Epilepsy and Seizures 

Updated: May 30, 2019
Author: David Y Ko, MD; Chief Editor: Selim R Benbadis, MD 

Overview

Practice Essentials

Epilepsy is defined as a brain disorder characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition.[1]

Signs and symptoms

The clinical signs and symptoms of seizures depend on the location of the epileptic discharges in the cerebral cortex and the extent and pattern of the propagation of the epileptic discharge in the brain. A key feature of epileptic seizures is their stereotypic nature.

Questions that help clarify the type of seizure 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?

  • 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?

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of epileptic seizures is made by analyzing the patient's detailed clinical history and by performing ancillary tests for confirmation. Physical examination helps in the diagnosis of specific epileptic syndromes that cause abnormal findings, such as dermatologic abnormalities (eg, patients with intractable generalized tonic-clonic seizures for years are likely to have injuries requiring stitches).

Testing

Potentially useful laboratory tests for patients with suspected epileptic seizures include the following:

  • Prolactin levels obtained shortly after a seizure to assess the etiology (epileptic vs nonepileptic) of a spell; levels are typically elevated 3- or 4-fold and more likely to occur with generalized tonic-clonic seizures than with other seizure types; however, the considerable variability of prolactin levels has precluded their routine clinical use

  • Serum levels of anticonvulsant agents to determine baseline levels, potential toxicity, lack of efficacy, treatment noncompliance, and/or autoinduction or pharmacokinetic change

  • CSF examination in patients with obtundation or in patients in whom meningitis or encephalitis is suspected

Imaging studies

The following 2 imaging studies must be performed after a seizure:

  • Neuroimaging evaluation (eg, MRI, CT scanning)

  • EEG

The clinical diagnosis can be confirmed by abnormalities on 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 standard test for classifying the type of seizure or syndrome or to diagnose pseudoseizures (ie, to establish a definitive diagnosis of spells with impairment of consciousness). This technique is also used to characterize the type of seizure and epileptic syndrome to optimize pharmacologic treatment and for presurgical workup.

See Workup for more detail.

Management

Pharmacotherapy

The goal of treatment is to achieve a seizure-free status without adverse effects. Monotherapy is important, because it decreases the likelihood of adverse effects and avoids drug interactions.

Standard of care for a single, unprovoked seizure is avoidance of typical precipitants (eg, alcohol, sleep deprivation). No anticonvulsants are recommended unless the patient has risk factors for recurrence.

Special situations that require treatment include the following:

  • Recurrent unprovoked seizures: The mainstay of therapy is an anticonvulsant; if a patient has had more than 1 seizure, administration of an anticonvulsant is recommended

  • Having an abnormal sleep-deprived EEG that includes epileptiform abnormalities and focal slowing, diffuse background slowing, and intermittent diffuse intermixed slowing

Selection of an anticonvulsant medication depends on an accurate diagnosis of the epileptic syndrome. Although some anticonvulsants (eg, lamotrigine, topiramate, valproic acid, zonisamide) have multiple mechanisms of action, and some (eg, phenytoin, carbamazepine, ethosuximide) have only one known mechanism of action, anticonvulsant agents can be divided into large groups based on their mechanisms, as follows:

  • Blockers of repetitive activation of the sodium channel: Phenytoin, carbamazepine, oxcarbazepine, lamotrigine, topiramate

  • Enhancer of slow inactivation of the sodium channel: Lacosamide, rufinamide

  • Gamma aminobutyric acid (GABA)–A receptor enhancers: Phenobarbital, benzodiazepines, clobazam

  • NMDA receptor blockers: Felbamate

  • AMPA receptor blockers: Perampanel, topiramate

  • T-calcium channel blockers: Ethosuximide, valproate

  • N- and L-calcium channel blockers: Lamotrigine, topiramate, zonisamide, valproate

  • H-current modulators: Gabapentin, lamotrigine

  • Blockers of unique binding sites: Gabapentin, levetiracetam

  • Carbonic anhydrase inhibitors: Topiramate, zonisamide

  • Neuronal potassium channel (KCNQ [Kv7]) opener: Ezogabine

Nonpharmacologic therapy

The following are 2 nonpharmacologic methods in managing patients with seizures:

  • A ketogenic diet

  • Vagal nerve stimulation

Surgical options

The 2 major kinds of brain surgery for epilepsy are palliative and potentially curative. The use of a vagal nerve stimulator (VNS) for palliative therapy in patients with intractable atonic seizures has reduced the need for anterior callosotomy. Lobectomy and lesionectomy are among several possible curative surgeries.

See Treatment and Medication for more detail.

Background

Epileptic seizures are only one manifestation of neurologic or metabolic diseases. Epileptic seizures have many causes, including a genetic predisposition for certain types of seizures, head trauma, stroke, brain tumors, alcohol or drug withdrawal, repeated episodes of metabolic insults, such as hypoglycemia, and other conditions. Epilepsy is a medical disorder marked by recurrent, unprovoked seizures. Therefore, repeated seizures with an identified provocation (eg, alcohol withdrawal) do not constitute epilepsy.

As proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) in 2005, epilepsy is defined as a brain disorder characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition.[1]

Traditionally, the diagnosis of epilepsy requires the occurrence of at least 2 unprovoked seizures. Some clinicians also diagnose epilepsy when 1 unprovoked seizure occurs in the setting of a predisposing cause, such as a focal cortical injury, or a generalized interictal discharge occurs that suggests a persistent genetic predisposition. (See Clinical Presentation.)

Seizures are the manifestation of abnormal hypersynchronous or hyperexcitable discharges of cortical neurons. The clinical signs or symptoms of seizures depend on the location of the epileptic discharges in the cerebral cortex and the extent and pattern of the propagation of the epileptic discharge in the brain. Thus, seizure symptoms are highly variable, but for most patients with 1 focus, the symptoms are usually very stereotypic.

It should not be surprising that seizures are a common, nonspecific manifestation of neurologic injury and disease, because the main function of the brain is the transmission of electrical impulses. The lifetime likelihood of experiencing at least 1 epileptic seizure is about 9%, and the lifetime likelihood of receiving a diagnosis of epilepsy is almost 3%. However, the prevalence of active epilepsy is only about 0.8%. (See Epidemiology.)

This article reviews the classifications, pathophysiology, clinical manifestations, and treatment of epileptic seizures and some common epileptic syndromes. (See Pathophysiology, Presentation, DDx, and Treatment.)

For more information regarding seizure types and other conditions, see the following topics:

  • Absence Seizures

  • Complex Partial Seizures

  • Generalized Tonic-Clonic Seizures

  • Psychogenic Nonepileptic Seizures

  • Pediatric First Seizure

  • Epilepsia Partialis Continua

  • Status Epilepticus

  • Preeclampsia

  • Eclampsia

See the following articles for more information regarding epileptic syndromes and epilepsy treatment:

  • Benign Childhood Epilepsy

  • Benign Neonatal Convulsions

  • EEG in Common Epilepsy Syndromes

  • Pediatric Febrile Seizures

  • Neonatal Seizures

  • Frontal Lobe Epilepsy

  • Temporal Lobe Epilepsy

  • Juvenile Myoclonic Epilepsy

  • Lennox-Gastaut Syndrome

  • Posttraumatic Epilepsy

  • Reflex Epilepsy

  • Vagus Nerve Stimulation

  • Women's Health and Epilepsy

  • Partial Epilepsies

  • Pediatric Status Epilepticus

  • Myoclonic Epilepsy Beginning in Infancy or Early Childhood

Historical information

Epileptic seizures have been recognized for millennia. One of the earliest descriptions of a secondary 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 other ancient cultures, including those of China, Egypt, and India. An ancient Egyptian papyrus described a seizure in a man who had previous 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 the cause was excessive phlegm leading to 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 19th century, excessive masturbation was considered a cause of epilepsy. This hypothesis is credited as leading to the use of the first effective anticonvulsant (ie, bromides).

Modern investigation of the etiology of epilepsy began with the work of Fritsch, Hitzig, Ferrier, and Caton in the 1870s. These researchers 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 by using scalp electrodes; this discovery led to the use of electroencephalography (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 currently used: localization-related syndromes and generalized-onset syndromes. An excellent historical review of seizures and epilepsy, written by E. Goldensohn, was published in the journal Epilepsia to commemorate the 50th anniversary of the creation of the American Epilepsy Society in 1997. A decade later, another review in Epilepsia discussed the foundation of this professional society.[4]

Pathophysiology

Seizures are paroxysmal manifestations 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.

The brain is involved in nearly every bodily function, including the higher cortical functions. If the affected cortical network is in the visual cortex, the clinical manifestations are visual phenomena. Other affected areas of primary cortex give rise to sensory, gustatory, or motor manifestations. The psychic phenomenon of déjà-vu occurs when the temporal lobe is involved.

The pathophysiology of focal-onset seizures differs from the mechanisms underlying generalized-onset seizures. Overall, cellular excitability is increased, but the mechanisms of synchronization appear to substantially differ between these 2 types of seizure and are therefore discussed separately. For a review, see the epilepsy book of Rho, Sankar, and Cavazos.[5] For a more recent review, see Kramer and Cash.[6]

Pathophysiology of focal seizures

The electroencephalographic (EEG) hallmark of focal-onset seizures is the focal interictal epileptiform spike or sharp wave. The cellular neurophysiologic correlate of an interictal focal 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 sodium-mediated action potentials during the depolarization phase, and it is followed by a prominent after-hyperpolarization, which is a hyperpolarized membrane potential beyond the baseline resting potential. Calcium-dependent potassium channels mostly mediate the after-hyperpolarization phase. When multiple neurons fire PDSs in a synchronous manner, the extracellular field recording shows an interictal spike.

If the number of discharging neurons is more than several million, they can usually 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. The spike has to recruit more neural tissue to become a seizure. When any of the mechanisms that underlie an acute seizure becomes a permanent alteration, the person presumably develops a propensity for recurrent seizures (ie, epilepsy).

The following mechanisms (discussed below) may coexist in different combinations to cause focal-onset seizures:

  • Decreased inhibition

  • Defective activation of gamma-aminobutyric acid (GABA) neurons

  • Increased activation

If the mechanisms leading to a net increased excitability become permanent alterations, patients may develop pharmacologically intractable focal-onset epilepsy.

Currently available medications were screened using acute models of focal-onset or generalized-onset convulsions. In clinical use, these agents are most effective at blocking the propagation of a seizure (ie, spread from the epileptic focus to secondary generalized tonic-clonic seizures). Further understanding of the mechanisms that permanently increase network excitability may lead to development of true antiepileptic drugs that alter the natural history of epilepsy.

Decreased inhibition

The release of GABA from the interneuron terminal inhibits the postsynaptic neuron by means of 2 mechanisms: (1) direct induction of an inhibitory postsynaptic potential (IPSP), which a GABA-A chloride current typically mediates, and (2) indirect inhibition of the release of excitatory neurotransmitter in the presynaptic afferent projection, typically with a GABA-B potassium current. Alterations or mutations in the different chloride or potassium channel subunits or in the molecules that regulate their function may affect the seizure threshold or the propensity for recurrent seizures.

Mechanisms leading to decreased inhibition include the following:

  • Defective GABA-A inhibition

  • Defective GABA-B inhibition

  • Defective activation of GABA neurons

  • Defective intracellular buffering of calcium

Normal GABA-A inhibitory function

GABA is the main inhibitory neurotransmitter in the brain, and it binds primarily to 2 major classes of receptors: GABA-A and GABA-B. GABA-A receptors are coupled to chloride (negative anion) channels, and they are one of the main targets modulated by the anticonvulsant agents that are currently in clinical use.

The reversal potential of chloride is about negative 70 mV. The contribution of chloride channels during resting potential in neurons is minimal, because the typical resting potential is near -70 mV, and thus there is no significant electromotive force for net chloride flux. However, chloride currents become more important at more depolarized membrane potentials.

These channels make it difficult to achieve the threshold membrane potential necessary for an action potential. The influence of chloride currents on the neuronal membrane potential increases as the neuron becomes more depolarized by the summation of the excitatory postsynaptic potentials (EPSPs). In this manner, the chloride currents become another force that must be overcome to fire an action potential, decreasing excitability.

Properties of the chloride channels associated with the GABA-A receptor are often clinically modulated by using benzodiazepines (eg, diazepam, lorazepam, clonazepam), barbiturates (eg, phenobarbital, pentobarbital), or topiramate. Benzodiazepines increase the frequency of openings of chloride channels, whereas barbiturates increase the duration of openings of these channels. Topiramate also increases the frequency of channel openings, but it binds to a site different from the benzodiazepine-receptor site.

Alterations in the normal state of the chloride channels may increase the 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 the summation of EPSPs induced by activation of the excitatory input.

The EPSPs are the main form of communication between neurons, and the release of the excitatory amino acid glutamate from the presynaptic element mediates EPSPs. Three main receptors mediate the effect of glutamate in the postsynaptic neuron: N -methyl-D-aspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate, and metabotropic. These are coupled by means of different mechanisms to several depolarizing channels.

IPSPs temper the effects of EPSPs. IPSPs are mediated mainly by the release of GABA in the synaptic cleft with postsynaptic activation of GABA-A receptors.

All channels in the nervous system are subject to modulation by several mechanisms, such as phosphorylation and, possibly, a change in the tridimensional conformation of a protein in the channel. The chloride channel has several phosphorylation sites, one of which topiramate appears to modulate. Phosphorylation of this channel induces a change in normal electrophysiologic behavior, with an increased frequency of channel openings but for only certain 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 made up of molecularly related but different proteins.

