pathophysiology of seizures an

Official reprint from UpToDate www.uptodate.com ©2014 UpToDate

Authors Carl E Stafstrom, MD, PhD Jong M Rho, MD

Section Editor Timothy A Pedley, MD

Deputy Editor April F Eichler, MD, MPH

Pathophysiology of seizures and epilepsy

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2014. | This topic last updated: Jul 30, 2014.

INTRODUCTION — An epileptic seizure is an episode of neurologic dysfunction in which abnormal neuronal firing is manifest clinically by changes in motor control, sensory perception, behavior, and/or autonomic function. Epilepsy is the condition of recurrent spontaneous seizures arising from aberrant electrical activity within the brain. While anyone can experience a seizure under the appropriate pathophysiological conditions, epilepsy suggests an enduring alteration of brain function that facilitates seizure recurrence. Epileptogenesis is the process by which the normal brain becomes prone to epilepsy [1].

The aberrant electrical activity that underlies epilepsy is the result of biochemical processes at the cellular level promoting neuronal hyperexcitability and neuronal hypersynchrony. However, a single neuron, discharging abnormally, is insufficient to produce a clinical seizure, which occurs only in the context of large neuronal networks. Several key cortical and subcortical structures are involved in generating a seizure.

This topic will review the cellular basis for focal and generalized seizure activity, with specific attention to ion channels, the essential currency of neuronal excitability, and the hippocampus, one of the most seizure-prone areas of the brain. The pharmacology of antiepileptic drugs and issues related to the assessment and management of patients with epilepsy are discussed separately. (See "Overview of antiepileptic drugs" and "Overview of the management of epilepsy in adults".)

CLASSIFICATION OF SEIZURES — Epilepsy is not a singular disease, but is heterogeneous in terms of clinical expression, underlying etiologies, and pathophysiology (table 1). As such, specific mechanisms and pathways underlying specific seizure types may vary. Epileptic seizures are broadly classified according to their site of origin and pattern of spread (figure 1).

While there are differences in the mechanisms that underlie partial versus generalized seizures, it is useful to view any seizure as the result of a perturbation in the normal balance between inhibition and excitation in a localized region or throughout the brain [2-4].

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Focal seizures arise from a localized region of the brain and have clinical manifestations that reflect that area of brain. Focal discharges can remain localized or they can spread to nearby cortical areas, to subcortical structures and/or transmit through commissural pathways to involve the whole cortex. The latter sequence describes the secondary generalization of focal seizures. As an example, a seizure arising from the left motor cortex may cause jerking movements of the right upper extremity. If epileptiform discharges spread to adjacent areas and then the entire brain, a secondary generalized tonic-clonic seizure ensues.

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Primary generalized seizures begin with abnormal electrical discharges in both hemispheres simultaneously. Generalized seizures involve reciprocal connections between the thalamus and neocortex. The manifestations of such widespread epileptiform activity can range from brief impairment of consciousness (as in an absence seizure) to generalized motor activity accompanied by loss of consciousness (generalized tonic-clonic seizure).

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CELLULAR PHYSIOLOGY — At a basic level, an epileptic seizure may be understood to represent an imbalance between excitatory and inhibitory currents within neural circuits of the brain [2-5]. Neuronal circuits are composed of excitatory and inhibitory neurons and their dendrites and axons, synapses, and glial cells. All of the following circuit components function via ion channels:

Ion channels — Ion channels are membrane-spanning proteins that form selective pores for sodium, potassium, chloride, or calcium ions. Movement of ions across the neuronal membrane determines the electrical membrane potential and generates the action potential. A gradient of sodium and potassium ions (in relatively high concentration outside and inside the cell, respectively) is maintained by an ATP-dependent sodium/potassium pump that maintains the resting membrane potential in a polarized state (about -70 mV) (figure 2). When an ion channel opens, the ion moves passively into or out of the cell along its electrochemical gradient.

Two major types of ion channels are responsible for inhibitory and excitatory activity:

Passage of ions across these voltage-gated and ligand-gated channels results in either depolarization (eg, inward flux of cations) or hyperpolarization (eg, inward flux of anions or outward flux of cations).

Voltage-dependent conductances

Depolarizing conductances — Depolarizing conductances are excitatory and are mediated by inward sodium and calcium currents.

Neuronal dendrites and somata, which convert incoming synaptic current into propagated electrical activity which is integrated at the axon initial segment,

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Axons, which propagate action potentials along the neuronal axon, and●

Synapses the site of chemical neurotransmission between neurons.●

Voltage-gated channels are activated by changes in the membrane potential that alter the conformational state of the channel, allowing selective passage of charged ions. Voltage-gated sodium and calcium channels function to depolarize the cell membrane toward action potential threshold and are excitatory. Voltage-gated potassium channels largely function to hyperpolarize the cell membrane away from the action potential threshold and are inhibitory.

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Ligand-gated receptors mediate signals from neurotransmitters such as glutamate and gamma-aminobutyric acid (GABA). After release from a presynaptic terminal into the synaptic cleft, the neurotransmitter binds with selective affinity to a membrane-bound receptor on the postsynaptic membrane. This in turn activates a cascade of events, including a conformational shift to reveal an ion-permeant pore.

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Inward sodium conductances include the rapidly-inactivating current that underlies the depolarizing phase of the action potential (figure 2). A noninactivating, persistent sodium current can augment cell depolarization (eg, produced by excitatory synaptic input) in the range immediately subthreshold for spike initiation [6]. Augmentation of noninactivating sodium channel activity may promote burst firing in neurons [7]. Each sodium channel exists as a complex of polypeptide subunits; there is a major alpha subunit and one or more smaller beta subunits, which influence the kinetic properties of the alpha subunit. The shape of action potentials is determined by the types of alpha and beta subunits present in an individual neuron [8]. Genetic alterations in the structure of sodium channels underlie the syndrome of generalized epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome, a severe myoclonic epilepsy of infancy as well as other epilepsy syndromes [9]. (See "Epilepsy syndromes in children", section on 'Myoclonic epilepsy of infancy' and "Clinical features and evaluation of febrile seizures", section on 'Genetic epilepsies with febrile seizures'.)



