You are in: eMedicine Specialties > Neurology > Seizures and Epilepsy Seizures and Epilepsy: Overview and ClassificationArticle Last Updated: Nov 30, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Jose E Cavazos, MD, PhD, Assistant Professor, Departments of Medicine (Neurology), Pharmacology, and Physiology, University of Texas Health Science Center at San Antonio Jose E Cavazos is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and Society for Neuroscience Coauthor(s): Frank Lum, MD, Instructor, Department of Neurology, University of Colorado Health Sciences Center; Mark Spitz, MD, Professor, Department of Neurology, University of Colorado Health Sciences Center Editors: Ramon Diaz-Arrastia, MD, PhD, Assistant Professor, Department of Neurology, Comprehensive Epilepsy Center, University of Texas Southwestern; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants Author and Editor Disclosure Synonyms and related keywords: spells, convulsions, attacks, seizures, epilepsy, epileptic seizures, overview of seizures and epilepsy, classification of seizures, classification of epilepsy, partial-onset seizures, generalized-onset seizures, unclassified seizures, epileptic syndromes INTRODUCTIONSection 2 of 10
  BackgroundEpileptic 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 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.1 Definitions That seizures are a common, nonspecific manifestation of neurologic injury and disease should not be surprising because the main function of the brain is the transmission of electrical impulses. The lifetime likelihood of experiencing at least 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%. This article reviews the classifications, pathophysiology, clinical manifestations, and treatment of epileptic seizures and some common epileptic syndromes. Several articles in this electronic journal of neurology are dedicated particularly to epileptic syndromes and their treatment. They are not reviewed in this introductory article. Related articles in the Neurology section of the eMedicine journal are the following:
Classification of epileptic seizuresIn 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 the semiological classification advanced by Luders and others, have been proposed.2 A refinement of this semiological classification led to a 5-dimensional patient-oriented classification of epilepsy.3 The ILAE commission on classification has developed additional reports4, 5, but no proposed new revisions to the 1981 classification have been made. Partial-onset seizures Partial-onset seizures are further classified as simple partial seizures, complex partial seizures, or secondarily generalized tonic-clonic seizures. The defining element of simple partial seizures is a seizure with preserved consciousness. Many patients with complex partial seizures have an aura warning them of their seizure. An aura is a simple partial seizure. The many kinds of simple partial seizures include sensory, motor, autonomic, and psychic types. Any discrete experience that involves the cerebral cortex could be a simple partial seizure. The diagnosis is based on the repeated, stereotypic occurrence of the same experience in association with focal EEG changes or on recurrent auras leading to a complex partial seizure or a secondarily 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 partial seizures may last a few seconds to a few minutes. However, if the aura lasts longer than 30 minutes, it is considered simple partial status epilepticus by definition. Consciousness is impaired during a complex partial 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 might be able to remember their aura but are unaware that they were briefly unable to respond to the environment. A complex partial seizure typically begins with behavioral arrest and is followed by staring, automatisms, and postictal confusion. Automatisms frequently consist of 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 partial seizure lasts about 60-90 seconds and is followed by brief postictal confusion. However, generalized weakness, asthenia, and fatigue may last for a few days. Complex partial seizures of frontal-lobe origin may feature bizarre motor behaviors such as bicycling or a fencing posture. They have more prominent motor features than those of complex partial seizures of temporal-lobe onset. Frontal lobe onset complex partial seizures might have a fast postictal recovery to baseline, and often they appear in clusters of seizures. The great majority of complex partial seizures have an ictal correlate on the EEG. A normal alpha rhythm during behavioral impairment of consciousness is highly suggestive of nonepileptic seizures. Secondarily generalized seizures often begin with an aura that evolves into a complex partial seizure and then into a generalized tonic-clonic seizure. However, a complex partial seizure may evolve into a generalized tonic-clonic seizure, or an aura may evolve into a generalized tonic-clonic seizure without an obvious complex partial seizure. Clinically classifying a generalized tonic-clonic seizure as being secondarily generalized (partial 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 secondarily generalized seizure. Generalized-onset seizures Generalized-onset seizures are classified into 6 major categories: (1) absence seizures, (2) tonic seizures, (3) clonic seizures, (4) myoclonic seizures, (5) primary generalized tonic-clonic seizures, and (6) atonic seizures. Absence seizures 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. Facial automatisms are most common, and repetitive blinking is the most common facial automatism. Hyperventilation or photic stimulation often precipitates these seizures which typically begin during childhood or adolescence, though they may persist into adulthood. A diagnosis of new-onset absence seizures in adulthood is incorrect in the vast majority of cases. Adults often have complex partial seizures with relatively minor automatisms. In children, absence seizures are often unrecognized until a child develops a generalized tonic-clonic seizure and is brought to medical attention. Sudden decreased performance in school or overall attention might be a subtle manifestation of frequent absence seizures. The classic ictal EEG correlate of absence seizures consists of 3.5-Hz generalized spike-and–slow wave complexes. Twin studies have demonstrated a significant inherited predisposition for typical childhood absence seizures. 