primary generalized tonic-clonic seizures: This seizure type also responds to valproic acid, topiramate, or lamotrigine. • Partial-onset seizures: Carbamazepine is considered the first line of therapy. • However, the Veterans Administration (VA) cooperative studies clearly demonstrated similar efficacies for carbamazepine, phenytoin, primidone, and phenobarbital; carbamazepine and phenytoin were tolerated better by men than women. 11

• The VA Cooperative Study II showed that carbamazepine and valproic acid had similar efficacies. • All new medications were tested as adjunctive therapy, and head-tohead comparison trials have been conducted between new drugs and carbamazepine in Europe. In general, the new drugs have similar statistical efficacies but fewer adverse effects. • If carbamazepine fails to control the seizures, lamotrigine, topiramate, tiagabine, gabapentin, levetiracetam, oxcarbazepine, and zonisamide are considered for second- or third-line therapy. Several of the new anticonvulsants, including lamotrigine and oxcarbazepine, are indicated as monotherapy. Topiramate is widely expected to be approved for that indication soon. • Although the new anticonvulsants are considered second- or third-line therapy, in some patients they could be used as first-line therapy. • Discussing the side-effect profiles of anticonvulsants with patients is important, as the efficacies of anticonvulsants appear to be similar. • Future directions will involve antiepileptic drugs that alter the natural history of epilepsy. Some evidence in animal models of epilepsy suggests that at least 2 of the current anticonvulsants, topiramate and levetiracetam, have neuroprotective effects and might slow down the natural history of epilepsy. However, the applicability of animal data to human patients is unknown. The use of anticonvulsants is slightly different in several populations of patients, including neonates, children, elderly patients, pregnant women, and patients with hepatic or renal insufficiency. • Neonates and children: Children and neonates tend to require similar loading doses per kilogram of body weight, but they tend to metabolize the drugs faster than adults. They also have rapid increases in total volume of distribution. • Elderly patients: Older patients present the opposite problem. Slower hepatic metabolism, decreased renal clearance, and decreased volume of distribution are normal features of the aging process. These features translate to lower initial and maintenance doses than in other adults. • Women’s issues: The efficacy of birth control pills is decreased by the use of enzyme-inducing anticonvulsants, such as carbamazepine, phenytoin, phenobarbital, primidone, felbamate, lamotrigine, and oxcarbazepine. Some obstetricians use an estrogen/progesterone pill with higher hormonal doses. An alternative approach, and possibly a preferred approach, is to use a second method of contraception. • Woman of childbearing age should take at least 1 mg of folic acid to decrease the rate of neural tube malformations in the fetus. • The available evidence strongly suggests that, during pregnancy, women should take the medication that best controls their epilepsy. Switching medications during pregnancy is not recommended because of the risk of losing control. • Women should be treated with only one anticonvulsant rather than polytherapy. Data from Japan show an exponential risk of birth defects as more anticonvulsants are used in polytherapy. • Drug serum levels should be obtained frequently because of the many physiological changes that take place during pregnancy, including changes in volume of distribution, protein binding, and hepatic metabolism and erratic absorption. • The use of amniocentesis is a personal decision between the woman and her obstetrician. The most important point is to have a clear idea that the information obtained in that study would be useful for a clinical decision. • Hepatic and renal insufficiency: Considerable data are available on the use of phenytoin in both conditions. However, phenytoin is not a preferred medication 12