The heterogeneity of electrophysiologic responses of different GABA-A receptors results from different combinations of the subunits. In mammals, at least 6 alpha subunits and 3 beta and gamma subunits exist for the GABA-A receptor complex. A complete GABA-A receptor complex (which, in this case, is the chloride channel itself) is formed from 1 gamma, 2 alpha, and 2 beta subunits. The number of possible combinations of the known subunits is almost 1000, but in practice, only about 20 of these combinations have been found in the normal mammalian brain.

Defective GABA-A inhibition

Some epilepsies may involve mutations or lack of expression of the different GABA-A receptor complex subunits, the molecules that govern their assembly, or the molecules that modulate their electrical properties. For example, hippocampal pyramidal neurons may 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 subunits of the GABA-A receptor complex have been demonstrated in several animal models of focal-onset epilepsy, such as the electrical-kindling, chemical-kindling, and pilocarpine models. In the pilocarpine model, decreased concentrations of mRNA for the alpha 5 subunit of the surviving interneurons were observed in the CA1 region of the rat hippocampus.[7]

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 with 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 an ictal event (ie, focal-onset seizure). The molecular structure of the GABA-B receptor complex consists of 2 subunits with 7 transmembrane domains each.

G proteins, a second messenger system, mediate coupling to the potassium channel, explaining the latency and long duration of the response. In many cases, GABA-B receptors are located in the presynaptic element of an excitatory projection.

Defective activation of GABA neurons

GABA neurons are activated by means of feedforward and feedback projections from excitatory neurons. These 2 types of inhibition in a neuronal network are defined on the basis of the time of activation of the GABAergic neuron relative to that of the principal neuronal output of the network, as seen with 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 before or simultaneously with activation of the apical dendrites of the CA1 pyramidal neurons.

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. The feedforward projection thus primes the inhibitory system in a manner that allows it to inhibit, in a timely fashion, the pyramidal cell's depolarization and firing of an action potential.

Feedback inhibition is another system that allows 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 after the pyramidal neurons fire an action potential.

Experimental evidence has indicated that some other kind of interneuron may 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 inhibitory tone and activate GABAergic neurons. The mossy cells receive both feedback and feedforward activation, which they convey to the GABAergic neurons.

In certain circumstances, the mossy cells appear highly vulnerable to seizure-related neuronal loss. After some of the mossy cells are lost, activation of GABAergic neurons is impaired.[8]

Synaptic reorganization is a form of brain plasticity induced by neuronal loss, perhaps triggered by the loss of the synaptic connections of the dying neuron, a process called deafferentation. Formation of new sprouted circuits includes excitatory and inhibitory cells, and both forms of sprouting have been demonstrated in many animal models of focal-onset epilepsy and in humans with intractable temporal-lobe epilepsy.

Most of the initial attempts of hippocampal sprouting are likely to be attempts to restore inhibition. As the epilepsy progresses, however, the overwhelming number of sprouted synaptic contacts occurs with excitatory targets, creating recurrent excitatory circuitries that permanently alter the balance between excitatory and inhibitory tone in the hippocampal network.

Defective intracellular buffering of calcium

In rodents, recurrent seizures induced by a variety of methods result in a pattern of interneuron loss in the hilar polymorphic region, with striking loss of the neurons that lack the calcium-binding proteins parvalbumin and calbindin. In rat hippocampal sections, these interneurons demonstrate a progressive inability to maintain a hyperpolarized resting membrane potential; eventually, the interneurons die.

In an experiment, researchers used microelectrodes containing the calcium chelator BAPTA and demonstrated reversal of the deterioration in the membrane potential as the calcium chelator was allowed to diffuse in the interneuron.[9] These findings showed the critical role of adequate concentrations of calcium-binding proteins for neuronal survival in settings with sustained rises of intracellular calcium, such as in status epilepticus and other brain insults. This mechanism may contribute to medical intractability in some epilepsy patients.

The vulnerability of interneurons to hypoxia and other insults also correlates to the relative presence of these calcium-binding proteins. The premature loss of interneurons alters inhibitory control over the local neuronal network in favor of net excitation. This effect may explain, for example, why 2 patients who have a similar event (ie, simple febrile convulsion) may have remarkably dissimilar outcomes; that is, one may have completely normal development, and the other may have intractable focal-onset epilepsy after a few years.

Increased activation

Mechanisms leading to increased excitation include the following:

  • Increased activation of NMDA receptors

  • Increased synchrony between neurons due to ephaptic interactions

  • Increased synchrony and/or activation due to recurrent excitatory collaterals

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 by activating the glutaminergic receptors AMPA/kainate and NMDA and the metabotropic receptor.

Fast neurotransmission is achieved with the activation of the first 2 types of receptors. The metabotropic receptor alters cellular excitability by means of a second-messenger system with later onset but a prolonged duration. The major functional difference between the 2 fast receptors is that the AMPA/kainate receptor opens channels that primarily allow the 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 are generally 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, pilocarpine, and other focal-onset epilepsy models.

Some patients with epilepsy may have an inherited predisposition for fast or long-lasting activation of NMDA channels that alters their seizure threshold. Other possible alterations include the ability of intracellular proteins to buffer calcium, increasing the vulnerability of neurons to any kind of injury that otherwise would not result in neuronal death.

Increased synchrony between neurons caused by 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. Changes in extracellular ionic concentrations of potassium and calcium are another possible nonsynaptic interaction, as is increased coupling of neurons due to permanent increases in the functional availability of gap junctions. This last may be a mechanism that predisposes to seizures or status epilepticus.

Increased synchrony and/or activation from recurrent excitatory collaterals

Neuropathologic studies of patients with intractable focal-onset epilepsy have revealed frequent abnormalities in the limbic system, particularly in the hippocampal formation. A common lesion is hippocampal sclerosis, which consists of a pattern of gliosis and neuronal loss primarily affecting the hilar polymorphic region and the CA1 pyramidal region. These changes are associated with relative sparing of the CA2 pyramidal region and an intermediate severity of the lesion in the CA3 pyramidal region and dentate granule neurons.

Prominent hippocampal sclerosis is found in about two thirds of patients with intractable temporal-lobe epilepsy. Animal models of status epilepticus have reproduced this pattern of injury; however, animals with more than 100 brief convulsions induced by kindling seizures had a similar pattern, suggesting that repeated temporal lobe seizures may contribute to the development of hippocampal sclerosis.[10]

More subtle and apparently more common than overt hippocampal sclerosis is mossy-fiber sprouting.[11] The mossy fibers are the axons of the dentate granule neurons, and they typically project into the hilar polymorphic region and toward the CA3 pyramidal neurons. As the neurons in the hilar polymorphic region are progressively lost, their synaptic projections to the dentate granule neurons degenerate.

Denervation resulting from loss of the hilar projection induces sprouting of the neighboring mossy fiber axons. The net consequence of this phenomenon is the formation of recurrent excitatory collaterals, which increase the net excitatory drive of dentate granule neurons.

Recurrent excitatory collaterals have been demonstrated in human temporal lobe epilepsy and in all animal models of intractable focal-onset epilepsy. The effect of mossy-fiber sprouting on the hippocampal circuitry has been confirmed in computerized models of the epileptic hippocampus. Other neural pathways in the hippocampus, such as the projection from CA1 to the subiculum, have been shown to also remodel in the epileptic brain.

For further reading, a review by Mastrangelo and Leuzzi addresses how genes lead to an epileptic phenotype for the early age encephalopathies.[12]

Pathophysiology of generalized seizures

The best-understood example of the pathophysiologic mechanisms of generalized seizures is the thalamocortical interaction 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 observed in sleep spindles. The thalamocortical circuitry includes the pyramidal neurons of the neocortex, the thalamic relay neurons, and the neurons in the nucleus reticularis of the thalamus (NRT).

Altered thalamocortical rhythms may result in primary generalized-onset seizures. The thalamic relay neurons receive ascending inputs from the spinal cord and project to the neocortical pyramidal neurons. Cholinergic pathways from the forebrain and the ascending serotonergic, noradrenergic, and cholinergic brainstem pathways prominently regulate this circuitry.[13]

The thalamic relay neurons can have oscillations in the resting membrane potential, which increases the probability of synchronous activation of the neocortical pyramidal neuron during depolarization and which significantly lowers the probability of neocortical activation during relative hyperpolarization. The key to these oscillations is the transient low-threshold calcium channel, also known as T-calcium current.

In animal studies, inhibitory inputs from the NRT control the activity of thalamic relay neurons. 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 must be de-inactivated 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 cannot 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 released from the NRT projection to the thalamic relay neuron. The result is a hyperpolarization that switches the T-calcium channels away from the inactive state into the closed state, which is ready for activation when needed. The switch to closed state permits the synchronous opening of a large population of the T-calcium channels every 100 milliseconds or so, creating the oscillations observed in the EEG recordings from the cerebral cortex.

Findings in several animal models of absence seizures, such as lethargic mice, have demonstrated that GABA-B receptor antagonists suppress absence seizures, whereas GABA-B agonists worsen these seizures.[14] Anticonvulsants that prevent absence seizures, such as valproic acid and ethosuximide, suppress the T-calcium current, blocking its channels.

A clinical problem is that some anticonvulsants that increase GABA levels (eg, tiagabine, vigabatrin) are associated with an exacerbation of absence seizures. An increased GABA level is thought to increase the degree of synchronization of the thalamocortical circuit and to enlarge the pool of T-calcium channels available for activation.

Etiology

In a substantial number of cases, the cause of epilepsy remains unknown. Identified causes tend to vary with patient age. Inherited syndromes, congenital brain malformations, infection, and head trauma are leading causes in children. Head trauma is the most common known cause in young adults. Strokes, tumors, and head trauma become more frequent in middle age, with stroke becoming the most common cause in the elderly, along with Alzheimer disease and other degenerative conditions.

The genetic contribution to seizure disorders is not completely understood, but at the present time, hundreds of genes have been shown to cause or predispose individuals to seizure disorders of various types. Seizures are frequently seen in patients that are referred to a genetics clinic. In some cases, the seizures are isolated in an otherwise normal child. In many cases, seizures are part of a syndrome that may also include intellectual disability, specific brain malformations, or a host of multiple congenital anomalies.

For the sake of brevity and clarity, genetic disorders that can cause seizures will be broken into the following categories:

  • Syndromes in which seizures are common

  • Chromosomal deletion or duplication syndromes that cause seizures

  • Metabolic diseases

  • Mitochondrial diseases

  • Seizure disorders caused by single-gene mutations

Genetic syndromes with seizure disorder

A number of genetic syndromes are known to causes seizures; therefore, this list is not meant to be authoritative. However, a number of more common syndromes should be considered in the patient who presents with seizures and other findings.

Angelman syndrome

Angelman syndrome is an inherited disorder that is most frequently (68%) caused by a deletion in the maternally inherited region of chromosome 15q11.2-q13. Approximately 7% of cases are caused by paternal disomy of the same region. An additional 11% of cases of Angelman syndrome are due to sequence variants in the maternally inherited UBE3A gene.

Patients with Angelman syndrome generally have a normal prenatal and birth history, with the first evidence of developmental delay occurring between 6 and 12 months of age. Seizures occur in over 80% of patients with Angelman syndrome, with onset before age 3 years.

Patients generally have deceleration of head growth, resulting in microcephaly by early childhood. Dysmorphic facies are typical and include a protruding tongue, prognathia, and a wide mouth with widely-spaced teeth. Patients with a deletion also have hypopigmentation. Intellectual impairments are typically severe and speech impairment is quite severe, with most patients having few or no words. Patients also have ataxia and frequent laughter with a happy demeanor.

Rett syndrome

Rett syndrome in its classical form is caused by mutations in the MECP2 gene, although other similar forms caused by different genes are described. Additionally, although Rett syndrome has generally been described only in female patients (with the supposition that this would be a lethal disease in males), rare cases have been described in males.

Patients with Rett syndrome have a normal prenatal and birth history and normal psychomotor development for the first 6 months, followed by deceleration of head growth in most patients, loss of hand skills over the first 2-3 years of life, hand stereotypies, social withdrawal, communication dysfunction, loss of acquired speech, cognitive impairment, and impairment of movement.[15]

Seizures are reported in greater than 90% of females with Rett syndrome. Seizures may be of any type, but generalized tonic-clonic and complex partial seizures are the most common.[16]

Pitt-Hopkins syndrome

Pitt-Hopkins syndrome is classically caused by mutations in the TCF4 gene, although several forms of Pitt-Hopkins–like syndrome have been described. Patients with Pitt-Hopkins syndrome have severe intellectual disability, microcephaly, and little or no speech. They also have an unusual breathing pattern characterized by intermittent hyperventilation followed by periods of apnea.

Patients with Pitt-Hopkins also have distinctive facies, which may not be apparent in early childhood. These features include microcephaly with a coarse facial appearance, deeply set eyes, upslanting palpebral fissures, a broad and beaked nasal bridge with a downturned nasal tip, a wide mouth and fleshy lips, and widely spaced teeth. There is also a tendency toward prognathism.

Seizures are seen in this syndrome, with one study reporting a frequency of 20%.[17] Earlier studies suggested that around 50% of patients with Pitt-Hopkins have seizures.

Tuberous sclerosis

Tuberous sclerosis complex is caused by mutations in the TSC1 or TSC2 genes. Major features of this disease include the following[18] :

  • Facial angiofibromata

  • Ungual or periungual fibromas

  • Hypopigmented macules

  • Connective tissue nevi

  • Retinal hamartomas

  • Cortical tubers

  • Subependymal nodules or giant cell astrocytomas

  • Cardiac rhabdomyomas

  • Lymphangiomyomatosis

  • Renal angiomyolipomas

Minor features include the following:

  • Dental enamel pits

  • Rectal hamartomas

  • Bone cysts

  • Cerebral white matter migration lines

  • Gingival fibromas

  • Nonrenal hamartomas

  • Retinal achromic patches

  • Confetti skin lesions

  • Renal cysts

A definite diagnosis of tuberous sclerosis requires 2 major features or 1 major and 2 minor features. A probable diagnosis of tuberous sclerosis requires 1 major and 1 minor feature.

