Epilepsy and Seizures
- Author: Jose E Cavazos, MD, PhD, FAAN; Chief Editor: Selim R Benbadis, MD more...
Background
Epileptic seizures are only one manifestation of neurologic or metabolic diseases. Epileptic seizures have many causes, including a genetic predisposition for certain seizures, head trauma, stroke, brain tumors, alcohol or drug withdrawal, and other conditions. Epilepsy is a medical condition with recurrent, unprovoked seizures. Therefore, repeated seizures due to alcohol withdrawal are not epilepsy.
Definitions
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, psychologic, and social consequences of this condition.[1] Traditionally, the diagnosis of epilepsy requires the occurrence of at least 2 unprovoked seizures 24 hours apart. Some clinicians are also diagnosing epilepsy when one unprovoked seizure occurs in the setting of a predisposing cause such as a focal cortical injury or a generalized interictal discharge that suggests a persistent genetic predisposition. 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.
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%.
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%).
Studies in several countries have shown incidences and prevalences of seizures similar to those in the United States. In some countries, parasitic infections account for the increased incidence of seizures and epilepsy.
See Classification of Epileptic Seizures and Classification of Epileptic Syndromes.
Historical information
Epileptic seizures have been recognized for millennia. One of the earliest descriptions of a secondarily generalized tonic-clonic seizure was recorded over 3000 years ago in Mesopotamia. The seizure was attributed to the god of the moon. Epileptic seizures were described in 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 that caused abnormal brain consistency. Hippocratic teachings were forgotten, and divine etiologies again dominated beliefs about epileptic seizures during medieval times. Even at the turn of the 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. They recorded and evoked epileptic seizures in the cerebral cortex of animals. In 1929, Berger discovered that electrical brain signals could be recorded from the human head 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. 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 more recent review discusses the foundation of this professional society.[2]
This article reviews the classifications, pathophysiology, clinical manifestations, and treatment of epileptic seizures and some common epileptic syndromes. See below for links to several articles related to epileptic syndromes and their treatment that are not reviewed in this introductory article.
For more information regarding seizure types and other conditions, see the following topics:
See the following articles for more information regarding epileptic syndromes and epilepsy treatment:
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. 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 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 and are therefore discussed separately.
For a review, see the epilepsy book of Rho, Sankar, and Cavazos.[3]
Pathophysiology of Focal Seizures
The clinical neurophysiologic 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 electrographic (EEG) electrodes. Calculations show that the interictal spikes need to spread to about 6 cm2 of cerebral cortex before they can be detected with scalp electrodes. Several factors may be associated with the transition from an interictal spike to an epileptic seizure. When any of the mechanisms that underlie an acute seizure become a permanent alteration, patients are assumed to then develop a propensity for recurrent seizures (ie, epilepsy).
The mechanisms discussed below may coexist in different combinations to cause focal-onset seizures. If the mechanisms leading to a net increased excitability become permanent alterations, patients develop pharmacologically intractable focal-onset epilepsy. Current available medications were screened using acute models of focal-onset or generalized-onset convulsions. In clinical use, they 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.
Mechanisms leading to decreased inhibition and those leading to increased excitation are discussed in this section.
Mechanisms leading to decreased inhibition include the following:
- Defective gamma-aminobutyric acid (GABA)–A inhibition
- Defective GABA-B inhibition
- Defective activation of GABA neurons
- Defective intracellular buffering of calcium
Defective GABA-A inhibition
GABA is the main inhibiting 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 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 -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 to the neuronal membrane potential increases as the neuron becomes more depolarized by the summation of the excitatory postsynaptic potentials (EPSPs). In this manner, they 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 the anticonvulsant topiramate. Benzodiazepines increase the frequency of openings of chloride channels, whereas barbiturates increase the duration of openings of these channels. Topiramate increases the frequency of channel openings, but it binds to a site different from the benzodiazepine-receptor site. Either benzodiazepines or barbiturates, but not both, appear to modulate individual chloride channels. Whether combining topiramate with either class of agents increases the chloride currents is unknown.
Alterations in the normal state of the chloride channels might increase membrane permeability and conductance of chloride ions. In the end, the behavior of all individual chloride channels sum up to form a large chloride-mediated hyperpolarizing current that counterbalances the depolarizing currents created by summation of excitatory postsynaptic responses (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 release in the postsynaptic neuron: N -methyl-D-aspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate, and metabotropic, which are coupled by means of different mechanisms to several depolarizing channels. Inhibitory postsynaptic potentials (IPSPs), mediated mainly by the release of GABA in the synaptic cleft with postsynaptic activation of GABA-A receptors, temper these effects.
All channels in the nervous system (and essentially any living organism) 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 molecularly related but different proteins.