Hyperpolarizing conductances — An array of voltage-dependent hyperpolarizing currents, mediated primarily by potassium channels, counter balance depolarizing currents and function to inhibit or decrease excitation in the nervous system. Potassium channels represent the largest and most diverse family of voltage-gated ion channels. The prototypic voltage-gated potassium channel is composed of four membrane-spanning alpha subunits and four regulatory beta subunits that are assembled in an octameric complex to form an ion selective pore.

In hippocampal neurons, potassium conductances include a leak conductance, which is a major determinant of the resting membrane potential, and an inward rectifier (involving the flux of other ions), which is activated by hyperpolarization. (Rectification refers to a situation in which the direction of ion flow through a channel changes according to voltage; rectification can also be secondary to "blocking" of the pore by other ions.) Other potassium conductances include several delayed rectifiers that are involved in the termination of action potentials and repolarization of the neuron's membrane potential; a dendritic A-current, which helps determine interspike interval and thus affects the rate of cell firing; an M-current, which is inhibited by activation of cholinergic muscarinic agonists and hyperpolarizes the membrane potential, reducing the rate of cell firing [12]; and a set of calcium-activated potassium conductances, which are sensitive to intracellular calcium concentration and affect cell firing rate and interburst interval.

Facilitation of hyperpolarizing conductances may be anticonvulsant. Part of the anticonvulsant properties of topiramate and levetiracetam may include actions on potassium channels. The anticonvulsant retigabine acts by opening and activating voltage-gated potassium channels [13]. (See "Overview of antiepileptic drugs".)

Mutations in the KCNQ2 and KCNQ3 genes encoding the potassium channels responsible for the M-current have been linked to a rare form of inherited epilepsy, benign familial neonatal convulsions as well as to families with benign partial epilepsy and idiopathic generalized epilepsy [14-16]. (See "Neonatal epileptic syndromes", section on 'Benign familial neonatal convulsions' and "Benign partial epilepsies of childhood", section on 'Benign epilepsy with centrotemporal spikes'.)

Synaptic transmission

Excitatory transmission — The amino acid glutamate is the principal excitatory neurotransmitter of the central nervous system. Glutamatergic pathways are widespread throughout the brain, and excitatory amino acid activity is critical to normal brain development and activity-dependent synaptic plasticity [17]. Ionotropic glutamate receptors are broadly divided into N-methyl-D-aspartate (NMDA) and non-NMDA receptors, based on biophysical properties and pharmacological profiles. Each subtype of glutamate receptor consists of a multimeric assembly of subunits that determine its distinct

Many anticonvulsants act in part through interactions with voltage-dependent sodium channels [10]. Examples include phenytoin, carbamazepine, and lacosamide. (See "Overview of antiepileptic drugs", section on 'Drugs that affect voltage-dependent sodium channels'.)

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Activation of voltage-dependent calcium channels contributes to the depolarizing phase of the action potential. Calcium influx can also affect neurotransmitter release, gene expression, and neuronal firing patterns. There are several subtypes of calcium channels, with distinct electrophysiological properties, pharmacological profiles, molecular structures, and cellular localization [11]. Similar to sodium channels, the molecular structures of voltage-gated calcium channels are hetero-oligomeric complexes which form the pore as well as other subunits that can modulate the kinetic properties of the channel. Calcium currents in hippocampal CA3 pyramidal cells underlie burst discharges in these cells and may contribute to epileptic synchronization. Alteration in calcium channels also play a role in childhood absence epilepsy. (See 'Primary generalized epilepsy: Absence epilepsy' below.)

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functional properties. Glutamate receptor channel subunits are currently classified into several subfamilies based on amino acid sequence homology.

Alterations in glutamate-activated channels may lead to their increased activation, as is observed in animal models of epilepsy and in human epilepsy [25]. NMDA and other glutamate receptor agonists induce epilepsy in animals. Glutamate receptor autoantibodies have been identified in Rasmussen encephalitis and other focal epilepsies [26-28]. Upregulation of a vesicular glutamate transporter was found in patients with temporal lobe epilepsy in one study [29].

Inhibitory transmission — Synaptic inhibition in the hippocampus is mediated by two basic circuit configurations:

Both of these inhibitory circuits utilize gamma-aminobutyric acid (GABA), a neutral amino acid, as the neurotransmitter. After release from axon terminals, GABA binds to at least two classes of receptors, GABA-A and GABA-B receptors, which are found on almost all cortical neurons. GABA-A receptors are also found on glia, although their functional significance on these cells is unclear.

The NMDA receptor contains a binding site for glutamate (or NMDA), and a recognition site for a variety of modulators (eg, glycine, polyamines, MK-801, zinc). A voltage-dependent blockade of the NMDA receptor by magnesium ions is reversed when the membrane is depolarized [18,19]. When this happens, the NMDA receptor is activated, resulting in an influx of calcium and sodium ions and generation of relatively slow and long-lasting excitatory post-synaptic potentials (EPSPs). Calcium entry also initiates a number of "second messenger" pathways. These synaptic events can contribute to epileptiform burst discharges. Recurrent excitatory circuits produced by mossy fiber sprouting in mesial temporal epilepsy are associated with increased NMDA conductances [20]. (See 'Synchronizing mechanisms' below.) NMDA receptor blockade attenuates bursting activity in many models of epileptiform activity.