More than 80% of patients with tuberous sclerosis are reported to have seizures, although this may be an overestimate. However, this diagnosis should always be strongly considered in the case of infantile spasms.

Prader-Willi syndrome

Prader-Willi syndrome is most frequently (70%) caused by a deletion in the paternal inherited portion of chromosome 15q11.2-q13. The remainder of cases are caused by maternal uniparental disomy of chromosome 15, complex chromosomal rearrangements, or defects in specific imprinting centers.

Patients with Prader-Willi syndrome have neonatal hypotonia and failure to thrive during infancy. Patients have hyperphagia, and onset of weight gain occurs between age 1 and 6 years. Affected individuals also have mild-moderate intellectual impairment, hypogonadism, and characteristic facies consisting of a narrow bifrontal diameter, almond-shaped eyes, a round face, and downturned corners of the mouth. Hands and feet will tend to be small for size. Seizures occur in approximately 10-20% of patients.

Sturge-Weber syndrome

Sturge-Weber syndrome has an unknown cause and appears to occur in a sporadic fashion. This disorder is characterized by intracranial vascular anomalies called arteriovenous malformations and port-wine stains on the face. Patients with Sturge-Weber syndrome also have seizures and glaucoma. The seizures can be very difficult to control in some of these patients.

Chromosomal deletion or duplication syndromes with seizures

Chromosomal 22q deletion syndrome is a spectrum of findings caused by a deletion on chromosome 22q11.2. This disorder has previously been known by a variety of names, including DiGeorge syndrome, velocardiofacial syndrome, Shprintzen syndrome, Opitz G/BBB syndrome, and Cayler asymmetrical crying facies, among others. The most common features of this syndrome are congenital heart disease, palate anomalies, hypocalcemia, immune deficiencies, and learning difficulties. Seizures occur in 7% of patients with chromosomal 22q deletion syndrome.[19]

Wolf-Hirschhorn syndrome is caused by deletions of chromosome 4p16.3. Typical facies in these patients include a broad nasal bridge continuing to the forehead (the “Greek warrior helmet” appearance), microcephaly, high forehead, hypertelorism, and highly arched eyebrows. The mouth tends to be turned downward. Growth retardation is seen, as is a variable degree of intellectual disability. Although seizures are present in between 50-100% of patients with Wolf-Hirschhorn syndrome, they tend to improve with age.[20]

Chromosomal 1p36 deletion syndrome is characterized by dysmorphic facies, including straight eyebrows, deeply set eyes, a long philtrum, and microcephaly. All patients with this syndrome have developmental delay and hypotonia, and 44-58% have seizures.[21]

Metabolic disorders that can cause seizures

Many different metabolic disorders can cause seizures, some as a result of a metabolic disturbance such as hypoglycemia or acidosis and some as a primary manifestation of the seizure disorder. Some seizures are responsive to administration of certain vitamins (eg, pyridoxine-responsive or folinic acid-responsive seizures).

Peroxisomal biogenesis disorders, which can cause seizures, result from homozygosity for mutation in one of the many PEX genes. One of these disorders, Zellweger syndrome, presents in the neonatal period as hypotonia, seizures, and hepatic dysfunction. Death typically occurs from respiratory failure within the first year of life.

Congenital disorders of glycosylation are a group of disorders that (as their name suggests) involve malfunction in one of the many enzymes involved in the pathway that attaches certain oligosaccharides to proteins. These disorders vary significantly in their severity and characteristic manifestations. Hypotonia, intellectual disability, failure to thrive/feeding difficulties, and unusual fat distribution are common. Seizures occur in some cases.

Other rare diseases also commonly cause seizures, including the following:

  • Neuronal ceroid lipofuscinosis

  • Disorders of metal and metal cofactor deficiency

  • Disorders of neurotransmitter metabolism

  • Lysosomal storage diseases

Mitochondrial diseases

Mitochondrial disorders are underdiagnosed but often involve seizures and other neurologic manifestations. Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome is a mitochondrial disorder that is associated with seizures; often, seizures are the presenting manifestation. Patients can also have recurrent headache and vomiting.

Myoclonic epilepsy with ragged red fibers (MERRF) is characterized by myoclonus, seizures, and ataxia; myopathy, hearing loss, and vision loss can also occur. Genetic tests are available for these disorders.

Seizure disorders caused by single-gene mutations

Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in the CHRNA4, CHRNB2, or CHRNA2 genes. It is characterized by nocturnal motor seizures. The severity of autosomal dominant nocturnal frontal lobe epilepsy can be variable, can include awakening episodes, and can result in impressive dystonic effects. Affected individuals are generally otherwise normal, and the attacks tend to become less severe with age.

Autosomal dominant juvenile myoclonic epilepsy is caused by a mutation in one of a number of genes. Patients report myoclonic jerks, most commonly in the morning, but they can also have both generalized tonic-clonic seizures and absence seizures. The onset of this disorder is typically in late childhood or early adolescence.

Benign familial neonatal seizures are caused by mutations in the KCNQ2 or KCNQ3 genes and are inherited in an autosomal dominant manner. Neonates with this disorder will experience tonic-clonic seizures a few days after birth, and these seizures will remit within 1 month. Most infants will have normal development, but there is a 10-15% risk of seizure disorder later in life.

Mutations in other genes, such as SCN1A, can cause a range of seizure syndromes. At the mild end of this spectrum, patients may have familial febrile seizures and may otherwise be normal. At the severe end, patients may have severe myoclonic epilepsy of infancy (also known as Dravet syndrome).

Mutations in SCN2A and SCN1B are known to cause generalized epilepsy with febrile seizures.

Mutations in SCN9A, GPA6, and GPR98 are known to cause familial febrile seizures.

Mutation in GABRG2 is known to cause generalized epilepsy with febrile seizures, and familial febrile seizures.

Epidemiology

Hauser and collaborators demonstrated that the annual incidence of recurrent nonfebrile seizures in Olmsted County, Minnesota, was about 100 cases 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 3400 per 100,000 men (3.4%) and 2800 per 100,000 women (2.8%).[22]

Studies in several developed countries have shown incidences and prevalences of seizures similar to those in the United States. In some countries, parasitic infections account for an increased incidence of epilepsy and seizures.

Prognosis

The patient's prognosis for disability and for a recurrence of epileptic seizures depends on the type of epileptic seizure and the epileptic syndrome in question. Impairment of consciousness during a seizure may unpredictably result in morbidity or even mortality.

Regarding morbidity, trauma is not uncommon among people with generalized tonic-clonic seizures. Injuries such as ecchymosis; hematomas; abrasions; tongue, facial, and limb lacerations; and even shoulder dislocation can develop as a result of the repeated tonic-clonic movements. Atonic seizures are also frequently associated with facial injuries, as well as injuries to the neck. Worldwide, burns are the most common serious injury associated with epileptic seizures.

SUDEP

Regarding mortality, seizures cause death in a small proportion of individuals. Most deaths are accidental and result from impaired consciousness. However, sudden, unexpected death in epilepsy (SUDEP) is a risk in persons with epilepsy, and it may occur even when patients are resting in a protected environment (ie, in a bed with rail guards or in the hospital).

The incidence of SUDEP is low, about 2.3 times higher than the incidence of sudden death in the general population. The increased risk of death is seen mostly in people with long-standing focal-onset epilepsy, but it is also present in individuals with primary generalized epilepsy. The risk of SUDEP increases in the setting of uncontrolled seizures and in people with poor medication compliance. The risk increases further in people with uncontrolled secondary generalized tonic-clonic seizures.

The mechanism of death in SUDEP is controversial, but suggestions include cardiac arrhythmias, neurogenic pulmonary edema, and suffocation during an epileptic seizure with impairment of consciousness. Treatment with anticonvulsants decreases the likelihood of an accidental seizure-related death, and successful epilepsy surgery decreases the risk of SUDEP to that of the general population.

In 2011, the National Institutes of Health (NIH) convened a workshop on SUDEP to focus research efforts and to determine benchmarks for further study.[23] A summary of their report can be found at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115809/ .

Patient Education

To prevent injury, provide education about seizure precautions to patients who have lapses of consciousness during wakefulness and in whom seizures are suspected. Most accidents occur when patients have impaired consciousness. This is one of the reasons for restrictions on driving, swimming, taking unsupervised baths, working at significant heights, and the use of fire and power tools for people who have epileptic seizures and other spells of sudden-onset seizures.

The restrictions differ for each patient because of the individual features of the seizures, the degree of seizure control, and, in the United States, state laws. Other countries have more permissive or more restrictive laws regarding driving. Check state driving laws before making recommendations.

Epilepsy Foundation of America has a large library of educational materials that are available to healthcare professionals and the general public. The American Epilepsy Society is a professional organization for people who take care of patients with epilepsy. Their Website provides a large amount of credible information.

For patient education information, see the Brain and Nervous System Center, as well as Epilepsy and Seizures Emergencies.

 

Presentation

History

The diagnosis of epileptic seizures is made by analyzing the patient's detailed clinical history and by performing ancillary tests for confirmation. Someone who has observed the patient's repeated events is usually the best person to provide an accurate history. However, the patient also provides invaluable details about auras, preservation of consciousness, and postictal states. A key feature of epileptic seizures is their stereotypic nature.

Questions that help to clarify the type of seizure include the following:

  • Was any warning noted before the seizure? If so, what kind of warning occurred?

  • What did the patient do during the seizure?

  • Was the patient able to relate to the environment during the seizure and/or does the patient have recollection of the seizure?

  • How did the patient feel after the seizure? How long did it take for the patient to get back to baseline condition?

  • How long did the seizure last?

  • How frequently do the seizures occur?

  • Is anything known to precipitate the seizures?

  • Has the patient shown any response to therapy for the seizures?

Physical Examination

The clinical diagnosis of seizures is based on the history obtained from the patient and, most importantly, the observers. Physical examination helps in the diagnosis of specific epileptic syndromes that cause abnormal findings, such as dermatologic abnormalities (eg, neurocutaneous syndromes such as Sturge-Weber, tuberous sclerosis, and others). In addition, patients who for years have had intractable generalized tonic-clonic seizures are likely to have suffered injuries requiring stitches.

Overview of Epileptic Seizures Classification

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 a focal area of the cerebral cortex, whereas generalized-onset seizures have an onset recorded simultaneously in both cerebral hemispheres. Some seizures are difficult to fit into a single class, and they are considered unclassified seizures. This classification is still widely accepted.

Other classifications, such as a semiologic classification advanced by Luders and others, have been proposed.[24] A refinement of this semiologic classification led to a 5-dimensional (5-D), patient-oriented classification of epilepsy.[25]

The ILAE commission on classification developed additional reports.[26, 27] In 2006, a new proposed classification of seizures was published.[26, 27] The 2 main changes in this classification are (1) the use of focal rather than partial and (2) the proposal that a single seizure in the setting of a predisposition for further seizures be considered epilepsy. In 2010, the ILAE commission on classification explained in more detail the decision for using the changes in terminology in the revised proposed classification.[28] Nevertheless, there remains controversy over the classification of epileptic seizures among clinicians. A revised proposal is expected after the 2013 ILAE meeting.

Focal-Onset Seizures

Focal-onset seizures are further classified as simple focal seizures, complex focal seizures, and secondary generalized tonic-clonic seizures.

Simple and complex focal seizures

The defining element of simple focal seizures is a seizure with preserved consciousness. A complex partial seizure is defined as one in which there is some alteration or impairment of consciousness. Many patients with complex focal seizures have an aura warning them of their seizure; the aura itself is a simple focal seizure. The many kinds of simple focal seizures include sensory, motor, autonomic, and psychic types. Any discrete experience that involves the cerebral cortex could be a simple focal-onset seizure.

The diagnosis of the seizure type is based on the repeated, stereotypic occurrence of the same experience in association with focal electroencephalographic (EEG) changes or on recurrent auras leading to a complex focal-onset seizure or a secondary generalized seizure. Resolution of the recurrent clinical phenomena with anticonvulsants is presumptive but not diagnostic evidence for epileptic seizures.

The clinical diagnosis is difficult, as many stereotypic auras may be induced in areas of the cerebral cortex that are not recorded well on a typical EEG. About 20-40% of auras have an ictal correlate on the scalp EEG. Simple focal seizures may last a few seconds to a few minutes. However, if the aura lasts longer than 30 minutes, it is considered simple focal status epilepticus by definition.

As noted above, consciousness is impaired during a complex focal seizure. In practice, assessing the patient's history to determine whether consciousness was impaired is difficult. The most common way to assess preserved consciousness is asking patients if they remembered the event. Patients may be able to remember their aura but are unaware that they were briefly unable to respond to the environment.

A complex focal seizure typically begins with behavioral arrest and is followed by staring, automatisms, and postictal confusion. Typical automatisms are chewing, lip smacking, mumbling, and fumbling with the hands. Dystonic posturing of the contralateral upper extremity is often seen when a complex partial seizure originates from the mesial temporal lobe. A typical complex focal 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 focal seizures of frontal-lobe origin may feature bizarre motor behaviors such as bicycling or a fencing posture, and they may have more of a nocturnal occurrence. These seizures have more prominent motor features than those of complex focal seizures of temporal-lobe onset. Frontal lobe–onset complex focal seizures may have a fast postictal recovery to baseline, and they often appear in clusters.