The heterogeneity of electrophysiologic responses of different GABA-A receptors is due to 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; therefore, more than 1000 receptor types theoretically exist.
In practice, only about 20 of these combinations have been found in the normal mammalian brain. Some epilepsies may be due to 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 might not be able to assemble alpha 5 beta 3 gamma 3 receptors because of deletion of chromosome 15 (ie, Angelman syndrome).
Changes in the distribution of 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 last model, decreased concentrations of mRNA for the alpha 5 subunit of the surviving interneurons were observed in the CA1 region of the rat hippocampus.[4]
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. Therefore, release of GABA from the interneuron terminal inhibits the postsynaptic neuron by means of 2 mechanisms: (1) direct induction of an 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. Once again, alterations or mutations in the different subunits or in the molecules that regulate their function might affect the seizure threshold or the propensity for recurrent seizures.
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 neuron output of the network, such as the hippocampal pyramidal CA1 cell. In feedforward inhibition, GABAergic cells receive a collateral projection from the main afferent projection that activates the CA1 neurons, namely, the Schaffer collateral axons from the CA3 pyramidal neurons. This feedforward projection activates the soma of GABAergic neurons 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 timely inhibit 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. In the last few years, experimental evidence has indicated that some other kind of interneuron might be a gate between the principal neurons and the GABAergic neurons. In the dentate gyrus, the mossy cells of the hilar polymorphic region appear to gate inhibitory tone and activate GABAergic neurons. The mossy cells receive both feedback and feedforward activation, which they convey to the GABAergic neurons. However, in certain circumstances they appear highly vulnerable to seizure-related neuronal loss.
After some of the mossy cells are lost, activation of GABAergic neurons is impaired.[5] 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 de-afferentation. 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, but as the epilepsy progresses, 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
Recurrent seizures induced by a variety of methods result in a pattern of interneuron loss in the hilar polymorphic region in rodents, with striking loss of the neurons that lack calcium-binding proteins parvalbumin and calbindin. In rat hippocampal sections, these interneurons demonstrate a progressive inability to maintain a hyperpolarized resting membrane potential; eventually, they die. An experiment in which researchers used microelectrodes containing the calcium chelator BAPTA demonstrated reversal of the deterioration in the membrane potential as the calcium chelator was allowed to diffuse in the interneuron[6] ; the experiment demonstrated 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 might be a possible contributor 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) might have remarkably dissimilar outcomes: One may have completely normal development, and the other may have intractable focal-onset epilepsy after a few years.
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 due to ephaptic interactions
Electrical fields created by synchronous activation of pyramidal neurons in laminar structures, such as the hippocampus, may increase further the excitability of neighboring neurons by nonsynaptic (ie, ephaptic) interactions. Other possible nonsynaptic interactions include electrotonic interactions due to gap junctions or changes in extracellular ionic concentrations of potassium and calcium. Increased coupling of neurons due to permanent increases in the functional availability of gap junctions might be a mechanism that predisposes to seizures or status epilepticus.
Increased synchrony and/or activation due to 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 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 might contribute to the development of hippocampal sclerosis.[7]
A situation more subtle and apparently more common than overt hippocampal sclerosis is mossy-fiber sprouting.[8] 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 due to 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.
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 primarily generalized-onset seizures. The thalamic relay neurons receive ascending inputs from 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.[9]
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 gamma aminobutyric acid (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 release 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.[10] Anticonvulsants that prevent absence seizures, such as valproic acid and ethosuximide, suppress the T-calcium current, blocking its channels. One clinical problem is that some anticonvulsants that increase GABA levels (eg, gabapentin, 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.
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.
Regarding morbidity, trauma is not uncommon among people with generalized tonic-clonic seizures. Injuries such as ecchymosis; hematomas; abrasions; and tongue, facial, and limb lacerations often develop as a result of the repeated tonic-clonic movements. Atonic seizures are also frequently associated with facial and neck injuries. Worldwide, burns are the most common serious injury associated with epileptic seizures.
Regarding mortality, seizures cause death in a small proportion of individuals. Most deaths are accidental due to impaired consciousness. However, sudden unexpected death in epilepsy (SUDEP) is a risk of having 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 increase risk of death is mostly seen in people with long-standing focal-onset epilepsy but is also present in those with primary generalized epilepsy. The risk of SUDEP increases in the setting of uncontrolled seizures and in people with poor compliance. The risk increases further in people with uncontrolled secondarily 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 the same as the general population.
Patient Education
To prevent injury, educate patients who have lapses of consciousness during wakefulness and in whom seizures are suspected about seizure precautions. 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 in 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 the state laws for driving before making recommendations.
Epilepsy Foundation of America has a large library of educational materials that are available to health care professionals and the general public. The American Epilepsy Society is the professional organization of people who take care of patients with epilepsy. Their Web site 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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