because of its nonlinear kinetics, hepatic autoinduction, large number of drug interactions, and high degree of protein binding. Among all anticonvulsants, phenytoin, valproic acid, and felbamate have been associated with acute hepatic injury. Gabapentin, topiramate, and levetiracetam are excreted mostly via renal clearance. They are useful in patients with hepatic failure, especially when a druginduced etiology is suspected. Their doses could be adjusted for renal insufficiency. Serum levels of anticonvulsants: Obtaining serum levels of anticonvulsants could aid in better care for patients with seizures and epilepsy. Obtain a serum concentration to answer a clinical question. In practice, the authors do not advise routine serum levels. Their 5 recommended indications for the use of serum levels are as follows: • Baseline: Once efficacy has been achieved in controlling seizures, determine the drug levels needed to make a patient seizure free. • Toxicity: Determine the upper level of the anticonvulsant that the patient can tolerate without toxic effects. • Lack of efficacy: Before giving up on an anticonvulsant, knowing whether the patient has achieved an adequate drug level is imperative. • Noncompliance: Approximately 30% of patients miss one dose of medication every month. • Autoinduction: After using an anticonvulsant for several weeks, the baseline trough serum concentration begins to decrease slowly because of hepatic autoinduction. Most often, this phenomenon is seen with carbamazepine, oxcarbazepine, and lamotrigine. Like any medical test, serum concentrations of anticonvulsants help in making clinical decisions, but the individual patient’s response should be the main consideration. For example, a patient with JME might be seizure free with a valproic acid level of 30 mcg/mL, which typically is considered subtherapeutic. Therefore, clinical judgment regarding how well the patient is doing (ie, no seizures, no adverse effects) should prevail over a laboratory reading. The usual therapeutic ranges include peak and trough levels of a group of adult patients. If the problem under study is toxicity, a peak level is desirable. However, under most circumstances, a trough level is a better indication of efficacy. Nonpharmacologic treatments • Diet: The ketogenic diet has a role in children with severe epilepsy. One major problem with the diet is that despite television programs and a movie supporting its use, fewer than 10% of people continue using the diet after a year. Furthermore, any small carbohydrate intake (eg, a lollypop, a piece of candy) resets ketone metabolism for 2 weeks, losing its antiseizure efficacy. The diet, which relies heavily on Crisco, is very difficult to maintain. The diet is unquestionably efficacious in some refractory cases, but the authors do not consider a teenager or an adult for this treatment unless all intake is being delivered via a gastric tube. • Vagal nerve stimulator: The vagal nerve stimulator (VNS) is a palliative device approved for treatment of medically refractory partial-onset epilepsy in adults. Some studies demonstrate its efficacy in partial-onset seizures and in a smaller number of patients who had primary generalized epilepsy. Randomized studies showed modest efficacy at 3 months, but postmarketing experience shows another group of patients who take a longer time to show improvement. According to the manufacturer's registry, the efficacy of the device at 18 months is in the range of 40-50%, where efficacy is defined as having a reduction in seizures of 50% or more. In addition, a great number of patients report improvement in seizure intensity and general mood. However, seizure-free rates for pharmacologically intractable partial-onset epilepsy are under 10%. Discontinuation of anticonvulsants • Once a person has been seizure free for a significant period of time, typically 2-5 years, physicians consider the possibility of discontinuing medication. A large proportion of patients outgrow many epileptic syndromes of childhood. These 13