The great majority of complex focal seizures have an ictal correlate on the EEG. A normal alpha rhythm during behavioral impairment of consciousness is highly suggestive of nonepileptic seizures, but this should be interpreted by an experienced epileptologist, as some true seizures may not have surface EEG changes, and some true seizures can have somewhat atypical features (eg, bilateral motor activity is present, but the patient may be conscious from supplementary motor seizures).

Secondary generalized seizures

Secondary generalized seizures often begin with an aura that evolves into a complex focal seizure and then into a generalized tonic-clonic seizure. However, a complex focal seizure may evolve into a generalized tonic-clonic seizure without a preceding aura, or an aura may evolve into a generalized tonic-clonic seizure without an obvious complex focal seizure.

Clinically classifying a generalized tonic-clonic seizure as being secondarily generalized (focal onset) or primarily generalized is difficult on the basis of the history alone. In most cases, the association with prominent amnesia for the aura increases with the severity of a secondary generalized seizure.

Generalized-Onset Seizures

Generalized-onset seizures are classified into 6 major categories, as follows:

  • Absence seizures

  • Myoclonic seizures

  • Clonic seizures

  • Tonic seizures

  • Primary generalized tonic-clonic seizures

  • Atonic seizures

Each seizure type is classified by its clinical and electroencephalographic (EEG) manifestations. Definitive classification of seizures is best made by ictal recordings over a period of several days to capture seizures.

Absence seizures

Absence seizures are brief episodes of impaired consciousness with no aura or postictal confusion. They typically last less than 20 seconds and are accompanied by few or no automatisms. Of the automatisms that develop, the facial ones are most common, with repetitive blinking occurring most often. Hyperventilation or photic stimulation frequently precipitates these seizures, which typically begin during childhood or adolescence and may persist into adulthood.

A diagnosis of new-onset absence seizures in adulthood is not likely in the vast majority of cases. (Adults often have complex focal seizures with relatively minor automatisms.) Confusion arises when patients and some healthcare providers incorrectly use the term “absence seizure” (or “petit mal seizure”) and “petit mal/absence seizure” to describe a seizure that is not “grand mal.”

Twin studies have demonstrated a significant inherited predisposition for typical childhood absence seizures. In children, the seizures are subtle, manifesting as “staring episodes” and often going unrecognized until the child develops a generalized tonic-clonic (previously known as “grand mal”) seizure. Sudden decreased performance in school or overall attention may be a subtle manifestation of frequent absence seizures.

The classic ictal EEG correlate of absence seizures consists of 3-Hz generalized spike-and–slow wave complexes that may be induced by activation during EEG by hyperventilation and sometimes photic stimulation. EEG abnormalities may persist into adulthood despite the absence of clinical seizures. However, compared with the EEG discharges in children, those in adults occur less often, are less well formed, and are of lesser amplitude.

Myoclonic, clonic, and tonic seizures

Myoclonic seizures consist of brief arrhythmic jerking motor movements that last less than 1 second and often cluster within a few minutes. If the seizures 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 on the EEG consists of fast polyspike-and–slow wave complexes.

Clonic seizures consist of rhythmic jerking motor movements with or without impairment of consciousness; they can have a focal origin. The focal seizures are classified as simple or complex partial seizures. The typical generalized clonic seizures simultaneously involve the upper and lower extremities. The ictal EEG correlate consists of bilateral, rhythmic, epileptiform discharges.

Tonic seizures consist of sudden-onset tonic extension or flexion of the head, trunk, and/or extremities for several seconds. These seizures typically occur in relation to drowsiness, shortly after patients fall asleep, or just after they awaken. Tonic seizures are often 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 with that of the background rhythm. This pattern may evolve into slow spike-and-wave complexes or diffuse polyspikes.

Primary generalized tonic-clonic seizures

Tonic-clonic seizures are commonly 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. On clinical evaluation, the only behavioral difference between these seizures and secondary generalized tonic-clonic seizures is that these seizures lack an aura, or there are partial seizure signs and symptoms. However, the aura preceding the partial seizure with secondary generalization is often forgotten because of postictal amnesia, and observers may not see partial seizure signs and come upon the patient in the grand mal phase.

The ictal correlate of generalized tonic-clonic seizures consists of generalized (bilateral) complexes of spikes or polyspike and slow waves. These epileptiform discharges often have increased amplitude in the frontal regions.

Atonic seizures

Atonic seizures are also called “drop attacks.” These seizures occur in people with clinically significant neurologic abnormalities and consist of brief loss of postural tone, often resulting in falls and injuries (hence, some patients need helmets). The ictal EEG correlate is similar to EEG abnormalities observed in tonic seizures.

Classification of Epileptic Syndromes

Epileptic seizures are symptoms of neurologic dysfunction, and they are but 1 manifestation of many neurologic diseases. As with 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.

In 1989, the International League Against Epilepsy (ILAE) developed a classification of epileptic syndromes, which is in the process of being revised. The current system comprises 2 major categories: localization-related syndromes and generalized-onset syndromes. Physicians would ideally classify their patients' seizures by using the classification for seizure types and make a syndromic diagnosis, if possible.

Localization-related epilepsies and syndromes include the following:

  • Idiopathic, with age-related onset

  • Benign childhood epilepsy with centrotemporal spikes

  • Childhood epilepsy with occipital paroxysms

  • Symptomatic

  • Mesial temporal lobe sclerosis

Generalized epilepsies and syndromes include the following:

  • 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 (JME)

  • 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

In 2001, the ILAE Task Force on Classification and Terminology proposed that rather than revising the entire classifications of seizures (1981) or epilepsy syndromes (1989), a better strategy was to devise a 5-axis diagnostic scheme, as follows[29] :

  • Axis 1: Descriptive ictal terminology

  • Axis 2: Seizure type, from the “List of Epileptic Seizures,” with specific brain location (if known)

  • Axis 3: Syndrome, from the “List of Epilepsy Syndromes”; not always possible

  • Axis 4: Etiology, including specific genetic defects or pathologic substrates

  • Axis 5: Impairment; optional but useful parameter that can be derived from the World Health Organization (WHO) revised International Classification of Functioning, Disability and Health (ICIDH-2) impairment classification

The 2001 task force report also discussed the abandonment of the terms “partial-onset” and “localization-related” seizure and epilepsy for the term “focal.” The 2006 review of the terminology formalized the change from partial to focal, but localization-related epilepsy remains an accepted term. In addition, the task force recommended that the term “cryptogenic ” be replaced for the more precise wording “probably symptomatic.” However, cryptogenic remains an accepted term.

Despite the fact that for many years psychiatrists have successfully used a somewhat similar 5-axis diagnostic scheme, critics indicate that this system is unnecessarily complex and its reliability, accuracy, and clinical use are uncertain. (For a more complete description of these controversies see Wolf[30] and the resultant discussions by Engel, Luders et al, Berg and Blackstone, and Avanzini. Similarly, see Fisher et al[1] and its resultant discussion.)

To increase the controversy on this subject, there is evidence that epilepsy syndromes are not static diagnoses but ones that may evolve over time. They also have poor prognostic predictivity, and the interobserver reliability of classifying epileptic syndromes is poor.[31]

 

DDx

Diagnostic Considerations

The diagnosis of seizures is based on the patient’s clinical history. The history as related by a witness is of high importance, because many types of seizures are associated with impairment of consciousness, and patients are unaware of their occurrence.

The clinical diagnosis can be confirmed by abnormalities on the interictal electroencephalogram (EEG). However, these abnormalities can be present in otherwise healthy individuals, and their absence does not exclude the diagnosis of epilepsy.

Not all “spells” are seizures. (See the Differentials section, below.) Other conditions that should be considered include the following:

  • Syncope (eg, cardiac arrhythmia, vasovagal syncope, dysautonomia)

  • Metabolic conditions (eg, hypoglycemia, hyponatremia)

  • Migraine (eg, migrainous aura, migraine equivalent)

  • Vascular conditions (eg, transient ischemic attacks)

  • Sleep disorders (eg, cataplexy, narcolepsy, night terror)

  • Movement disorders (eg, paroxysmal dyskinesia)

  • Gastrointestinal conditions (eg, esophageal reflux in neonates and infants)

  • Psychiatric conditions (eg, conversion, panic attacks, breath-holding spells, malingering, secondary gain)

Differential Diagnoses

 

Workup

Approach Considerations

Two studies are often recommended after a seizure: neuroimaging evaluation (eg, brain magnetic resonance imaging [MRI], head computed tomography [CT] scanning) and electroencephalography (EEG). For neuroimaging, a CT scan is often obtained in the emergency department to exclude an obvious structural lesion, but an MRI is indicated if the patient continues to have seizures. In addition, lumbar puncture for cerebrospinal fluid (CSF) examination has a role in the patient with obtundation or in patients in whom meningitis, encephalitis, or subarachnoid hemorrhage is suspected.

Epileptic seizures have many causes, and some epileptic syndromes have specific histopathologic abnormalities. For more information, see the articles about specific epileptic syndromes listed in the Background section.

Prolactin Study

Historically, prolactin levels obtained shortly after a seizure (within 20 min) have been used to assess the etiology (epileptic or nonepileptic) of a spell. levels are typically elevated 3- or 4-fold, and elevations are more likely to occur with generalized tonic-clonic seizures than with other seizure types. However, not only has the considerable variability of prolactin levels precluded routine clinical use of such testing, but a baseline prolactin level is often obtained the next day at the same time as when the seizure first occurred, which makes the testing more cumbersome.

The American Academy of Neurology (AAN) recommends serum prolactin assays, measured in the appropriate clinical setting at 10-20 minutes after a suspected event as a useful adjunct for differentiating generalized tonic-clonic or complex partial seizure from psychogenic nonepileptic seizure in adults and older children.[32]

The AAN notes, however, that prolactin assays do not distinguish epileptic seizures from syncope and have not been established in the evaluation of status epilepticus, repetitive seizures, and neonatal seizures.[32] It should also be noted that wider availability of bedside video electroencephalography (EEG), the gold standard, has replaced prolactin testing for the evaluation of epileptic versus nonepileptic episodes.

Serum Studies of Anticonvulsant Agents

Judicious testing of serum levels of antiepileptic drugs (AEDs) may help to improve the care for patients with seizures and epilepsy. However, note that many new AEDs do not have readily obtainable or established levels. The following situations may be indications for obtaining serum AED levels:

  • Baseline measurements: After the seizures are controlled, the AED dose is then established, and the levels needed to achieve seizure-free effectiveness if there are expected changes in the levels, such as occurs with pregnancy, may be also be obtained

  • Toxicity and efficacy: The toxicity and efficacy of an AED is a clinical decision not based on levels per se but on how the patient is doing; an AED level may be helpful if the patient is at the recommended maximum dose but the serum level is not near that of the recommended maximum (thus, the clinician knows the drug dose can be increased, as there is room to achieve a higher AED level)

  • Medication noncompliance: Approximately 30% of patients miss at least 1 dose of their medication every month

  • Autoinduction or pharmacokinetic change, or patients who are unusual metabolizers of a medication

After an anticonvulsant has been used for several weeks, the baseline trough serum concentration slowly decreases because of hepatic autoinduction; this phenomenon is most often seen with carbamazepine, oxcarbazepine, and lamotrigine. Adding other medications with similar metabolic pathways may substantially change the clearance of some anticonvulsants.

The usual therapeutic range for an AED includes peak and trough levels measured in a group of adult patients. If a drug’s toxicity is under study, the peak level is desirable. In most circumstances, however, a trough level is the best indication of efficacy.

As with any medical test, serum concentrations of AEDs help clinical decision making, but the patient's individual response should be the main consideration. For example, a patient with juvenile myoclonic epilepsy (JME) might be seizure free with a valproic acid level of 30 mcg/mL, which is typically considered “subtherapeutic,” but if the patient is seizure free, the level is therapeutic. Therefore, clinical judgment regarding how well the patient is doing (ie, no seizures, no adverse effects) should prevail over a laboratory reading. Again, many new AEDs do not have a recommended level for testing, which is cost saving for that AED relative to many other AEDs in which serum levels are obtained reflexively (thus, adding to the cost of care).

Neuroimaging Studies

A neuroimaging study, such as brain magnetic resonance imaging (MRI) or head computed tomography (CT) scanning, may show structural abnormalities that could be the cause of a seizure. If the patient has normal findings on neurologic examination and his or her condition (eg, cognitive, motor) returns to the usual baseline level between seizures, the preferred study is a brain MRI because of its resolution, which can depict subtle abnormalities.

Not every brain MRI study provides the same quality of information. Studies obtained with 3.0 Tesla (T) scanners may show better resolution than do conventional 1.5 T scanners or the "open-sided" scanners of 0.5 T. Brain MRIs obtained for epilepsy should have thin coronal sections via fast spin-echo (FSE) or fluid attenuation inversion recovery (FLAIR) sequences from the presumed region of epileptogenic zone; these are useful for assessing cortical lesions, which may be amenable to potentially curative surgery.

There are many new advances in MRI sequences to help in epilepsy presurgical evaluation. For more information, see Identification of Potential Epilepsy Surgery Candidates regarding imaging studies.

Electroencephalography and Video-Electroencephalography

Interictal epileptiform discharges or focal abnormalities on electroencephalography (EEG) strengthen the diagnosis of epileptic seizures and provide some help in determining the prognosis. Although the criterion standard for diagnosis and classification of epileptic seizures includes the interpretation of EEG, the clinical history remains the cornerstone for the diagnosis of epileptic seizures.

Video-EEG monitoring is the criterion standard for classifying the type of seizure or syndrome or for diagnosing pseudoseizures; that is, for establishing a definitive diagnosis of spells with impairment of consciousness. This study can be performed to 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 is also used to characterize the type of seizure and epileptic syndrome to optimize pharmacologic treatment and for presurgical workup.

