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Pathophysiology of Seizures and Epilepsy
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5/27/2014 Pathophysiology of seizures and epilepsy http://www.uptodate.com/contents/pathophysiology-of-seizures-and-epilepsy?topicKey=NEURO%2F2232&elapsedTimeMs=0&source=search_result&searchT… 1/22 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: Apr 2014. | This topic last updated: Jan 15, 2010. 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. Cortical and several key 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. The pharmacology of antiepileptic drugs and issues related to the assessment and management of patients with epilepsy is discussed separately. (See "Pharmacology 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 ). Focal or partial 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. 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). While there are differences in the mechanisms that underlie partial versus generalized seizure activity, 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 ]. CELLULAR PHYSIOLOGY — At a basic level, an epileptic seizure may be understood to represent an imbalance ® ®
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Page 1: Pathophysiology of Seizures and Epilepsy

5/27/2014 Pathophysiology of seizures and epilepsy

http://www.uptodate.com/contents/pathophysiology-of-seizures-and-epilepsy?topicKey=NEURO%2F2232&elapsedTimeMs=0&source=search_result&searchT… 1/22

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

AuthorsCarl E Stafstrom, MD, PhDJong M Rho, MD

Section EditorTimothy A Pedley, MD

Deputy EditorApril 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: Apr 2014. | This topic last updated: Jan 15, 2010.

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.

Cortical and several key 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. The pharmacology of antiepileptic drugs and issues

related to the assessment and management of patients with epilepsy is discussed separately. (See "Pharmacology

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).

Focal or partial 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.

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).

While there are differences in the mechanisms that underlie partial versus generalized seizure activity, 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].

CELLULAR PHYSIOLOGY — At a basic level, an epileptic seizure may be understood to represent an imbalance

®

®

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between excitatory and inhibitory currents within neural circuits of the brain [2-4]. 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:

Neuronal dendrites and somata, which convert incoming synaptic current into propagated electrical activity

which is integrated at the axon initial segment,

Axonal conduction, the propagation of action potentials along the neuronal axon, and

Synaptic transmission, which occurs between neurons.

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 which maintains the resting membrane potential in a polarized state (about -70 mV) (figure 2). When an ion

channel is opened, 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:

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.

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.

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). This is discussed in more

detail.

Voltage-dependent conductances

Depolarizing conductances — Depolarizing conductances are excitatory and are mediated by inward sodium

and calcium currents.

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 [5].

Augmentation of noninactivating sodium channel activity may promote burst firing in neurons [6].

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 [7].

Genetic alterations in the structure of sodium channels are believed to 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 [8]. (See "Febrile seizures", section on 'Genetic susceptibility' and

"Epilepsy syndromes in children", section on 'Myoclonic epilepsy of infancy'.)

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Many anticonvulsants act in part through interactions with voltage-dependent sodium channels [9].

Examples include phenytoin, carbamazepine, and lacosamide. (See "Pharmacology of antiepileptic drugs",

section on 'Drugs that affect voltage-dependent sodium channels'.)

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 [10]. 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.)

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 a large set of 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 resting membrane potential, reducing the rate of cell firing [11]; 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. While none of the anticonvulsants in clinical

use today act principally on voltage-gated potassium channels, part of the anticonvulsant properties of topiramate

and levetiracetam may include such effects [12,13]. The anticonvulsant retigabine acts by opening and activating

voltage-gated potassium channels [14]. (See "Pharmacology 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 [15-17]. (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 [18]. 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 functional properties. Glutamate receptor channel subunits are currently classified into

several subfamilies based on amino acid sequence homology.

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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 [19,20]. At this time, activation of the NMDA

receptor results 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 [21]. (See 'Synchronizing mechanisms' below.) NMDA receptor blockade attenuates bursting

activity in many models of epileptiform activity.

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 [22]. 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.

Metabotropic glutamate receptors (those not directly coupled to ion channels) represent a large,

heterogeneous family of G-protein coupled receptors. These 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].

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].

Upregulation of a vesicular glutamate transporter in patients with temporal lobe epilepsy was identified in one

pathologic study [27].

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

configurations:

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 simultaneous inhibitory

input to the same target neuron which the primary neuron activates.

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).

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.

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 [28]. The ion channel is selectively permeable to chloride (and

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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

"Pharmacology 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 [29,30]. 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 [31]. Outward flux of bicarbonate through GABA-A channels also contributes

to the depolarization [32]. (See 'Susceptibility of the immature brain' below.)

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 [33].

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 and epilepsy. 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. (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 "Pharmacology 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 [34].

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, particularly extracellular potassium levels, after

neuronal activity [34]. 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 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 at least two 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 [35].

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Glia can modulate neuronal excitability in a number of other ways. First, they 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 appears to play an important role in epileptic discharge [36]. Second, glia are also now thought to

release powerful neuroactive agents into the extracellular space. Glutamate released from glia can excite

neighboring neurons [37]. Other investigations have suggested that other glia-related factors, such as the cytokine,

IL-1beta, can have profound anticonvulsant efficacy [38].

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 mesial temporal lobe structures can produce a seizure aura, such as an olfactory

hallucination, an epigastric sensation, or psychic symptoms. Progression of the seizure is often associated with

loss of awareness and motor automatisms. (See "Localization-related (partial) 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 [39].