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Non-NMDA ionotropic receptors are α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and kainate receptors, which are both coupled to sodium and potassium ion channels [21] Activation of the postsynaptic AMPA receptor by glutamate is responsible for the fast-rising, brief EPSP. In addition, the depolarization generated via AMPA receptors is necessary for effective activation of NMDA receptors. Consequently, AMPA receptor antagonists block most excitatory synaptic activity in pyramidal neurons. One AMPA receptor antagonist, perampanel, is approved as a treatment for refractory focal seizures [22]. (See "Overview of antiepileptic drugs", section on 'Perampanel'.)

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Metabotropic glutamate receptors (those not directly coupled to ion channels) represent a large, heterogeneous family of G-protein coupled receptors. G-proteins activate various transduction pathways and are important modulators of voltage-dependent potassium and calcium channels, non-selective cation currents, ligand-gated receptors (ie, GABA and glutamate receptors), and can regulate glutamate release [23]. Different metabotropic glutamate receptor subtypes are specific for different intracellular processes and are differentially localized within the brain. Knowledge of the role of metabotropic glutamate receptors in epilepsy is expanding rapidly and this receptor may eventually provide a therapeutic target [24].

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Feed-forward inhibition occurs when a collateral projection from an axon of an excitatory principal neuron synapses with and directly activates an inhibitory interneuron, which then provides inhibitory input to the same target neuron which the primary neuron activates.

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Feedback or recurrent inhibition occurs when an excitatory principal neuron synapses with and excites inhibitory interneurons, which then project back onto the principal neuron and inhibit it as well as surrounding principal neurons. This circuit functions as a negative-feedback loop, controlling repetitive firing and limiting recruitment of surrounding neurons (ie, inhibitory surround).

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The summation of individual GABA receptor mediated activation produces a largely chloride-mediated membrane hyperpolarization that counterbalances the depolarization generated by the summation of EPSPs. Impairment of this inhibitory activity can lead to seizures. As an example, drugs such as picrotoxin and bicuculline bind to the GABA-A receptor and block chloride channels and are proconvulsant. Infants deficient in pyridoxine, a coenzyme required for GABA synthesis, are prone to seizures [36]. (See "Etiology and prognosis of neonatal seizures".) Angelman syndrome, which includes severe epilepsy, is associated with a genetic defect involving a GABA-A receptor subunit. (See "Congenital cytogenetic abnormalities".)

Conversely, enhanced GABA-mediated inhibition is an important mechanism of antiepileptic drugs such as phenobarbital and the benzodiazepines. (See "Overview of antiepileptic drugs", section on 'Drugs that affect GABA activity'.)

Role of glia — The contribution of glia to the regulation of epileptiform discharges is increasingly appreciated [37]. Among other functions, glia play an important part in maintaining extracellular levels of membrane permeant ions and neurotransmitters.

One important role for glia is the restoration of ionic homeostasis after neuronal activity, particularly extracellular potassium levels. A variety of inwardly-rectifying potassium channels mediate potassium uptake. The location of glial end-feet on brain microvasculature provides a convenient "sink" for potassium release. Glial membrane potential changes are directly correlated with changes in

GABA-A receptors are macromolecular complexes consisting of an ion pore, as well as binding sites for agonists and a variety of allosteric modulators, such as benzodiazepines and barbiturates, each differentially affecting the kinetic properties of the receptor [30]. The ion channel is selectively permeable to chloride (and bicarbonate) ions. At least seven different polypeptide subunits have been described, each with one or more subtypes. In theory, several thousand isoforms of these subunits are possible, however, a limited number of functional combinations are thought to exist. The precise subunit composition of native GABA-A receptors has yet to be identified. Because individual subunits may be differentially sensitive to pharmacological agents, GABA receptor subunits represent potentially useful molecular targets for new anticonvulsants. (See "Overview of antiepileptic drugs", section on 'Drugs that affect GABA activity'.) Activation of GABA-A receptors on the soma of a mature cortical neuron generally results in influx of chloride ions and membrane hyperpolarization, thus inhibiting cell discharge. However, in immature neurons, GABA-A receptor activation causes depolarization of the postsynaptic membrane instead [31-33]. This reversal of the conventional GABA-A effect is thought to reflect a reversed chloride electrochemical gradient, a consequence of the immature expression of the potassium/chloride cotransporter, KCC2, which ordinarily renders GABA hyperpolarizing [34]. Outward flux of bicarbonate through GABA-A channels also contributes to the depolarization. (See 'Susceptibility of the immature brain' below.)

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GABA-B receptors are located on both the postsynaptic membrane and on presynaptic terminals. These so-called metabotropic receptors do not form an ion pore as ionotropic receptors do. Rather, they act to control calcium or potassium conductances through second messenger GTP-binding proteins. Whereas GABA-A receptors generate fast high-conductance inhibitory postsynaptic potentials (IPSPs) close to the cell body, GABA-B receptors on the postsynaptic membrane mediate slow long-lasting low-conductance IPSPs, primarily in hippocampal pyramidal cell dendrites. Perhaps of more functional significance, activation of GABA-B receptors on the presynaptic terminal blocks the synaptic release of neurotransmitter. It is thought that some GABA-B receptors are associated with terminals that release GABA onto postsynaptic GABA-A receptors. In such cases, activation of GABA-B receptors reduces the amount of GABA released, resulting in disinhibition [35].

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extracellular potassium, and blockade of glia-selective potassium channels results in neuronal hyperexcitability.

Transport of glutamate out of the extracellular space may be an important role for glia in the maintenance of neuronal excitability. Glial cells have powerful glutamate transport molecules in their membranes. Rapid and efficient removal of extracellular glutamate is essential in normal brain tissue since residual glutamate would continue to excite surrounding neurons. Blockade of glutamate transporters or "knockout" of the genes for these transport proteins results in epilepsy or excitotoxicity [38].