However, video-EEG monitoring is an expensive and laborious study; therefore, monitoring all patients is impractical. Only those whose condition does not respond to treatment or in whom pseudoseizures are suspected should undergo video-EEG. Referral to an epilepsy center should be reserved for patients whose seizures are refractory to treatment. There is now a formal definition of patients who have medically refractory epilepsy: individuals who have tried 2 adequate doses of AED without a clinical response. Some frontal-lobe seizures are considered pseudoseizures for many years until appropriate diagnosis is made by means of video-EEG.

 

Treatment

Approach Considerations

The goal of treatment in patients with epileptic seizures is to achieve a seizure-free status without adverse effects. This goal is accomplished in more than 60% of patients who require treatment with anticonvulsants. Many patients experience adverse effects from these drugs, however, and some patients have seizures that are refractory to medical therapy. A 2017 study found that fewer than two thirds of patients with newly diagnosed epilepsy are seizure-free after 1 year. A smaller study published in 2000 found the seizure-free rate to be 64%, which is almost identical to the rate found in the newer study.[75]

Monotherapy is desirable because it decreases the likelihood of adverse effects and avoids drug interactions. In addition, monotherapy may be less expensive than polytherapy, as many of the older anticonvulsant agents have hepatic enzyme–inducing properties that decrease the serum level of the concomitant drug, thereby increasing the required dose of the concomitant drug.

People with seizures experience psychosocial adjustments after their diagnosis; therefore, social and/or vocational rehabilitation may be needed. Many physicians underestimate the consequences that an epilepsy diagnosis may have on patients. For example, patients with epilepsy may live in fear of experiencing the next seizure, and they may be unable to drive or work at heights.

Refer patients with intractable spells to a neurologist or an epileptologist for further workup, including video-electroencephalographic (EEG) monitoring, to characterize the etiology of their seizures. A neurosurgical consult is recommended when the possibility of surgical management is considered.

Recurrence risk

For patients who have had more than 1 unprovoked seizure, treatment with an anticonvulsant is recommended. However, the standard of care for a single unprovoked seizure is avoidance of typical precipitants (eg, alcohol, sleep deprivation); anticonvulsants are not recommended unless the patient has risk factors for recurrence.

The risk of recurrence in the 2 years after a first unprovoked seizure is 15-70%. Principal factors that increase the risk of recurrence are an abnormal brain magnetic resonance image (MRI) study, an abnormal electroencephalogram (EEG), and a partial-onset seizure.

On brain magnetic resonance imaging (MRI), a focal abnormality in the cortical or limbic regions that indicates a possible substrate for an epileptogenic zone is the finding that most often suggests increased risk for seizure recurrence. Diffuse abnormalities, such as hydrocephalus, may increase the risk by injuring the cerebral cortex.

Abnormalities on an EEG may include any of the following:

  • Epileptiform discharges

  • Focal slowing

  • Diffuse background slowing

  • Intermittent diffuse intermixed slowing

Epileptiform abnormalities and focal slowing are the EEG findings associated with the highest risk of seizure recurrence. Nevertheless, even a normal EEG does not eliminate recurrence risk.

The risk of recurrence in a person with 1 generalized tonic-clonic seizure, a normal EEG, a normal brain MRI, and no evidence of focal onset is about 15%; in this case, the patient is not treated. If a patient has all risk factors, the risk is approximately 80%, and the patient is treated.

The major unresolved question is how to treat patients with 1 abnormality, whose recurrence risk is 30-50%. One approach is to base the decision on a discussion with the patient that includes the risk of seizure recurrence, the risk of toxic effects from the anticonvulsant, and the benefits of avoiding another seizure. The clinician should also describe seizure precautions, including not driving for a specific time. Treatment with anticonvulsants does not alter the natural history of seizure recurrence; it only reduces the risk for the duration of treatment.

The First Seizure Trial Group randomly selected 397 patients with an unprovoked, generalized tonic-clonic first seizure to either receive prophylaxis with a conventional anticonvulsant (ie, carbamazepine, phenobarbital, phenytoin, valproic acid) or to receive no treatment and reported that about 18% of treated patients had seizure recurrence within 1 year, compared with 39% of untreated patients.[33] Therefore, patients must be told that anticonvulsants can reduce their risk of having another seizure but will not eliminate that risk.

Anticonvulsant Therapy

The mainstay of seizure treatment is anticonvulsant medication. The drug of choice depends on an accurate diagnosis of the epileptic syndrome, as response to specific anticonvulsants varies among different syndromes. The difference in response probably reflects the different pathophysiologic mechanisms in the various types of seizure and the specific epileptic syndromes.

Some anticonvulsants (eg, lamotrigine, topiramate, valproic acid, zonisamide) have multiple mechanisms of action, and some (eg, phenytoin, carbamazepine, ethosuximide) have only 1 known mechanism of action. Anticonvulsants can be divided into large groups based on their mechanisms, as follows:

  • Blockers of repetitive activation of the sodium channel: Phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, topiramate

  • Enhancers of slow inactivation of the sodium channel: Lacosamide, rufinamide

  • Gamma-aminobutyric acid (GABA)–A receptor enhancers: Phenobarbital, benzodiazepines, clobazam

  • N -methyl-D-aspartic acid (NMDA) receptor blockers: Felbamate

  • Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor blockers: Perampanel, topiramate

  • T-calcium channel blockers: Ethosuximide, valproate

  • N- and L-calcium channel blockers: Lamotrigine, topiramate, zonisamide, valproate

  • H-current modulators: Gabapentin, lamotrigine

  • Blockers of unique binding sites: Gabapentin, levetiracetam, perampanel

  • Carbonic anhydrase inhibitors: Topiramate, zonisamide

  • Neuronal potassium channel (KCNQ [Kv7]) opener: Ezogabine

  • Other anticonvulsants: Cannabidiol, stiripentol

For more information, see Antiepileptic Drugs.

Anticonvulsants for Specific Seizure Types

This section discusses the use of anticonvulsant agents for absence, tonic or atonic, myoclonic, and tonic-clonic seizures. A discussion of treatment for focal-onset seizures, including refractory cases, also follows, with some findings from the Veterans Administration (VA) Cooperative Studies and Standard and New Antiepileptic Drugs (SANAD) trial.

Absence seizures

If only absence seizures are present, most neurologists treat them with ethosuximide. If absence seizures are present along with other seizure types (eg, generalized tonic-clonic seizures, myoclonic seizures), the choices are valproic acid, lamotrigine, or topiramate. Do not use carbamazepine, gabapentin or tiagabine, because these drugs may exacerbate absence seizures. It is uncertain whether pregabalin, a medication related to gabapentin, may also exacerbate this type of seizure.

Investigators of a single, double-blind, randomized, controlled trial that compared the efficacy, tolerability, and neuropsychologic effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy concluded that ethosuximide was the drug of choice for this clinical scenario.[34] Valproate was equally as effective as ethosuximide in newly diagnosed childhood absence epilepsy, but it was associated with more adverse effects.

Tonic or atonic, myoclonic, and tonic-clonic seizures

Tonic or atonic seizures are dramatic seizures. Patients with Lennox-Gastaut syndrome may have seizures, and this syndrome is best treated with broad-spectrum drugs (eg, valproic acid, lamotrigine, topiramate) or felbamate as a last resort. Other treatment modalities include the use of vagal nerve stimulation (VNS). The US Food and Drug Administration (FDA) has approved several agents—rufinamide, clobazam,[35]  extended-release topiramate,[36, 37, 38, 39] cannabidiol,[81, 82]  and stiripentol[83]  —as adjunctive therapies for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome.

Myoclonic seizures have a bimodal distribution. Infants with myoclonic epilepsies 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. The seizures associated with JME are usually readily controlled with the appropriate broad-spectrum antiepileptic drug (AED), but JME has a high recurrence rate of approximately 80-90% after discontinuation of anticonvulsants.

The best medications for JME and myoclonic seizures are valproic acid, lamotrigine, and topiramate. Levetiracetam is approved by the FDA for adjunctive therapy of JME; this is the first medication approved for this syndrome. Anecdotal evidence suggests that zonisamide might be helpful in JME. Note that if partial seizure medications, such as phenytoin and carbamazepine, are used to treat JME, these agents may not only be ineffective, but in certain cases they may exacerbate the seizures.

Primary generalized tonic-clonic seizures respond to valproic acid, topiramate, or lamotrigine. Levetiracetam and perampanel are indicated as adjunctive therapy for these seizures.

Generalized and unclassified epilepsies

The SANAD trial investigators concluded that valproate should remain the drug of first choice for many patients with generalized and unclassified epilepsies, as it is better tolerated than topiramate and more efficacious than lamotrigine.[40] However, in women of childbearing age, the known potential adverse effects of valproate during pregnancy (ie, black box warnings of severe birth defects and impaired cognitive development) must be balanced against the benefits of seizure control. Levetiracetam and zonisamide were not included in SANAD, which tested only lamotrigine, topiramate, and valproate.

A 2014 study by Shallcross et al, however, indicated that whereas in utero exposure to the AED valproate is associated with language and motor development deficits in children, the same is not true for levetiracetam. In the study, valproate exposure resulted in children having lower scores on tests of comprehension, expressive language abilities, and motor skills compared with children exposed to levetiracetam. In fact, children exposed to levetiracetam did not differ from children unexposed to any AED on tests of thinking, movement, and language when tested at age 36-54 months.[41, 42]

Focal-onset seizures

In focal-onset seizures, there are many AED choices with monotherapy indications, including carbamazepine, lacosamide, lamotrigine, oxcarbazepine, and topiramate. (see Anticonvulsants in Specific Patient Populations, below). Adjunctive therapy with levetiracetam, tiagabine, gabapentin, pregabalin, lacosamide, or ezogabine may be considered if the first or second monotherapy trial with first-line treatments fails. Discussing the adverse-effect profiles of anticonvulsants with patients is important, because the efficacies of anticonvulsants appear to be similar.[43]

The VA Cooperative Study I clearly demonstrated similar efficacies for carbamazepine, phenytoin, primidone, and phenobarbital.[44] However, carbamazepine and phenytoin were tolerated better by men than women. The VA Cooperative Study II findings showed that carbamazepine and valproic acid had similar efficacies.[45] However, subset analysis for complex focal seizures suggested that carbamazepine may be a better choice than valproate.[45]

In elderly subjects (patients aged ≥60 years) in the VA Cooperative Study, lamotrigine and gabapentin were better tolerated than carbamazepine and were similarly effective.[46] However, gabapentin caused more adverse effects than lamotrigine. Those results led to the recommendation of lamotrigine as first-line monotherapy in elderly patients.[46]

The focal seizures arm of the SANAD trial demonstrated that although carbamazepine is the standard drug treatment, lamotrigine is clinically better with respect to time to treatment failure.[47] This study also determined that lamotrigine is a cost-effective alternative to carbamazepine for patients with focal-onset seizures. Carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate were included for comparison.[47] However, the cost-effectiveness of medications has changed, as many new AEDs also have generic formulations.

All new medications have been tested as adjunctive therapy, and head-to-head comparisons of new drugs with carbamazepine have been conducted in Europe. In general, the new drugs have similar statistical efficacies but fewer adverse effects than carbamazepine; this puts the results of the SANAD trial somewhat in doubt, as the SANAD investigators did not find any important differences or trends for scores on the Adverse Events Profile among the drugs.

Of the new anticonvulsants, lamotrigine and topiramate appear to have broad spectrum of action in many seizure types.[48, 49] The American Academy of Neurology and the American Epilepsy Society assembled a task force that reviewed the literature and provided evidence-based recommendations for monotherapy, adjunctive therapy, treatment of primary generalized seizures, treatment in children, and treatment of subgroups of new-onset and refractory epilepsy.[48, 49]

If carbamazepine fails to control the seizures, lamotrigine, topiramate, tiagabine, gabapentin, levetiracetam, oxcarbazepine, pregabalin, and zonisamide are considered for second- or third-line therapy. Several new anticonvulsants, including lamotrigine, topiramate, and oxcarbazepine, are indicated as monotherapy. Although the new anticonvulsants are considered second- or third-line therapy, they can be used as first-line therapy in some patients, especially as these medications have become generic.

In October 2013, the FDA approved labeling changes for ezogabine, including a boxed warning, emphasizing increased risks for potentially permanent adverse effects, such as retinal abnormalities, vision loss, and skin discoloration. The agency recommended that the use of ezogabine be limited to patients who have had an inadequate response to several other therapies and in whom the treatment benefits outweigh the risks. The FDA also recommended eye examinations for patients before they start on ezogabine, as well as every 6 months over the course of treatment.[50, 51, 52]

Medically refractory epilepsy

Although the term medically refractory epilepsy has been used for cases that fail to respond to three antiepileptic drugs, the International League Against Epilepsy (ILAE) has proposed defining drug-resistant epilepsy as the failure to achieve sustained seizure freedom despite adequate trials of two antiepileptic drugs, either as monotherapy or in combination.[53, 54] The drugs must have been appropriately chosen and used, and failure must have occurred because of lack of efficacy and not because of adverse effects.

A study of the ILAE criteria in pediatric epilepsy patients found that the probability of achieving seizure freedom was 65%, 29%, 27% and 21%, respectively, with trials of successive therapeutic regimens.[53, 54] Patients with medically refractory epilepsy should be referred to an epileptologist.

Immunotherapy may be a viable treatment strategy in a subset of epileptic patients whose seizures are refractory to management with conventional AEDs and whose poor seizure control may result from the presence of neural-specific antibodies.[55, 56] Iorio et al found autoantibodies specific to neural antigen in 2 of 29 patients with epilepsy and other neurologic symptoms and/or autoimmune diseases (group 1) and in 9 of 30 patients with AED-resistant epilepsy (group 2).

