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Epilepsy and Seizures

  • Author: David Y Ko, MD; Chief Editor: Selim R Benbadis, MD  more...
 
Updated: Jul 12, 2016
 

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.

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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]

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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.

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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.

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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.

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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/ .

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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.

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Contributor Information and Disclosures
Author

David Y Ko, MD Associate Professor of Clinical Neurology, Associate Director, USC Adult Epilepsy Program, Keck School of Medicine of the University of Southern California

David Y Ko, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Headache Society, American Clinical Neurophysiology Society

Disclosure: Received honoraria from UCB for speaking and teaching; Received consulting fee from Lundbeck for consulting; Received consulting fee from Westward for consulting; Received consulting fee from Esai for consulting; Received consulting fee from Supernus for consulting; Received consulting fee from Sunovion for speaking and teaching.

Chief Editor

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cyberonics; Eisai; Lundbeck; Sunovion; UCB; Upsher-Smith<br/>Serve(d) as a speaker or a member of a speakers bureau for: Cyberonics; Eisai; Glaxo Smith Kline; Lundbeck; Sunovion; UCB<br/>Received research grant from: Cyberonics; Lundbeck; Sepracor; Sunovion; UCB; Upsher-Smith.

Acknowledgements

Jose E Cavazos, MD, PhD, FAAN, FANA, FACNS Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, Assistant Dean for the MD/PhD Program, Program Director of the Clinical Neurophysiology Fellowship, University of Texas School of Medicine at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center, University Hospital System; Director, San Antonio Veterans Affairs Epilepsy Center of Excellence and Neurodiagnostic Centers, Audie L Murphy Veterans Affairs Medical Center

Jose E Cavazos, MD, PhD, FAAN, FANA, FACNS is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American Neurological Association, and Society for Neuroscience

Disclosure: LGCH, Inc Ownership interest Consulting

Ramon Diaz-Arrastia, MD, PhD Professor, Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Southwestern Medical School; Director, North Texas TBI Research Center, Comprehensive Epilepsy Center, Parkland Memorial Hospital

Ramon Diaz-Arrastia, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, New York Academy of Sciences, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Mark Spitz, MD Professor, Department of Neurology, University of Colorado Health Sciences Center

Mark Spitz, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, and American Epilepsy Society

Disclosure: pfizer Honoraria Speaking and teaching; ucb Honoraria Speaking and teaching; lumdbeck Honoraria Consulting

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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