Glia can modulate neuronal excitability in a number of other ways [39]. First, glia play a critical role in regulating extracellular pH, via a proton exchanger and bicarbonate transporter mechanisms. Even low levels of neuronal activity create significant pH transients. Furthermore, pH modulates receptor function, particularly the NMDA receptor, which plays an important role in epileptic discharge. Second, glia are also now thought to release powerful neuroactive agents into the extracellular space. Glutamate released from glia can excite neighboring neurons [40]. Other glia-related factors, such as the cytokine, IL-1beta, can have profound anticonvulsant efficacy [41].

PATHOPHYSIOLOGY OF EPILEPSY — In an epileptic seizure, neurons transition from their normal firing pattern to interictal epileptiform bursts, and then to an ictal state. Each of these stages in the evolution of a seizure is governed by distinct electrophysiological mechanisms. Much of our understanding of the mechanisms regulating each stage comes from cellular electrophysiological studies in which microelectrodes record intracellular potential changes from individual neurons.

Focal epilepsy: Mesial temporal lobe epilepsy — The most prevalent form of focal epilepsy is mesial temporal lobe epilepsy. Ictal onset in the mesial temporal lobe can produce a seizure aura, such as an olfactory hallucination, an epigastric sensation, or a psychic symptom. Progression of the seizure is often associated with loss of awareness and motor automatisms. (See "Localization-related (focal) epilepsy: Causes and clinical features", section on 'Mesial temporal lobe epilepsy'.) As a consequence, hippocampal pyramidal cells have become one of the most intensively studied cell types in the central nervous system.

The hippocampal formation consists of the dentate gyrus, the hippocampus proper (Ammon's horn) (with subregions CA1, CA2, and CA3), the subiculum, and the entorhinal cortex (figure 3). These four regions are linked by excitatory, largely unidirectional, feed-forward connections. Backwards projections include those from the entorhinal cortex to Ammon's horn and those from the CA3 field to the dentate gyrus. The predominant forward-projecting circuit begins with neurons in layer II of the entorhinal cortex that project axons to the dentate gyrus along the perforant pathway where they synapse on granule cell (and interneuron) dendrites. Granule cells send their axons, called mossy fibers, to synapse on cells in the hilus and in the CA3 field of Ammon's horn. CA3 pyramidal cells, in turn, project to other CA3 pyramidal cells via local collaterals, to the CA1 field of Ammon's horn via Schaffer collaterals, and to the contralateral hippocampus. CA1 pyramidal cell axons project onto the subicular complex, and neurons of the subicular complex project to the entorhinal cortex, as well as to other cortical and subcortical targets.

In hippocampal sclerosis, the pathologic hallmark of mesial temporal lobe epilepsy, there is a pattern of gliosis and neuronal loss primarily in the hilar polymorphic and CA1 pyramidal regions with relative sparing of the CA2 pyramidal region, and an intermediate degree of cell loss in the CA3 pyramidal region and dentate gyrus. A form of synaptic reorganization known as mossy fiber sprouting results from denervation of dentate granule cells; axons of dentate granule cells then innervate neurons of the dentate gyrus rather than CA3 and hilus, causing a form of recurrent hyperexcitability (see 'Synchronizing mechanisms' below). It is not known whether these pathologic findings are primarily the cause or the result of epileptic activity.



A wide variety of brain injuries can increase the propensity for seizures to develop. Examples of insults to the brain that are associated with the development of epilepsy include physical trauma to the brain, hypoxia, prolonged fever (in young children), central nervous system infection, and stroke. Mechanisms of epileptogenesis in these circumstances can involve any of the physiologic factors previously discussed that increase excitation or decrease inhibition. As an example, mossy fiber sprouting can result from numerous initiating brain insults, confirming a similar response of neural circuits to a wide variety of epileptogenic stimuli [42].

Paroxysmal depolarization shift — The neurophysiologic hallmark of a partial seizure is the interictal epileptiform discharge on EEG. The cellular correlate of the focal interictal epileptiform discharge is known as the paroxysmal depolarization shift (PDS) (figure 4).

A PDS is characterized by an initial rapid and prolonged depolarization of the membrane potential, followed by a burst of repetitive action potentials lasting several hundred milliseconds. The initial depolarization is mediated by AMPA receptors, while the sustained depolarization is a consequence of NMDA receptor activation. The PDS terminates with a prolonged hyperpolarization phase that is mediated primarily by inhibitory potassium and chloride conductances, carried by voltage-gated potassium channels and GABA receptors, respectively. This constitutes a refractory period (figure 4).

Experimental techniques used to promote epileptogenesis, such as blockade of GABA inhibition and/or potentiation of excitatory transmission, such as with NMDA, can induce PDS-like activity in cortical neurons [20].

A PDS is an event occurring in a single neuron. An interictal epileptiform discharge represents synchronously occurring PDS in several million neurons, involving an area of cortex of at least 6 cm .

For discharges of a localized group of hyperexcitable neurons to spread to adjacent areas, the epileptic firing must overcome the powerful inhibitory influences that normally keep aberrant excitability in check (ie, "inhibitory surround") (figure 4).

Synchronizing mechanisms — Synchronization of neuronal activity is an important part of normal hippocampal function. In various regions of the hippocampus, sharp waves, dentate spikes, theta activity (range 8 to 13 Hz), 40 Hz oscillations, and 200 Hz oscillations are all forms of neuronal synchronization that can be recorded [43].

Neuronal synchronization is also a hallmark of epilepsy. This may result from exaggerated synchrony among hippocampal neurons. Alternatively, or in addition, normal forms of synchronized activity may become epileptogenic in a hippocampus that has undergone selective neuronal loss, synaptic reorganization, or changes in expression of specific receptor subtypes.