Of the patients in group 2 who received (1) immunotherapy with intravenous (IV) steroids and IV immunoglobulin for 6 months, (2) IV methylprednisolone, IV immunoglobulin, and rituximab, or (3) IV steroids, 5 cycles of plasmapheresis, and oral steroids, 75% had a reduction in seizure frequency of 50% or greater.[56] The remaining patients in group 2 who received immunotherapy were evenly distributed between those who had a reduction in seizure frequency of 20-50% and those with a reduction of less than 20%.[56]

Looking ahead

Future advances in AEDs will involve agents that alter the natural history of epilepsy and modify disease as opposed to providing primarily symptomatic treatment.

Anticonvulsants in Specific Patient Populations

The use of anticonvulsants is slightly different in several populations of patients, including the following:

  • Neonates

  • Children

  • Elderly patients

  • Women on contraceptive agents

  • Pregnant women[57]

  • Patients with hepatic or renal insufficiency

  • Human immunodeficiency virus (HIV) ̶ infected patients[58]

Neonates, children, and elderly patients

In general, neonates and children require similar loading doses per kilogram of body weight, but they tend to metabolize the drugs faster than adults. This younger population also has rapid increases in the total volume of distribution.

In contrast, elderly patients need lower initial and maintenance doses, owing to the following normal features of the aging process:

  • Slowed hepatic metabolism

  • Decreased renal clearance

  • Decreased volumes of distribution

Women on contraceptive agents

Anticonvulsants that induce hepatic enzymes, such as carbamazepine, phenytoin, phenobarbital, primidone, felbamate, lamotrigine, topiramate, and oxcarbazepine, decrease the efficacy of oral contraceptive pills. Some anticonvulsants cause this drug interaction in a dose-dependent manner, with a negligible effect at low doses. Some obstetricians use a high-dose estrogen-progesterone contraceptive to counteract this effect. An alternative and possibly preferable approach is to use a second method of contraception.

Women of childbearing age and pregnant women

In 2009, the American Academy of Neurology and the American Epilepsy Society issued new guidelines for the management of antiepileptic drugs (AEDs) during pregnancy.[57, 59, 60] These guidelines cover obstetric complications and change in seizure frequency; teratogenesis and perinatal outcomes; and vitamin K, folic acid, blood levels, and breastfeeding.

Woman of childbearing age should take folic acid, at least 0.4 mg per day, to decrease the rate of neural-tube malformations in the fetus. In addition, 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 seizure control and because it exposes the fetus to polypharmacy. Data from multiple studies show an exponential risk of birth defects as anticonvulsants are added in polytherapy.

Frequent drug serum levels should be obtained because of the many physiologic changes that take place during pregnancy, including changes in volume of distribution, protein binding, and hepatic metabolism and erratic absorption. In particular, decreased serum concentration of lamotrigine in the third trimester is well documented, and the dose needs to be adjusted after delivery.

Whether to perform amniocentesis is a personal decision between the woman and her obstetrician. The most important point is to have a clear idea about how the information obtained will be useful for clinical decision making.

Patients with hepatic and renal insufficiency

Gabapentin, pregabalin, levetiracetam, and lacosamide are excreted mostly by means of renal clearance, and their doses can be adjusted for renal insufficiency. These agents are useful in patients with hepatic failure, especially when a drug-induced etiology is suspected. Lamotrigine, which is metabolized by means of glucuronidation, a phase II reaction, is also used in some patients with hepatic insufficiency.

Considerable data are available on the use of phenytoin in the presence of hepatic and renal insufficiency. However, phenytoin is not a preferred medication because of its nonlinear kinetics, hepatic autoinduction, numerous drug interactions, and high degree of protein binding. Among all anticonvulsants, phenytoin, carbamazepine, valproic acid, and felbamate have been associated with acute hepatic injury.

Discontinuing Anticonvulsant Agents

After a person has been seizure free for typically 2-5 years, the physician may consider discontinuing that patient’s medication. Many patients outgrow many epileptic syndromes of childhood and do not need to take anticonvulsants. The relapse rate for seizures in adults is about 40-50%; for children, it is about 25%. This difference probably reflects the different epileptic syndromes that are prevalent in the 2 populations.

The recurrence rate during adulthood for patients with juvenile myoclonic epilepsy (JME) is about 80-90% in 2 years, even in patients who have spent many years being seizure free on low doses of appropriate anticonvulsants.

Risk of seizure recurrence

Many neurologists use the risk factors for new-onset seizures to assess patients for discontinuation of anticonvulsants. Normal findings on an electroencephalogram (EEG) and a brain magnetic resonance imaging (MRI) scan lower the risk of relapse after drug discontinuation, whereas epileptiform or focal abnormalities on an EEG and/or focal cortical or limbic abnormalities on a brain MRI scan significantly increase the relapse risk.

Additional factors associated with an increased risk of seizure recurrence after discontinuation include the following:

  • Several seizure types (eg, worse if tonic or atonic seizures are present)

  • High number and frequency of seizures

  • Long duration of epilepsy before the seizures were controlled

  • Short duration of seizure freedom

Seizure relapse

About 75% of seizure relapses after medication discontinuation occur in the first year, and at least 50% of patients who have another seizure do so in the first 3 months. Therefore, advise patients to observe strict seizure precautions (including not driving) during tapering and for at least 3 months after discontinuation, depending on state laws. The need to drive is an impediment for some patients, who may opt to continue therapy for that reason.

Some authors recommend that all anticonvulsants, except primidone, phenobarbital, and benzodiazepines, be gradually discontinued over 6-10 weeks if they were used for a long period. Discontinue primidone, phenobarbital, and benzodiazepines over 10-16 weeks.

Nonpharmacologic Management

A ketogenic or modified Atkins diet and vagal nerve stimulation (VNS) are nonpharmacologic methods for managing patients with seizures that are unresponsive to antiepileptic drugs. The ketogenic diet is typically used in children. The FDA has approved VNS stimulation for adolescents and adults with refractory partial epilepsy, but clinical experience also suggests efficacy and safety in children and in patients with generalized epilepsies.

Ketogenic diet and modified Atkins diet

The ketogenic diet, which relies heavily on the use of fat, such as hydrogenated vegetable oil shortening (eg, Crisco), has a role in the treatment of children with severe epilepsy. Support for the efficacy of these diets comes from large observational studies rather than from randomized, controlled trials.[61]

Although this diet is unquestionably effective in some refractory cases of seizure, a ketogenic diet is difficult to maintain; less than 10% of patients continue the diet after a year. Furthermore, any small carbohydrate intake (eg, lollypop, piece of candy) resets ketone metabolism for 2 weeks, thereby eliminating antiseizure efficacy. Consequently, some authors do not consider using this treatment in teenagers or adults unless all of the patient’s caloric intake is being delivered by means of a gastric tube.

Preliminary data have been published about improvement of seizure frequency following a modified Atkins (low-carbohydrate) diet that mimics the ketogenic diet but does not restrict protein, calories, and fluids. In small studies of children with intractable epilepsy, seizure reductions of more than 50% have been seen within 3 months in some children placed on this diet, particularly with carbohydrate limits of 10 g per day.[62, 63]

Preliminary studies of a modified Atkins diet have also been performed in adults. For example, Smith et al found that this diet demonstrates modest efficacy as adjunctive therapy for some adults with medically resistant epilepsy, and it may be also helpful for weight loss but can pose financial and logistical difficulties.[64]

Vagal nerve stimulation

VNS is a palliative technique that involves surgical implantation of a stimulating device (see Guidelines). VNS is FDA approved to treat medically refractory focal-onset epilepsy in patients older than 12 years. Some studies demonstrate its efficacy in focal-onset seizures and in a small number of patients with primary generalized epilepsy. Randomized studies showed modest efficacy at 3 months, but postmarketing experience showed delayed improvement in another group of patients.

According to the manufacturer's registry, efficacy of the stimulating device at 18 months is 40-50%, where efficacy is defined as a seizure reduction of 50% or more. Many patients report improvement in seizure intensity and general mood. However, seizure-free rates for pharmacologically intractable focal-onset epilepsy are less than 10%.

A meta-analysis of VNS clinical studies reported an average reduction in seizures of at least 50% in approximately 50% of patients at last follow-up. Although VNS was not initially FDA approved for children or patients with generalized epilepsy, the authors also found that these groups benefitted significantly from VNS.

Positive predictors of a favorable outcome with VNS therapy include posttraumatic epilepsy and tuberous sclerosis. Few patients achieve complete seizure freedom with VNS, and about a quarter of patients receive no benefit in their seizure frequency.[67] Some patients have clinical improvement in terms of milder and shorter seizures.

Implantable neurostimulator

The NeuroPace RNS System, a device that is implanted into the cranium, senses and records electrocorticographic patterns and delivers short trains of current pulses to interrupt ictal discharges in the brain. The Neurological Devices panel of the FDA concluded that this device was safe and effective in patients with partial-onset epilepsy in whom other antiepileptic treatment approaches have failed and that the benefits outweigh the risks.[68]

In November 2013, the FDA approved the NeuroPace RNS System for the reduction of seizures in patients with drug-resistant epilepsy.[69, 70] Approval was based on a clinical trial involving 191 subjects with drug-resistant epilepsy. The neurostimulator was implanted in all of these patients but activated in only half of them. After 3 months, the average number of seizures per month in patients with the activated device fell by a median of 34%, compared with an approximately 19% median reduction in patients with an unactivated device.

Lobectomy and Lesionectomy

The 2 major kinds of brain surgery for epilepsy are palliative and potentially curative. In the past, the most common palliative surgery was anterior callosotomy, which was indicated for patients with intractable atonic seizures, who often sustain facial and neck injuries from falls. This surgery is still performed as the use of vagal nerve stimulation (VNS) in such patients has good efficacy.

Several curative surgeries are possible, including lobectomy and lesionectomy. In general, the epileptogenic zone must be mapped by using video-electroencephalographic (video-EEG) monitoring and, in some patients, with intracranial electrodes.

Lobectomy

Outcomes of temporal-lobe surgeries are better than those for surgeries in other areas. If a patient has unilateral temporal-lobe seizures (as observed on video-EEG) and unilateral hippocampal sclerosis (as observed on brain magnetic resonance imaging [MRI]), the likelihood of a class I outcome (no seizures or only auras) at 2 years is about 85%.

In a randomized, controlled trial of surgery in 80 patients with temporal lobe epilepsy, 58% of patients in the group randomized to anterior temporal lobe resective surgery were free from seizures impairing awareness at 1 year, as compared with 8% in the group that received anticonvulsant treatment.[71] Quality of life was also superior for patients in the surgical group.

According to research, MRI-guided selective laser amygdalohippocampectomy (SLAH) is at least as effective as standard resection. In a study of 7 patients who received SLAH and 10 patients who underwent standard resection (either open anterior temporal lobectomy or selective amygdalohippocampectomy), 9 of 10 patients in the latter group showed a significant decline on visual/verbal memory tasks (P< .002), compared with 1 of 7 patients in the former group.[41] Whereas 6 of 7 laser-ablation patients showed significant improvement on 1 or more memory measures, only 4 of 10 standard-resection patients did (P< .02).[41]

Lesionectomy

In a study presented at the 66th Annual Meeting of the American Epilepsy Society, investigators suggested that, in select pediatric patients, smaller lesionectomy resections in the surgical treatment of seizures may be as effective as larger resections, and they may spare children the functional and developmental deficits associated with the larger resections.[72, 73]

The researchers reported on the outcomes of 25 children with MRI-negative, intractable partial epilepsy who underwent focal corticectomies. Epileptogenic regions were identified by 3-dimensional EEG, single-photon emission computed tomography (SPECT) scanning, positron emission tomography (PET) scanning, and invasive EEG data. Seizure-free outcomes occurred in 3 of 7 patients with type I focal cortical dysplasia, 7 of 12 patients with type II focal cortical dysplasia, and 3 of 6 patients with mild malformations of cortical development.[72, 73]

Surgery for drug-resistant epilepsy

Although surgery for drug-resistant epilepsy is often considered a last resort, results of a multicenter trial suggested that early surgery may be helpful in some patients with newly intractable and disabling temporal lobe epilepsy. In this trial, patients who had had no more than 2 consecutive years of disabling seizures refractory to adequate trials of 2 anticonvulsant medications were randomized to anteromesial temporal lobe resection plus continued medication (n = 15) or continued medication alone (n = 23).[74]

At follow-up, 11 of the 15 surgery patients (73%) were seizure free during postoperative year 2; none of the patients in the medication-only group were seizure free over the same period. The researchers warned, however, that the results must be interpreted cautiously, as the trial was halted prematurely because of slow accrual.[62]

For more information on surgical management, see Identification of Potential Epilepsy Surgery Candidates and Outcome of Epilepsy Surgery.

Activity Modification and Restrictions

The major problem for patients with seizures is the unpredictability of the next seizure. Clinicians should discuss the following types of seizure precautions with patients who have epileptic seizures or other spells of sudden-onset seizures:

  • Driving

  • Ascending heights

  • Working with fire or cooking

  • Using power tools or other dangerous equipment

  • Taking unsupervised baths

  • Swimming

These lifestyle precautions are clearly more applicable to some patients than to others. Document on the patient's chart that driving and occupational hazards for people with seizures were discussed.

Safety must be balanced with the risk for seizures. A patient with many poorly controlled diurnal seizures may exercise more caution than a patient who has only nocturnal seizures. Encourage the use of helmets to prevent head trauma while the patient is biking, skiing, or participating in other high-risk activities.

Driving motorized vehicles

Driving restrictions differ for each patient because of the individual features of their seizures, their degree of seizure control, and, in the United States, state laws. US physicians should be aware of the state regulations regarding driving, which vary considerably among states. If clinicians practice in a state that requires mandatory reporting of patients with epilepsy to the Department of Motor Vehicles, they must ensure they are compliant with state laws and have documentation. International variation regarding reporting is also considerable; some countries have more permissive or more restrictive laws regarding driving than does the United States.