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, they are less well formed, and they are of lesser amplitude. Myoclonic seizures consist of brief, arrhythmic, jerking, motor movements that last less than a second. Myoclonic seizures often cluster within a few minutes. If they evolve into rhythmic, jerking movements, they are classified as evolving into a clonic seizure. Myoclonus is not always epileptic in origin. For example, the myoclonic jerks during phase I of sleep are normal release phenomena. The classic ictal correlate of myoclonic seizures in the EEG consists of fast polyspike-and–slow wave complexes. Clonic seizures consist of rhythmic, motor, jerking movements with or without impairment of consciousness. Clonic seizures can have a focal origin with or without impaired consciousness. 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 the person falls asleep, or just after he or she awakens. They 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. 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 secondarily generalized tonic-clonic seizures is that these seizures lack an aura. However, the aura preceding the secondarily generalized seizure is often forgotten because of postictal amnesia. 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 occur in people with clinically significant neurologic abnormalities. These seizures consist of brief loss of postural tone, often resulting in falls and injuries. The ictal EEG correlate is similar to abnormalities observed in tonic seizures. Unclassified seizures Each seizure type is classified by its clinical and EEG manifestations. On occasion, classifying seizures is difficult despite videotape review of the data. Classification of epileptic syndromesEpileptic seizures are symptoms of neurologic dysfunction and are but one manifestation of many neurologic diseases. Like any other syndrome in medicine, an epileptic syndrome is a group of signs and symptoms that share a common pathogenesis, prognosis, and response to treatment. In 1989, the ILAE developed a classification of epileptic syndromes. At present, a task force is revising this syndromic classification. 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.
PathophysiologySeizures 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 partial-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 recent review, please see the epilepsy book of Rho, Sankar and Cavazos.6 Partial-onset seizuresThe clinical neurophysiologic hallmark of partial-onset seizures is the focal interictal epileptiform spike or sharp wave. The cellular neurophysiologic correlate of an interictal epileptiform discharge in single cortical neurons is the paroxysmal depolarization shift (PDS). The PDS is characterized by a prolonged calcium-dependent depolarization that results in multiple 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. When any of the mechanisms that underlie an acute seizure become a permanent alteration, patients are assumed to then develop a propensity for recurrent seizures (ie, epilepsy). Mechanisms leading to decreased inhibition Mechanisms leading to decreased inhibition include defective gamma-aminobutyric acid (GABA)-A inhibition, defective GABA-B inhibition, defective activation of GABA neurons, and defective intracellular buffering of calcium. Defective GABA-A inhibition: GABA is the main inhibiting neurotransmitter in the brain. GABA binds to 2 major classes of receptors: GABA-A and GABA-B. GABA-A receptors are coupled to chloride channels, and they are one of the main targets modulated by the anticonvulsants that are currently available. The reversal potential of chloride is about -70 mV. The contribution of chloride channels during resting potential in neurons is minimal because at the typical resting potential, which is near -70 mV, no significant electromotive force exists 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. Their influence in the neuronal membrane potential increases, as the neurons become more depolarized by summation of the excitatory postsynaptic potentials (EPSPs). 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 anticonvulsive drug 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 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 described above increase membrane permeability and conductance of chloride ions. In the end, the behavior of all individual chloride channels sum to form a large chloride-mediated hyperpolarizing current that counterbalances the depolarizing currents created by summation of EPSPs induced by activation of the excitatory input. The EPSPs are the main form of communication between neurons, and 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) appear to be 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 electrophysiological 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 partial-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.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 to the chloride current evoked by activation of the GABA-A receptor. Because of the long duration of action, alterations in the GABA-B receptor are thought to possibly play a major role in the transition between the interictal abnormality and a partial-onset seizure. The molecular structure of the GABA-B receptor complex consists of 2 subunits with 7 transmembrane domains each. 