patients do not need to take anticonvulsants. On the other hand, the seizure recurrence rate during adulthood for patients with the diagnosis of JME is about 80% in 2 years. This is despite many years of being seizure free with low doses of appropriate anticonvulsants. The relapse rate for adults is about 40-50%; for children, it is about 25%. This difference in outcome is probably due to the different epileptic syndromes that are prevalent in the 2 populations. • Many neurologists use the risk factors for new-onset seizures to assess patients for discontinuation of anticonvulsants. A normal sleep-deprived EEG and normal brain MRI lower the risk of relapse after discontinuation. Epileptiform or focal abnormalities in a sleep-deprived EEG and/or focal cortical abnormalities in a brain MRI significantly increase the risk of seizure recurrence after discontinuation. Other factors that have been associated with increased risk of seizure recurrence after discontinuation include the following: • Abnormal EEG (worse if epileptiform discharges or focal abnormalities are present) • Abnormal brain MRI (especially injury in cortical and limbic regions) • Several seizure types (worse if tonic or atonic seizures are present) • High number and frequency of seizures • Longer duration of epilepsy prior to controlling seizures • Shorter duration of seizure freedom • Most of the relapses after discontinuation occur in the first year (approximately 75%), and at least half of the patients who have another seizure have it during the first 3 months. Therefore, advise the patients to observe strict seizure precautions (including not driving) during the tapering and for at least 3 months after discontinuation, depending upon the laws of individual states. Obviously, the driving issue is an impediment in some patients and some opt for continuing therapy. The authors recommend that all anticonvulsants, except primidone, phenobarbital, and benzodiazepines, be discontinued gradually over 6-10 weeks, if they were used over a long period. Discontinue primidone, phenobarbital, and benzodiazepines over 1016 weeks. Surgical Care: • Brain surgery: The 2 major kinds of epilepsy surgery are palliative surgery and potentially curative surgery. • The most often used palliative surgery is the anterior callosotomy. This surgery has been indicated for patients with intractable atonic seizures, who often have facial and neck injuries due to a fall. This surgery still is performed, but quite rarely. The use of a VNS in such patients has reduced the need for an anterior callosotomy. • Several kinds of potentially curative surgeries exist, including lobectomies and lesionectomies. • In general, the epileptogenic zone must be mapped using video-EEG monitoring with intracranial electrodes unless the patient has a clear unilateral temporal lobe onset. • The outcomes of temporal lobe surgeries are better than those for surgeries in other areas. If a patient has unilateral temporal lobe seizures (as observed in video-EEG) and unilateral hippocampal sclerosis (as observed in brain MRI), the chances for a class I outcome (no seizures or only auras) at 2 years is 85%. • If the same patient with medically refractory epilepsy attempts another anticonvulsant, the chances for a class I outcome are less than 5% at 2 years. A patient with medically refractory epilepsy is one in whom 3 anticonvulsants with adequate serum concentrations have failed because of lack of efficacy and not because of adverse effects. After 3 anticonvulsants have failed, 14

patients with partial-onset seizures should be referred for a consultation with an epileptologist. Consultations: Two levels of referral exist. • The first level is for diagnosis and treatment. Consult a neurologist if patients with recurrent spells have not been diagnosed or have not responded to conventional therapy. Establishing the correct diagnosis is the first step to providing adequate treatment. • The second level of referral is to an epileptologist. Patients in whom at least 2 and preferably 3 anticonvulsants at adequate serum concentrations have failed should be referred to an epileptologist to consider all available therapies, including pharmacologic, dietary, and surgical treatments. Transfer: • Refer patients with intractable spells to a neurologist or an epileptologist for further workup, including video-EEG monitoring, to characterize the etiology of the seizures. Deterrence/Prevention: • Encourage use of helmets to prevent head trauma while biking, skiing, riding a motorcycle, or participating in other activities. Prognosis: • Prognosis for disability and recurrence of epileptic seizures depends upon the epileptic seizure type and the epileptic syndrome in question. See other articles regarding specific epileptic syndromes. Medical/Legal Pitfalls: • Medicolegal pitfalls can be divided in 2 sections: inappropriate diagnosis and liability of having seizures. • Inappropriate diagnosis: Diagnosis of seizures is based on clinical history. As many types of seizures are associated with impairment of consciousness, patients are unaware of their occurrence. The history as related by a witness is of high importance. The clinical diagnosis can be confirmed by abnormalities in the interictal EEG, but these abnormalities could be present in otherwise healthy individuals and their absence does not exclude the diagnosis of epilepsy. Video-EEG monitoring is the criterion standard for classification of seizure type or syndrome, or to make the diagnosis of pseudoseizures. However, as it is an expensive and laborious study, monitoring all patients is impractical; only those who do not respond to treatment should undergo video-EEG. Not all spells are seizures. Referral to an epilepsy center should be reserved for those patients whose seizures are refractory to treatment. Some cases of frontal lobe seizures are considered pseudoseizures for many years until appropriate diagnosis is made by video-EEG. • Liability of having seizures: Patients who have lapses of consciousness during wakefulness and in whom seizures are suspected should be educated and warned about seizure precautions. Documenting in the patient's chart that driving and occupational hazards for people with seizures were discussed is useful. Physicians should be aware of the state regulations regarding driving, which vary considerably among states and nations. Special Concerns: • People who have epileptic seizures and other spells of sudden-onset seizures should be placed under restrictions for driving, heights, and swimming to avoid unnecessary injury. The restrictions in each case differ because of the individual features of the seizures; degree of seizure control; and, in the US, state laws. Other countries have more permissive or restrictive laws regarding driving.

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