Aside from state laws, recommendations regarding driving motorized vehicles also vary depending on whether the patient has seizures that occur exclusively during sleep. Consult current state and federal laws and regulations. For example, to resume commercial driving across state lines, a patient must have a 5-year seizure-free period. The recommendation for driving cars and trucks extends to the operation of other motorized vehicles, such as boats and motorcycles. Aircraft pilots are typically no longer permitted to fly.

Water precautions

Common sense dictates that patients with seizures should not swim alone, and they should be particularly aware of the importance of the presence of an adult lifeguard who can pull them out of the water if needed. Wearing a life jacket in a boat is important. Activities as simple as taking a bath may be risky, because a person can drown in as little as 1 inch of water during the flaccid postictal phase. In addition, a patient who has a seizure while waiting for bath water to warm up may suffer hot-water burns.

Heights, fire, and power tools

Patients with seizures may experience an episode in situations such as being up on a roof or engaging in some activity at considerable height from the floor. In addition, burns from injuries related to cooking are not uncommon, and injuries can occur with the use of power tools and other dangerous equipment. Caution—in particular, supervision—is advised when power tools are used, and the use of safety devices, such as an automatic shutoff switch, is recommended.

Long-Term Monitoring

In 2018, the FDA cleared for marketing the first smart watch for seizure tracking and epilepsy management. The Embrace smart watch identifies convulsive seizures and sends an alert via text and phone message to caregivers. The watch also records sleep, rest, and physical activity data. The device was tested in a study of 135 epileptic patients and found the watch's algorithm detected 100% of patient seizures.[80]

 

Medication

Medication Summary

Anticonvulsant medication is the mainstay of treatment for seizures, although the choice of anticonvulsant drug varies with different seizure types and epileptic syndromes. The number of anticonvulsants has increased, offering many more medication choices for physicians and their patients. For more information, see Antiepleptic Drugs.

Anticonvulsants, Other

Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity. Anticonvulsants are normally reserved for patients who are at increased risk for recurrent seizures.

Carbamazepine (Tegretol, Tegretol XR, Carbatrol, Epitol, Equetro)

Carbamazepine is indicated for the management of partial seizures and generalized tonic-clonic seizures. It has an active metabolite, 10-11 epoxide, which has anticonvulsant activity and can be measured in the serum. This agent works by binding to voltage-dependent sodium channels and inhibiting the generation of action potentials. Serum carbamazepine levels should be measured frequently when initially starting this medication, with a goal of being seizure free. Like phenytoin, carbamazepine has been associated with osteopenia.

Felbamate (Felbatol)

Felbamate is approved by the FDA for medically refractory partial seizures and Lennox-Gastaut syndrome. This agent has multiple mechanisms of action, including (1) inhibition of N-methyl-D-aspartate (NMDA)–associated sodium channels, (2) potentiation of GABAergic activity, and (3) inhibition of voltage-sensitive sodium channels. Felbamate is used only as a drug of last resort in medically refractory cases because of the risk of aplastic anemia and hepatic toxicity, which necessitates regular blood tests.

Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

Lamotrigine, a triazine derivative, is an antiepileptic drug with a very broad spectrum of activity, like valproate. It is approved by the FDA for primary generalized and partial-onset epilepsy. Other indications include adjunctive therapy in the treatment of generalized seizures of Lennox-Gastaut syndrome, treatment of juvenile myoclonic epilepsy (JME) and maintenance treatment of bipolar I disorder. The mechanism of action is based on inhibiting the release of glutamate and voltage-sensitive sodium channels, leading to stabilization of the neuronal membrane.

Lamotrigine is quickly absorbed when given orally, and 55% is bound to plasma proteins. The therapeutic serum levels have not been definitively established.

Side effects of lamotrigine include rash and nausea. The dose has to be increased very slowly over several weeks to minimize the chance of rash, especially if the patient is on valproic acid. The risk of developing Stevens-Johnson syndrome, toxic epidermal necrolysis, and angioedema is 1 in 1000 adults and higher in children, but this risk is decreased with slower titration.

Levetiracetam (Keppra, Keppra XR)

Levetiracetam is indicated for adjunctive therapy in the treatment of primary generalized tonic-clonic seizures, JME, and partial-onset seizures in adults and children. The mechanism of action is thought to be through modulation of synaptic vesicle proteins. The metabolism of this drug is independent of the CYP450 system, which limits the potential for interaction with other antiepileptic drugs.

Levetiracetam has a rapid onset of action and is well tolerated. Common side effects include fatigue, somnolence, dizziness, and irritability. This medication is available in oral (including extended-release) and intravenous formulations.

Rufinamide (Banzel)

Rufinamide modulates sodium channel activity, particularly prolongation of the channel's inactive state. It significantly slows sodium channel recovery and limits sustained, repetitive firing of sodium-dependent action potentials. Rufinamide is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. It is well tolerated, with the most common side effects being somnolence and vomiting.

Topiramate (Topamax)

Topiramate is an AED with a broad spectrum of antiepileptic activity. This agent is approved for generalized, primary generalized, tonic-clonic, and partial-onset seizures. Topiramate has multiple mechanisms of action, including state-dependent sodium channel ̶ blocking action, enhancement of the inhibitory activity of the neurotransmitter GABA, and antagonism of the NMDA-glutamate receptor. It may block glutamate activity and is a weak carbonic anhydrase inhibitor. Weight loss, impaired cognition, and mood problems are common side effects of topiramate. The drug is also approved for migraine prevention.

Valproic acid (Depacon, Depakene, Stavzor)

Valproate, a broad-spectrum AED, is effective against most seizure types, including myoclonic seizures. It can also be used alone or in combination for the treatment of generalized or partial seizures. Valproate has multiple mechanisms of anticonvulsant action, including increasing GABA levels in the brain, as well as T-type calcium channel activity.

Divalproex sodium (Depakote, Depakote ER, Depakote Sprinkles)

Indicated for complex partial seizures and also for simple and complex absence seizures. May be used as monotherapy or adjunctive therapy. Valproate has multiple mechanisms of anticonvulsant action, including increasing GABA levels in the brain, as well as T-type calcium channel activity. The extended-release (ER) formulation allows for once-a-day administration.

Zonisamide (Zonegran)

Zonisamide is indicated for partial seizures. It blocks T-type calcium channels, prolongs sodium channel inactivation, and is a carbonic anhydrase inhibitor.

Dose adjustments may be required when zonisamide is given with other anticonvulsants, such as carbamazepine, phenytoin, and phenobarbital. The most common side effects of this drug include ataxia, anorexia, and fatigue.

Perampanel (Fycompa)

Perampanel is a noncompetitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor. It is indicated as adjunct treatment for partial-onset seizures (with or without secondary generalized seizures) and for primary generalized tonic-clonic seizures in adults and children aged 12 years or older.

Lacosamide (Vimpat)

Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. It is indicated as monotherapy or adjunctive therapy for partial-onset seizures.

Cannabidiol (Epidiolex)

Purified formulation of cannabidiol indicated for treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients aged 2 years or older. Cannabidiol is a structurally novel anticonvulsant and the exact mechanism by which it produces anticonvulsant effects is unknown. It does not appear to exert its anticonvulsant effects through CB1 receptors, nor through voltage-gated sodium channels.

Stiripentol (Diacomit)

Allylic alcohol that is unrelated to other anticonvulsants. The precise anticonvulsant effect in humans is unknown. Possible mechanisms of action include direct effects mediated through the GABA-A receptor and indirect effects involving inhibition of cytochrome P450 activity with resulting increase in blood levels of clobazam and its active metabolite. It is indicated for treatment of seizures associated with Dravet syndrome in patients aged 2 years or older who are taking clobazam. There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome.

Anticonvulsants, Barbiturates

Class Summary

Like benzodiazepines, barbiturates bind to the gamma-aminobutyric acid (GABA) receptor, enhancing the actions of GABA by extending GABA-mediated chloride channel openings and allowing neuronal hyperpolarization. The principal barbiturate used for status epilepticus is phenobarbital; for refractory cases, pentobarbital is used.

Phenobarbital (Luminal)

Phenobarbital works at GABA receptors in the central nervous system (CNS) to potentiate CNS inhibition. This agent is the best-studied barbiturate for the treatment of status epilepticus.

In status epilepticus, achieving therapeutic levels as quickly as possible is important. Intravenous dosing may require approximately 15 minutes to attain peak levels in the brain. To terminate generalized convulsive status epilepticus, administer up to 15-20 mg/kg. If the patient has received a benzodiazepine, the potential for respiratory suppression significantly increases. Ventilation and intubation may be necessary. Hypotension may require treatment.

In status epilepticus, phenobarbital is generally used after phenytoin or fosphenytoin fails. However, it can be used in lieu of phenytoin in certain circumstances. A trend is to recommend agents other than phenobarbital (propofol, midazolam, other barbiturates) for refractory status epilepticus; however, for super-refractory status epilepticus, phenobarbital should be used.

Primidone (Mysoline)

Primidone is indicated for the management of grand mal, psychomotor, and focal seizures. In addition, it is commonly used for benign familial tremors. When metabolized, primidone breaks down to phenobarbital, another active antiepileptic drug. Primidone decreases neuron excitability and increases the seizure threshold. Common side effects of this drug include sedation, drowsiness, fatigue, and depression.

Anticonvulsants, Benzodiazepine

Class Summary

These agents bind to the gamma-aminobutyric acid (GABA) receptor, thereby enhancing the actions of GABA.

Clobazam (ONFI)

Clobazam is a 1,5-benzodiazepine that possesses potent anticonvulsant properties. Its mechanism of action is binding to the gamma-aminobutyric acid–A (GABA-A) receptor. This agent is thought to potentiate GABAergic neurotransmission. The active metabolite, N-demethylclobazam, is largely responsible for its long duration of action. Clobazam is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients older than 2 years.

Midazolam intranasal (Nayzilam)

Short-acting, water-soluble imidazobenzodiazepine. Thought to potentiate GABAergic neurotransmission which results from binding at the benzodiazepine site of the GABA-A receptor. It is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in adults and children aged 12 years or older with epilepsy.

Anticonvulsants, Succinimide

Class Summary

These agents reduce current in T-type calcium channels.

Ethosuximide (Zarontin)

Ethosuximide is a succinimide antiepileptic drug (AED) that is effective only against absence seizures. It has no effect on generalized tonic-clonic, myoclonic, atonic, or partial seizures.

The mechanism of action is based on reducing current in T-type calcium channels on thalamic neurons. The spike-and-wave pattern during petit mal seizures is thought to be initiated in thalamocortical relays by activation of these channels. Ethosuximide is available in large 250-mg capsules, which may be difficult for some children to swallow, and as a syrup (250 mg/5 mL).

Blood levels should be measured 1-3 weeks after starting ethosuximide. The therapeutic concentration of ethosuximide is 40-100 mcg/mL. The major side effects of the drug include nausea, vomiting, drowsiness, hyperactivity and sleep disturbance.

Anticonvulsants, Neuronal Potassium Channel Opener

Class Summary

Stabilizes neuronal KCNQ (Kv7) channels in the open position, increasing the stabilizing membrane current and preventing bursts of action potentials during the sustained depolarizations associated with seizures.

Ezogabine (Potiga)

Ezogabine is a neuronal potassium channel opener that stabilizes neuronal KCNQ (Kv7) channels in the open position, increasing the stabilizing membrane current and preventing bursts of action potentials during the sustained depolarizations associated with seizures. It is indicated as adjunctive therapy in partial-onset seizures uncontrolled by current medications.

Owing to the presence of potassium channels in the bladder, there is a small risk of urinary retention. Ezogabine can cause skin discoloration and abnormalities of the eye characterized as changes in the pigment in the retina. Whether these changes are permanent and whether pigment changes in the retina have the potential to cause loss of vision are unknown.

The FDA recommends that all patients taking ezogabine undergo baseline and periodic eye examinations and discontinue the medication if changes are observed, unless there is no other treatment option. Skin discoloration most often appeared as blue around the lips and nail beds but was also reported to be widespread on the face and legs. In patients with skin discoloration, alternative treatments should be considered, but the FDA warns of serious and life-threatening reactions to the sudden discontinuance of the medication.

Anticonvulsants, Hydantoins

Class Summary

These agents stabilize sodium channels and prevent return of the channels to the active state.

Phenytoin (Dilantin, Phenytek)

Phenytoin is used to treat patients with partial, generalized, or mixed seizures, such as the tonic-clonic (grand mal) type. This agent works by blocking voltage-dependent neuronal sodium channels. The therapeutic concentration range of phenytoin in serum is 10-20 mcg/mL for patients who have normal renal function and serum albumin levels.

The risk of osteopenia and cerebellar ataxia, both of which are long-term adverse effects associated with phenytoin, now temper the drug's use by neurologists. This agent is one of the most difficult AEDs to use because of its zero-order kinetics and narrow therapeutic index. In addition, it can have significant bidirectional drug interactions.

 

Questions & Answers

Overview

What is epilepsy?

What determines the signs and symptoms of seizures in epilepsy?

Which questions are asked to help clarify the type of seizure a patient experienced?

How are epileptic seizures diagnosed?

What is the role of lab tests in the evaluation of suspected epileptic seizures?

Which imaging studies are performed after epileptic seizures?

How is the clinical diagnosis for epilepsy confirmed?

What is the role of video EEG monitoring in the diagnosis of seizures and epilepsy?

What is the goal of treatment for epilepsy?

What is the standard of care for a single, unprovoked epileptic seizure?