In the hippocampus, synchronizing mechanisms include input from subcortical nuclei as well as intrinsic interneuron-mediated synchronization [44]. As an example, high amplitude theta activity represents synchronized activity of hippocampal neurons that is largely dependent on input from the septum [43]. Subcortical nuclei, such as the septum, have divergent inputs that target hippocampal interneurons. In turn, the divergent axon projections of interneurons, and the powerful effect of the GABA-A-receptor-mediated conductances that they produce, enable interneurons to entrain the activity of large populations of principal cells. These characteristics make interneurons an effective target for subcortical modulation of hippocampal principal cell activity. In addition, mutual inhibitory interactions among hippocampal interneurons can produce synchronized discharges [45].

Recurrent excitatory circuits are another mode by which neuronal synchronization occurs in the hippocampus. Recurrent excitatory collaterals are a normal feature of the CA3 region; CA3 pyramidal cells form direct, monosynaptic connections with other CA3 pyramidal cells and contribute to the synchronized burst discharges that characterize this region. In the epileptic temporal lobe, synaptic reorganization and axonal sprouting might lead to aberrant recurrent excitation, providing a synchronizing mechanism in other parts of the hippocampal formation (figure 5). As an example, while granule cells in the dentate gyrus normally form few, if any monosynaptic contacts with neighboring

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granule cells, the mossy fiber sprouting seen in mesial temporal sclerosis results in direct excitatory interactions among granule cells that lower the threshold for synchronization [42].

Finally, mechanisms independent of chemical synaptic transmission might synchronize neuronal firing under some circumstances. Such mechanisms include:

Consequences of repeated seizures — Whether seizures cause brain damage has been the subject of intense study, but a simple answer has been elusive [50]. The consequences of seizures depend on many factors, including the etiology, epilepsy syndrome, age at the time of seizure onset, and seizure type, frequency, duration, and severity.

The longer a seizure, the more serious the potential consequences. As an example, status epilepticus causes damage to neurons even when systemic factors (eg, blood pressure, oxygen level) and underlying etiology are controlled. This can lead to increased risk for recurrent seizures and disabling neurologic deficits. (See "Convulsive status epilepticus in adults: Treatment and prognosis", section on 'Complications and outcome'.)

Brief seizures, if recurrent, can also lead to long-term changes in both brain structure and function. The process by which a normal brain gradually becomes epileptic as a result of repeated seizures, or even subclinical synchronous neuronal discharges, is known as kindling [51,52]. There is growing evidence that temporal lobe epilepsy can be a progressive disorder with an underlying mechanism akin to kindling [53]. Such considerations emphasize the need to suppress seizure occurrence.

Further considerations depend on how "brain damage" is defined, ie, structural brain changes versus a wider spectrum of cognitive, behavioral, and neurologic disabilities. Persons with epilepsy face numerous psychosocial and medical challenges, including intellectual impairment, mood disorders, psychological adjustment to the chronic nature of the disorder and to the unpredictability of seizures, the need to take antiepileptic drugs with their attendant side effects, and the dependence on others for certain daily tasks. Together, these epilepsy-related adverse psychosocial challenges are referred to as "comorbidities" [54]. Therefore, the consequences of epilepsy are both multiple and multifactorial. (See "Evaluation and management of drug-resistant epilepsy".)

Primary generalized epilepsy: Absence epilepsy — Childhood absence epilepsy is a subtype of generalized epilepsy with a distinct pathophysiological substrate. Seizures are characterized by a temporary loss of awareness and responsiveness, usually with a sudden cessation of motor activity without falling, and total amnesia for the event. These seizures are generally brief (most last less than 20 seconds), do not include an aura, and end abruptly without postictal changes. (See "Childhood absence epilepsy".)

The generalized spike-wave discharges seen on EEG during an absence seizure reflect widespread, phase-locked oscillations between excitation and inhibition in thalamocortical networks [2,55]. This network includes excitatory projections from pyramidal neurons in layer VI of the neocortex to thalamic

Gap junctions that allow electrical signals to pass directly between cells. Studies suggest that gap junctions are up-regulated in epileptic brain tissue, and that blockade of gap junctions significantly affects the duration of seizure activity [46].

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Electrical field ("ephaptic") effects generated by current flow through the extracellular space. Earlier studies demonstrated a potential synchronizing effect of these ephaptic interactions. Other experiments suggest that manipulations that alter the extracellular volume may affect current flow through this compartment, and can impact the epileptogenic synchronization of neurons [47].

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Changes in extracellular ion concentrations. Increased extracellular potassium concentrations are thought to affect epileptogenic excitability and/or synchronization [48]. Experiments have demonstrated epileptogenic effects of blocking potassium regulation (eg, through inwardly rectifying potassium channels) [49]. (See 'Role of glia' above.)

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relay (TR) neurons as well as to inhibitory GABA-ergic neurons comprising the nucleus reticularis thalami (NRT). In turn, excitatory outputs of the TR neurons activate layer VI pyramidal neurons in neocortex. This thalamocortical circuit is a critical substrate for the generation of cortical rhythms and is responsible in large part for normal EEG oscillations during wake and sleep states. It is influenced by sensory input as well as several brainstem nuclei.

In absence seizures, hyperactivity of this circuit causes rhythmic activation of the cortex, generating generalized spike-wave discharges. Involvement of this circuit is also implicated in other idiopathic generalized epilepsies, including juvenile myoclonic epilepsy [56,57].

Although multiple ionic conductances are involved in these pacemaking rhythms, two specific channels are believed to play a key role in regulating thalamocortical activity.