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 by 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 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.8 Synaptic reorganization is a form of brain plasticity induced by neuronal loss. Formation of new circuits that include excitatory and inhibitory cells has been demonstrated in several animal models and in humans with intractable temporal-lobe epilepsy. Insufficient sprouting that attempts to restore inhibition might alter the balance between excitatory and inhibitory tone in the neural 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; the result showed the critical role of adequate concentrations of calcium-binding proteins.9 A postulated contributor is medical intractability in some patients, which may contribute to the abnormally low concentrations or even dysfunction of these proteins. The end result is the premature loss of interneurons, which alters inhibitory control over the local neuronal network in favor of net excitation. This effect may explain, eg, why 2 patients who have a similar event (eg, simple febrile convulsion) have remarkably dissimilar outcomes: One may have completely normal development, and the other have intractable partial-onset epilepsy after a few years. Mechanisms leading to increased excitation Mechanisms leading to increased excitation include increased activation of NMDA receptors, increased synchrony between neurons due to ephaptic interactions, and 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 first 2 types. The metabotropic receptor alters cellular excitability by means of a second-messenger system with late onset but 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 status, pilocarpine, and other 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 synchrony and/or activation due to recurrent excitatory collaterals: Neuropathologic studies of patients with intractable partial-onset epilepsy have revealed frequent abnormalities in the limbic system, particularly 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 lesion in the CA3 pyramidal region with dentate granule cells. 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.10 A situation more subtle and apparently more common than that described above is mossy-fiber sprouting.11 Mossy fibers are the axons of the dentate granule cells and typically project into the hilar polymorphic region and the CA3 pyramidal neurons. As neurons in the hilar polymorphic region are lost, their feedback projection into the dentate granule cells degenerates. 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. The mechanisms discussed here may coexist in different combinations to cause partial-onset seizures. If the mechanisms leading to a net increased excitability become permanent alterations, patients may have pharmacologically intractable partial-onset epilepsy. Currently available medications were developed in acute models of convulsions. In clinical use, they are most effective at blocking propagation of a seizure. Further understanding of the mechanisms that permanently increase net excitability may lead to development of true antiepileptic drugs that alter the natural history of epilepsy. Generalized-onset seizuresThe 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, eg, in sleep spindles. The circuitry includes the pyramidal neurons of the neocortex, the thalamic relay neurons, and the neurons in the nucleus reticularis of the thalamus (NRT). 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.12 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 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, permitting the synchronous opening of a large population of the T-calcium channels every 100 milliseconds or so. 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.13 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. FrequencyUnited StatesThe lifetime likelihood of having at least 1 febrile or nonfebrile 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 0.8%. Hauser and collaborators demonstrated that the annual incidence of recurrent nonfebrile seizures in Olmstead 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%). InternationalStudies 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. Mortality/MorbidityRegarding morbidity, trauma is not uncommon among people with generalized tonic-clonic seizures. Injuries such as ecchymosis; 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) may occur even when patients are resting in a protected environment, eg, in a bed with rail guards.
SexSee Frequency above. AgeSee Frequency above. CLINICALSection 3 of 10
HistoryThe 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 clarify the type of seizure include the following:
PhysicalThe clinical diagnosis of seizures is based on the history obtained from the patient and, most important, the observers. Physical examination helps in the diagnosis of specific epileptic syndromes that cause abnormal findings, such as dermatologic abnormalities. For example, patients with intractable generalized tonic-clonic seizures for years are likely to have injuries requiring stitches. CausesEpileptic seizures are only 1 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. The causes of most epileptic syndromes are described in several articles of the eMedicine journal, such as those listed below. DIFFERENTIALSSection 4 of 10
Cardioembolic Stroke Confusional States and Acute Memory Disorders Febrile Seizures First Seizure in Adulthood: Diagnosis and Treatment First Seizure: Pediatric Perspective Frontal Lobe Epilepsy Idiopathic Orthostatic Hypotension and other Autonomic Failure Syndromes Migraine Headache Somnambulism (Sleep Walking) Transient Global Amnesia
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