When do seizures require treatment?

Which medications are used in the treatment of epileptic seizures?

What are nonpharmacologic treatment options for epileptic seizures?

What is the role of surgery in the treatment of epilepsy?

What are the possible causes of epileptic seizures?

How is epilepsy defined?

What is required for the diagnosis of epilepsy?

What are the clinical signs or symptoms of epileptic seizures?

Where can more information regarding seizure types be found?

Where can more information be found regarding epileptic syndromes and epilepsy treatment?

When were the first epileptic seizures recognized in history?

What role did Hippocrates have in the history of epilepsy?

When did modern investigation of the etiology of epilepsy begin?

What are epileptic seizures?

How is the brain involved in epileptic seizures?

How does the pathophysiology of focal-onset epileptic seizures differ from generalized-onset epileptic seizures?

What is the electroencephalographic (EEG) hallmark of focal-onset epileptic seizures?

How is paroxysmal depolarization shift (PDS) characterized in epileptic seizures?

How does an interictal spike transition to an epileptic seizure?

Which pathophysiologic mechanisms cause focal-onset epileptic seizures?

How do medications work to prevent epileptic seizures?

What is the role of gamma-aminobutyric acid (GABA) release in the pathophysiology of epileptic seizures?

Which mechanisms lead to decreased neurotransmitter inhibition in epileptic seizures?

What is the main inhibitory neurotransmitter in epileptic seizures?

What is the role of chloride channels in the pathophysiology of epileptic seizures?

Which medications modulate chloride channels in epilepsy?

How does alteration of the normal state of the chloride channels affect the pathophysiology of epilepsy?

What is the role of excitatory postsynaptic potentials (EPSPs) in the pathophysiology of epilepsy?

What is the role of inhibitory postsynaptic potential (IPSP) in the pathophysiology of epileptic seizures?

Which nervous system channels are subject to modulation in epilepsy?

What are the characteristics of each channel involved in the pathophysiology of epileptic seizures?

How many different electrophysiologic responses of gamma-aminobutyric acid A (GABA-A) receptors exist in epileptic seizures?

What is the role of gamma-aminobutyric acid A (GABA-A) inhibition in the pathophysiology of epileptic seizures?

What is the role of gamma-aminobutyric acid B (GABA-B) inhibition in the pathophysiology of epileptic seizures?

How are gamma-aminobutyric acid (GABA) neurons activated in epileptic seizures?

What is the role of feedforward inhibition in the pathophysiology of epileptic seizures?

How does the activation of gamma-aminobutyric acid (GABA)ergic neurons affect epileptic seizures?

What is the role of feedback inhibition in the pathophysiology of epileptic seizures?

What is the role of synaptic reorganization in the pathophysiology of epileptic seizures?

What is the role of hippocampal sprouting in the pathophysiology of epileptic seizures?

What is the role of intracellular calcium buffering in the pathophysiology of epileptic seizures?

Which mechanisms lead to increased excitation in the pathophysiology of epilepsy?

What is the role of glutamate in the pathophysiology of epileptic seizures?

How is fast neurotransmission achieved in the pathophysiology of epilepsy?

What is the role of calcium in the pathophysiology of epileptic seizures?

How do nonsynaptic interactions affect the pathophysiology of epilepsy?

What is the role of the limbic system in the pathophysiology of focal-onset epilepsy?

How frequently is hippocampal sclerosis found in epilepsy?

What is the role of mossy-fiber sprouting in the pathophysiology of epilepsy?

What is the role of denervation in the pathophysiology of epilepsy?

What is the role of recurrent excitatory collaterals in the pathophysiology of epilepsy?

What is the best understood pathophysiologic mechanism of generalized seizures?

What is the role of altered thalamocortical rhythms in the pathophysiology of generalized seizures?

What is the role of thalamic relay neurons in the pathophysiology of generalized seizures?

What is the role of nucleus reticularis of the thalamus (NRT) in the pathophysiology of generalized seizures?

What are the functional states of T-calcium in the pathophysiology of generalized seizures?

What is the role of hyperpolarization in the pathophysiology of generalized seizures?

What is the pathophysiologic mechanism of medications that prevent absence seizures?

What is the role of increased GANA levels in the pathophysiology of epileptic seizures?

What is the prevalence of seizures in Rett syndrome?

What is the prevalence of seizures in Prader-Willi syndrome?

What is Sturge-Weber syndrome?

What causes epilepsy?

What is the role of genetics in the etiology of epilepsy?

What categories of genetic disorders cause epileptic seizures?

Which genetic syndromes cause seizures?

What is the prevalence of seizures in Angelman syndrome?

What is the prevalence of seizures in Pitt-Hopkins syndrome?

What are major features of tuberous sclerosis?

What are minor features of tuberous sclerosis?

What is required for a definite diagnosis of tuberous sclerosis?

What is the prevalence of epileptic seizures in tuberous sclerosis?

What is the prevalence of seizures in chromosomal 22q deletion syndrome?

What is the prevalence of seizures in Wolf-Hirschhorn syndrome?

What is the prevalence of seizures in chromosome 1p36 deletion syndrome?

Which metabolic disorders may cause epileptic seizures?

Which rare diseases cause epileptic seizures?

Which mitochondrial diseases may cause epileptic seizures?

How is myoclonic epilepsy with ragged red fibers (MERRF) characterized?

What causes autosomal dominant nocturnal frontal lobe epilepsy?

What causes autosomal dominant juvenile myoclonic epilepsy?

What causes benign familial neonatal seizures?

Which genetic mutations cause seizure syndromes?

What is the incidence of recurrent nonfebrile seizures in the US?

What is the prevalence of epileptic seizures in developed nations?

Which factors affect the prognosis of epilepsy?

What are the common morbidities of epileptic seizures?

What are the mortality risks of epilepsy?

Which factors increase the risk for sudden, unexpected death in epilepsy (SUDEP)?

What is the mechanism of death in sudden, unexpected death in epilepsy (SUDEP)?

Where can the NIH report on sudden, unexpected death in epilepsy (SUDEP) be found?

What should be included in patient education about injury prevention during seizures?

Where are patient education resources found?

Presentation

How are epileptic seizures diagnosed?

Which questions may help to clarify the type of seizure in the evaluation of epilepsy?

What is the role of the physical exam in the diagnosis of epilepsy?

What is the 1981 International League Against Epilepsy (ILAE) classification of epileptic seizures?

What is semiologic classification of epileptic seizures?

What revisions have been made to the International League Against Epilepsy (ILAE) classification of epileptic seizures?

What are the types of focal-onset seizures?

How are simple and complex focal seizures differentiated?

What is the basis for the diagnosis of different seizure types?

How is impaired conscientiousness assessed in epileptic seizures?

How do complex focal seizures progress?

What are the signs and symptoms of complex focal seizures of frontal-lobe origin?

What are the features of complex focal seizures on EEG?

How do secondary generalized seizures progress?

How are generalized tonic-clonic seizures classified?

What are the types of generalized-onset seizures?

How are generalized-onset seizure types classified and diagnosed?

What are absence seizures?

How are absence seizures diagnosed in adults?

What are the signs and symptoms of absence seizures in children?

What is the role of the classic ictal EEG in the diagnosis of absence seizures?

What are myoclonic seizures?

What are clonic seizures?

What are tonic seizures?

What is the ictal correlate of tonic seizures?

What are tonic-clonic (grand mal) seizures?

What is the ictal correlate of generalized tonic-clonic seizures?

What are atonic seizures?

What is epileptic syndrome?

What is the International League Against Epilepsy (ILAE) classification of epileptic syndromes?

What are some localization-related epilepsies and syndromes?

What are some generalized epilepsies and syndromes?

What is the ILAE 5-axis diagnostic scheme for epilepsy?

Which epilepsy terms did ILAE propose abandoning in 2001?

What are the criticisms of the ILAE 5-axis diagnostic scheme for epilepsy?

DDX

What is the basis for diagnosis of epileptic seizures?

How is the clinical diagnosis of epileptic seizures confirmed?

Which conditions should be considered in the differential diagnoses of epileptic seizures?

What are the differential diagnoses for Epilepsy and Seizures?

Workup

Which imaging studies are recommended for the diagnosis of epileptic seizures?

What is the role of prolactin assays in the evaluation of epileptic seizures?

What are the American Academy of Neurology (AAN) recommendations for the use of prolactin to diagnose epileptic seizures?

When are serum antiepileptic drug (AED) levels measured in the management of epilepsy?

Why do serum antiepileptic drug (AED) baseline trough levels decrease over time?

How is the serum antiepileptic drug (AED) trough level used in the management of epilepsy?

What is the usefulness of serum concentrations of antiepileptic drugs (AEDs) in the management of epileptic seizures?

Which neuroimaging studies are used in the diagnosis of epileptic seizures?

Which findings on EEG aid in the diagnosis of epileptic seizures?

What is the role of video-EEG in the diagnosis of epileptic seizures?

Treatment

What is the goal of treatment for epilepsy?

What are the benefits of monotherapy in the treatment of epilepsy?

What are the indications for social and/or vocational rehabilitation in the treatment of epilepsy?

When is referral to a neurologist or epileptologist indicated for treatment of epileptic seizures?

What are the risk factors for recurrence of epileptic seizures?

Which abnormalities on the electroencephalogram (EEG) increase the risk of recurrent epileptic seizures?

What is the risk of recurrence in patients with one generalized tonic-clonic seizure?

How is the risk of recurrence of epileptic seizures managed in patients with one abnormality?

What is the mainstay of treatment for epilepsy?

Which anticonvulsants are used in the treatment of epileptic seizures?

Where can information be found on which anticonvulsants are used to treat specific epileptic seizure types?

Which anticonvulsants are used to treat absence seizures?

Which anticonvulsants are used to treat tonic or atonic seizures?

Which anticonvulsant drugs are used to treat myoclonic seizures?

Which anticonvulsant drugs are used to treat juvenile myoclonic epilepsy (JME)?

Which anticonvulsant drugs are used to treat primary generalized tonic-clonic seizures?

Which anticonvulsant drugs are used to treat generalized and unclassified epilepsies?

What are the antiepileptic drug (AED) options for the treatment of focal-onset seizures?

How does the efficacy of specific anticonvulsants for the treatment of epilepsy vary among patient groups?

What is the efficacy of lamotrigine in the treatment of epilepsy?

How do newer medications compare to carbamazepine in the treatment of epileptic seizures?

What are the medication options if carbamazepine fails to control epileptic seizures?

What are the FDA warnings regarding use of ezogabine in the treatment of epileptic seizures?

What are the treatment options for medically refractory epilepsy?

What is the probability of achieving seizure freedom in pediatric patients?

What is the role of immunotherapy in the treatment of epileptic seizures?

What is the efficacy of immunotherapy for the treatment of medically refractory epilepsy?

What is the focus of future advances in the medical treatment of epileptic seizures?

In which patient populations does the use of anticonvulsants vary for the treatment of epileptic seizures?

What are considerations when administering medications to neonates and children for the treatment of epilepsy?

What are considerations when administering medications to elderly patients for the treatment of epilepsy?

What are the medication options for the treatment of epilepsy in women taking oral contraceptives?

What are the AAN/AES treatment guidelines for epilepsy during pregnancy?

Why are frequent drug serum levels obtained in pregnant women with epilepsy?

What are the considerations for performing amniocentesis in women with epilepsy?

How is epilepsy managed in patients with hepatic and renal insufficiency?

When is discontinuation of medication considered for patients with epilepsy?

What is the recurrence rate of juvenile myoclonic epilepsy (JME) during adulthood?

How is the risk of epileptic seizure recurrence assessed?

Which factors increase the risk of epileptic seizure recurrence after discontinuation of medication?

What is the likelihood of epileptic seizure recurrence after discontinuation of medication?

How long does it take to gradually discontinue epilepsy medications?

What are some nonpharmacologic treatment options for epilepsy?

What is the role of a ketogenic diet in the treatment of epilepsy?

What is the efficacy of the Atkins diet in the treatment of epilepsy?

What is the role of vagus nerve stimulation (VNS) in the treatment of epilepsy?

What is the efficacy of vagus nerve stimulation (VNS) for the treatment of epilepsy?

What are positive predictors of a favorable outcome with vagal nerve stimulation (VNS) therapy for epilepsy?

What is the role of implantable neurostimulators in the treatment of epilepsy?

What are the surgical options for the treatment of epilepsy?

What are curative surgical options for patients with epilepsy?

What is the role of lobectomy in the treatment of epilepsy?

What is the role of lesionectomy in the treatment of epilepsy?

What is the role of surgery in the treatment of drug-resistant epilepsy?

What is the efficacy of surgery for drug-resistant epilepsy?

What activity restrictions are advisable for patients with epilepsy?

When are precautions against head trauma necessary in patients with epilepsy?

How do driving restrictions vary among patients with epilepsy?

Which precautions should patients with epilepsy take when swimming or bathing?

Which precautions should patients with epilepsy take when using power tools?

Are any devices approved for seizure tracking and epilepsy management?

Medications

Which medications are used for the treatment of epileptic seizures?

Which medications in the drug class Anticonvulsants, Hydantoins are used in the treatment of Epilepsy and Seizures?

Which medications in the drug class Anticonvulsants, Neuronal Potassium Channel Opener are used in the treatment of Epilepsy and Seizures?

Which medications in the drug class Anticonvulsants, Succinimide are used in the treatment of Epilepsy and Seizures?

Which medications in the drug class Anticonvulsants, Benzodiazepine are used in the treatment of Epilepsy and Seizures?

Which medications in the drug class Anticonvulsants, Barbiturates are used in the treatment of Epilepsy and Seizures?

Which medications in the drug class Anticonvulsants, Other are used in the treatment of Epilepsy and Seizures?