Susceptibility of the immature brain — Seizure incidence is highest during the first decade of life, especially during the first year [68]. Multiple physiological factors contribute to the increased susceptibility of the developing brain to seizures (table 2) [6,69-71]. Each factor alters the brain excitatory-inhibitory balance in favor of enhanced excitation. Examples include:

T-type calcium channel. A subtype of voltage-gated calcium channel is known as the low-threshold or T-type calcium channel, so-named because it can be activated by small membrane depolarizations. In thalamic relay neurons, calcium influx through these channels triggers low-threshold spikes, which in turn activate a burst of action potentials [58]. Such an excitatory burst is believed to underlie the spike portion of a generalized spike-wave discharge. Genetic alterations in the T-type calcium channel have been associated with childhood absence epilepsy as well as other generalized epilepsy syndromes [59,60]. Moreover, anticonvulsants known to be clinically effective against absence seizures (eg, ethosuximide and valproic acid) block T-type calcium currents, although it is uncertain as to whether this is the primary mechanism of their action [61,62].

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HCN channels and h-currents. The second important ion channel involved in the regulation of thalamocortical rhythmicity is the hyperpolarization-activated cation channel (HCN channel), responsible for the so-called Ih or h-current. HCN channels, densely expressed in the thalamus and hippocampus, are activated by hyperpolarization and produce a depolarizing current carried by an inward flux of sodium and potassium ions [63]. This depolarization helps to bring the resting membrane potential toward threshold for activation of T-type calcium channels, which in turn produces a calcium spike and a burst of action potentials. HCN channels are also critically involved in developmental plasticity [64]. Unlike other voltage-gated conductances that can be labeled either inhibitory or excitatory, h-currents are both inhibitory and excitatory [65,66]. HCN channels possess an inherent negative-feedback property; hyperpolarization activates them, which then leads to depolarization that deactivates them. The net effect of HCN channel activation is a decrease in the voltage change produced by a given synaptic current. H-currents tend to stabilize a neuron's membrane potential toward the resting potential against both hyperpolarizing and depolarizing inputs. The relevance of HCN channels in the pathogenesis of absence seizures is supported by the demonstration that lamotrigine, an AED effective against absence seizures, enhances activation of dendritic h-currents in hippocampal pyramidal neurons, and by the experimental finding that deletion of a specific HCN isoform results in absence epilepsy in mice [65].

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Other synaptic influences. Antagonists of GABA-B receptors and agonists of dopamine receptors can also interrupt abnormal thalamocortical discharges in experimental absence epilepsy models [67]. GABA-B receptors mediate long-lasting thalamic IPSPs involved in the generation of normal thalamocortical rhythms, while brainstem monoaminergic projections disrupt these rhythms.

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Seizure propensity in the young brain involves a complex interplay between the timing of these cellular and molecular changes.

SUMMARY — The precise pathophysiologic mechanisms underlying epileptic seizures remain to be elucidated. The pathophysiology is believed to be heterogeneous and include a complex array of perturbations occurring at multiple hierarchical levels of nervous system structure and function.

Ion channels that mediate depolarization develop earlier than those that mediate repolarization. Excitatory neurotransmitters develop before inhibitory ones [17,72,73].

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As discussed above, early in development, GABA exerts an excitatory action, rather than the inhibitory effect seen later in life [31]. (See 'Inhibitory transmission' above.)

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Electrical synapses appear to be more prevalent in the developing brain than in the mature brain; fast-acting electrical transmission can facilitate rapid synchrony of the neuronal network and precipitate seizures [74,75].

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Structural factors also play a role. During the second week of life in the rat, the hippocampal CA3 region is characterized by an abundance of excitatory connections between pyramidal cells that cause regional heightened excitability and epileptiform activity [76]. As part of development, these connections are pruned and excessive excitation is stabilized.

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The ability of glia to buffer extracellular potassium also varies with age and the expression of the neuronal membrane ATP-dependent sodium/potassium pump follows a developmental time course [77].

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At a basic level, an epileptic seizure represents a disruption in the normal balance between excitatory and inhibitory currents or neurotransmission in the brain. Drugs or pathogenic processes that augment excitation or impair inhibition tend to be epileptogenic, while antiepileptic drugs tend to facilitate inhibition and dampen excitation. These currents are mediated via two types of ion channels. (See 'Ion channels' above.)

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Voltage-gated ion channels are activated by changes in membrane potential. Depolarizing currents are excitatory and are mediated by inward sodium and calcium conductances while inhibitory, hyperpolarizing currents include inward chloride and outward potassium conductances. (See 'Voltage-dependent conductances' above.)

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Ligand-gated ion channels are activated by binding of a neurotransmitter to an ionotropic receptor on the postsynaptic membrane. The primary excitatory neurotransmitter in the brain is glutamate, while gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter. (See 'Synaptic transmission' above.)

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Glial cells also play an important role in epileptogenesis by regulating the extracellular concentrations of excitatory ions and neurotransmitters, as well as through other mechanisms. (See 'Role of glia' above.)

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The paroxysmal depolarization shift is the cellular correlate of the interictal epileptiform discharge, a hallmark of partial epilepsy. Abnormal neuronal circuitry is required for propagation of the PDS to other neurons to produce an epileptiform discharge on EEG or a clinical epileptic seizure. (See 'Focal epilepsy: Mesial temporal lobe epilepsy' above.)

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Seizures can result from injuries to the brain and by other circumstances that alter the balance between inhibition and excitation. Likewise, recurrent seizures not only lead to a subsequent decreased threshold to additional seizures, but are also associated with psychosocial comorbidities such as impairment of cognition, behavior, and mood regulation. (See 'Consequences of repeated seizures' above.)

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●

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Topic 2232 Version 7.0



GRAPHICS

Examples of specific pathophysiologic defects leading to epilepsy

Level of brain function

ConditionPathophysiologic

mechanism

Neuronal network Cerebral dysgenesis, post-traumatic scar, mesial temporal sclerosis (in TLE)

Altered neuronal circuits: Formation of aberrant excitatory connections ("sprouting")

Neuron structure Down syndrome and possibly other syndromes with mental retardation and seizures

Abnormal structure of dendrites and dendritic spines: Altered current flow in neuron

Neurotransmitter synthesis

Pyridoxine (vitamin B ) dependency

Decreased GABA synthesis: B , a co-factor for GAD

Neurotransmitter receptors: Inhibitory

Angelman syndrome, juvenile myoclonic epilepsy

Abnormal GABA receptor subunit(s)

Neurotransmitter receptors: Excitatory

Non-ketotic hyperglycinemia Excess glycine leads to activation of NMDA receptors

Synapse development

Neonatal seizures Many possible mechanisms, including the depolarizing action of GABA early in development

Ion channels ("channelopathies")

Benign familial neonatal convulsions

Potassium channel mutations: Impaired repolarization

TLE: temporal lobe epilepsy; GABA: gamma-aminobutyric acid; GAD: glutamic acid decarboxylase.

Reproduced with permission from: Rho JM, Stafstrom CE. Neurophysiology of epilepsy. In: Pediatric Neurology: Principles and Practice, 4th ed, Swaiman KF, Ashwal S, Ferreiro DM (Eds). Mosby Elsevier. Philadelphia 2006. Copyright © 2006.

Graphic 75633 Version 2.0

6 6



Coronal brain sections depicting seizure types and potential routes of seizure spread

A: Focal area of hyperexcitability (star under electrode 3) and spread to adjacent neocortex (solid arrow under electrode 4), via corpus callosum (dotted arrow) or other commissural pathways to the contralateral cerebral hemisphere, or via subcortical pathways (eg, thalamus, upward dashed arrows). Accompanying EEG patterns show brain electrical activity under electrodes 1-4. Focal epileptiform activity is maximal at electrode 3 and is also seen at electrode 4 (left tracings). If a seizure secondarily generalizes, activity may be seen synchronously at all electrodes, after a delay (right tracings). B: A primary generalized seizure begins simultaneously in both hemispheres. The characteristic bilateral synchronous spike-wave pattern on EEG is generated by reciprocal interactions between the cortex and thalamus, with rapid spread via corpus callosum (CC) contributing to bilateral synchrony. One type of thalamic neuron (dark neuron) is a GABAergic inhibitory cell that displays intrinsic pacemaker activity. Cortical neurons (open triangles) send impulses to both thalamic relay neurons (open diamond) and to inhibitory neurons, setting up oscillations of excitatory and inhibitory activity, which gives rise to the rhythmic spike-waves on EEG.

CC: corpus callosum; EEG: electroencephalogram; GABA: gamma-aminobutyric acid.

Reproduced with permission from: Stafstrom, CE. An introduction to seizures and epilepsy: cellular mechanisms underlying classification and treatment. In: Epilepsy



Normal neuronal firing

Schematic of neuron with one excitatory (E) and one inhibitory (I) input. Right tracing shows membrane potential, beginning at a typical resting potential (-70 mV). Activation of E leads to graded excitatory postsynaptic potentials (EPSPs), the larger of which reaches threshold (approximately -40 mV) for an action potential. The action potential is followed by an after-hyperpolarization (AHP), the magnitude and duration of which determine when the next action potential can occur. Activation of I causes an inhibitory postsynaptic potential (IPSP), which also keeps the membrane potential further from threshold for action potential generation. Inset (box) shows magnified portion of the neuronal membrane as a lipid bilayer with interposed voltage-gated Na+ and K+ channels; the direction of ion fluxes during excitatory activation is shown. After firing, the membrane-bound Na+ -K+ pump and star-shaped astroglial cells restore ionic balance.

AHP: after-hyperpolarization; EPSP: exciatory postsynaptic potential; IPSP: inhibitory postsynaptic potential; mV: millivolts.

Reproduced with permission from: Stafstrom, CE. An introduction to seizures and epilepsy: cellular mechanisms underlying classification and treatment. In: Epilepsy and the Ketogenic Diet, Stafstrom, CE, Rho, JM (Eds), Humana Press, Totowa, New Jersey 2004. p.11. Copyright © 2004 Springer-Verlag.




Hippocampal trisynaptic pathway

The hippocampal trisynaptic pathway begins with neurons in layer II of the entorhinal cortex (EC), which project axons to the dentate gyrus (DG) along the perforant path (PP) (1), where they synapse on granule cell dendrites. Next, dentate granule cells send their axons (called mossy fibers [MF]) to synapse on cells in the hilus and in the CA3 field of Ammon’s horn (2). CA3 pyramidal cells, in turn, project to the CA1 field of Ammon’s horn via Schaffer collaterals (SC) (3). Finally, CA1 neurons send projections outward through the fornix to other brain regions, as well as back to the subiculum. For simplicity, only the classic "feed-forward" projections of the trisynaptic pathway are shown. The known "backward" projections and local circuit interactions are omitted here for simplicity.

DG: dentate gyrus; EC: entorhinal cortex; MF: mossy fiber; PP: perforant path; SC: Shaffer collaterals; Subic: subiculum.

Courtesy of Carl E Stafstrom, MD, PhD.




Abnormal neuronal firing in epilepsy

Abnormal neuronal firing at the levels of (A) the brain and (B) a simplified neuronal network, consisting of two excitatory neurons (1 and 2) and an inhibitory interneuron (filled black circle, 3). EEG (top set of traces) and intracellular recordings (bottom set of traces) are shown for the normal (left column), interictal (middle column), and ictal conditions (right column). Numbered traces refer to like-numbered recording sites. Note time scale differences in different traces. A. Three EEG electrodes record activity from superficial neocortical neurons. In the normal case, activity is low voltage and “desynchronized” (neurons are not firing together in synchrony). In the interictal condition, large “spikes” are seen focally at electrode 2 (and to a lesser extent at electrode 1, where they might be termed “sharp waves”), representing synchronized firing of a large population of hyperexcitable neurons (expanded in time below). The ictal state is characterized by a long run of spikes. B. At the neuronal network level, the intracellular correlate of the interictal EEG spike is the “paroxysmal depolarization shift” (PDS). The PDS is initiated by a non-NMDA-mediated fast EPSP (shaded area), and is maintained by a longer, larger NMDA-mediated EPSP. The post-PDS hyperpolarization (*) temporarily stabilizes the neuron. If this post-PDS hyperpolarization fails (right column, thick arrow), ictal discharge can occur. The lowermost traces, recordings from neuron 2, show activity similar to that recorded in neuron 1, with some delay (double-headed horizontal arrow). Activation of inhibitory neuron 3 by firing of neuron 1 prevents neuron 2 from generating an action potential (the IPSP counters the depolarization caused by the EPSP). If neuron 2 reaches firing threshold, additional neurons will be recruited, leading to an entire network firing in synchrony (seizure).

EPSP: excitatory postsynaptic potential; IPSP: inhibitory postsynaptic potential; NMDA: N-methyl-D-aspartate; PDS: paroxysmal depolarization shift.

Reproduced with permission from: Stafstrom, CE. An introduction to seizures and epilepsy: cellular mechanisms underlying classification and treatment. In: Epilepsy and the Ketogenic Diet, Stafstrom, CE, Rho, JM (Eds), Humana Press, Totowa, New Jersey 2004. p.18. Copyright ©2004 Springer-Verlag.




Hippocampal axonal sprouting and hyperexcitability in epilepsy

A. Normal situation. Left: Dentate granule neurons (1, 2) make excitatory synapses (E) onto dendrites of hippocampal pyramidal neurons (3, 4). Right: Activation of dentate neuron 2 causes single action potential in pyramidal neuron 3. B. As a consequence of status epilepticus, many pyramidal neurons die (eg, 4, dashed lines), leaving axons of dentate neuron 1 without a postsynaptic target. Those axons then “sprout” and innervate the dendrites of granule neurons (thick curved arrow), creating the substrate for a hyperexcitable circuit. Now, when dentate granule neuron 1 is activated, multiple action potentials are fired in neurons 2 and 3, which fire repetitively, a manifestation of their hyperexcitability. This diagram represents a simplification; in fact, neurons of numerous types in the dentate hilus (labeled H) may die as a consequence of status epilepticus and the surviving neurons may become involved in seizure-induced synaptic plasticity. The resultant circuit function will depend upon the balance of excitation and inhibition in the reorganized neuronal network.

Reproduced with permission from: Stafstrom, CE. An introduction to seizures and epilepsy: cellular mechanisms underlying classification and treatment. In: Epilepsy and the Ketogenic Diet, Stafstrom, CE, Rho, JM (Eds), Humana Press, Totowa, New Jersey 2004. Copyright ©2004 Springer Science and Business Media.




Factors promoting increased seizure susceptibility in the developing brain

Factor Consequence

Input resistance and time constant: Increased in immature neurons

Small inputs result in relatively large voltage changes

Voltage-gated ion channels: Earlier maturation of sodium and calcium channels, delayed development of potassium channels

Longer action potentials, shorter refractory periods, increased neuron firing

Synapse development: Excitatory synapses appear before inhibitory synapses

Relative predominance of excitation over inhibition early in development

Synapse development: Over expression of excitatory synapses during critical period

Corresponds to window of heightened seizure susceptibility

Developmental changes in glutamate receptor subunits: NR2B/NR2A ratio favors prolonged depolarizing responses; NR2D relative over expression reduces Mg block

Favor relative hyperexcitability

Late appearance of functional inhibitory synapses

Along with other factors favoring excitation, contributes to neuronal excitatory drive and lack of functional inhibition

Developmental changes in GABA receptor function and Cl gradient due to differential development of the K /Cl co-transporters

GABA is depolarizing early in life, enhancing excitability

Developmental changes in GABA receptor subunits

Partially accounts for developmental differences in inhibitory effectiveness and benzodiazepine responsiveness

Developmental sensitivity to glutamate toxicity

Less glutamate-induced excitotoxicity early in development

Immature GABA binding pattern in substantia nigra

Proconvulsant effect

Electrical synapses: More common early in development

Mechanism for enhanced synchrony of neuronal networks

Immature homeostatic mechanisms: NaK-ATPase, glial K regulation, K /Cl co-transporters

Prolonged exposure to elevated extracellular K leads to further neuronal depolarization

GABA : gamma-aminobutyric acid A; NaK-ATPase: sodium-potassium adenosine triphosphatase.

Reproduced with permission from: Rho JM, Stafstrom CE. Neurophysiology of epilepsy. In: Pediatric Neurology: Principles and Practice, 4th ed, Swaiman KF, Ashwal S, Ferreiro DM (Eds). Mosby Elsevier. Philadelphia 2006. Copyright © 2006.


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Disclosures: Carl E Stafstrom, MD, PhD Nothing to disclose. Jong M Rho, MD Nothing to disclose. Timothy A Pedley, MD Other Financial Interest: American Academy of Neurology (President). April F Eichler, MD, MPH Equity Ownership/Stock Options: Johnson & Johnson [Dementia (galantamine), Epilepsy (topiramate)]. Employment: Employee of UpToDate, Inc. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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