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 is believed to result 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 subjects), 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 [40].

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

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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 [21].

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. 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 in various regions of the hippocampus

[41].

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 [42]. As an example, high amplitude theta activity represents synchronized

activity of hippocampal neurons that is largely dependent on input from the septum [41]. 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 [43]. 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 [44].

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 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 [40].

Finally, mechanisms independent of chemical synaptic transmission might synchronize neuronal firing under some

circumstances. Such mechanisms include:

Gap junctions that allow electrical signals to pass directly between cells. Recent studies suggest that gap

junctions are up-regulated in epileptic brain tissue [45], and that blockade of gap junctions significantly

affects the duration of seizure activity [46].

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].

Changes in extracellular ion concentrations. Increased extracellular potassium concentrations are thought to

2

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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.)

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 depends 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 "Status

epilepticus in adults".)

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 [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

consciousness, 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 "Epilepsy syndromes in children", section on 'Absence seizures'.)

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 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.

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.

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While the pathophysiology of absence seizures involves more T-type calcium channel dysfunction, 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].

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 [67,68].

Other synaptic influences. Antagonists of GABA-B receptors and agonists of dopaminergic receptors can

also interrupt abnormal thalamocortical discharges in experimental absence epilepsy models [69]. GABA-B

receptors mediate long-lasting thalamic IPSPs involved in the generation of normal thalamocortical rhythms,

while brainstem monoaminergic projections disrupt these rhythms.

Susceptibility of the immature brain — Seizure incidence is highest during the first decade of life, especially

during the first year [70]. Multiple physiological factors contribute to the increased susceptibility of the developing

brain to seizures (table 2) [5,71-73]. Each factor alters the brain excitatory-inhibitory balance in favor of enhanced

excitation. Examples include:

Ion channels that mediate depolarization develop earlier than those that mediate repolarization. Excitatory

neurotransmitters develop before inhibitory ones [18,74,75].

As discussed above, early in development, GABA exerts an excitatory action, rather than the inhibitory

effect seen later in life [29]. (See 'Inhibitory transmission' above.)

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

[76,77].

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 [78]. As part of development, these connections are pruned

and excessive excitation is stabilized.

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 [79].

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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.

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.)

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.)

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.)

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.)

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.)

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.)

Childhood absence epilepsy arises from alterations in the thalamocortical circuitry. (See 'Primary

generalized epilepsy: Absence epilepsy' above.)

A number of cellular and electrophysiologic changes in the developing brain make it vulnerable to

epileptogenesis. (See 'Susceptibility of the immature brain' above.)

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REFERENCES

1. Pitkänen A, Lukasiuk K. Molecular and cellular basis of epileptogenesis in symptomatic epilepsy. EpilepsyBehav 2009; 14 Suppl 1:16.

2. McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol2001; 63:815.

3. Faingold CL. Emergent properties of CNS neuronal networks as targets for pharmacology: application toanticonvulsant drug action. Prog Neurobiol 2004; 72:55.

Page 11: Pathophysiology of Seizures and Epilepsy

5/27/2014 Pathophysiology of seizures and epilepsy

http://www.uptodate.com/contents/pathophysiology-of-seizures-and-epilepsy?topicKey=NEURO%2F2232&elapsedTimeMs=0&source=search_result&search… 11/22

4. Chang BS, Lowenstein DH. Epilepsy. N Engl J Med 2003; 349:1257.

5. Rho JM, Stafstrom CE. Neurophysiology of epilepsy. In: Pediatric Neurology: Principles and Practice, 4th,Swaiman KF, Ashwal S, Ferreiro DM. (Eds), Mosby Elsevier, Philadelphia 2006. p.991.

6. Stafstrom CE. Persistent sodium current and its role in epilepsy. Epilepsy Curr 2007; 7:15.

7. Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature andstructure-function relationships of voltage-gated sodium channels. Pharmacol Rev 2005; 57:397.

8. Lossin C. A catalog of SCN1A variants. Brain Dev 2009; 31:114.

9. Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004; 5:553.

10. Catterall WA, Striessnig J, Snutch TP, et al. International Union of Pharmacology. XL. Compendium ofvoltage-gated ion channels: calcium channels. Pharmacol Rev 2003; 55:579.

11. Cooper EC, Jan LY. M-channels: neurological diseases, neuromodulation, and drug development. ArchNeurol 2003; 60:496.

12. Herrero AI, Del Olmo N, González-Escalada JR, Solís JM. Two new actions of topiramate: inhibition ofdepolarizing GABA(A)-mediated responses and activation of a potassium conductance. Neuropharmacology2002; 42:210.

13. Madeja M, Margineanu DG, Gorji A, et al. Reduction of voltage-operated potassium currents by levetiracetam:a novel antiepileptic mechanism of action? Neuropharmacology 2003; 45:661.

14. Stephen LJ, Brodie MJ. Pharmacotherapy of epilepsy: newly approved and developmental agents. CNS Drugs2011; 25:89.

15. Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inheritedepilepsy of newborns. Nat Genet 1998; 18:25.

16. Rogawski MA. KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications fortherapy. Trends Neurosci 2000; 23:393.

17. Neubauer BA, Waldegger S, Heinzinger J, et al. KCNQ2 and KCNQ3 mutations contribute to differentidiopathic epilepsy syndromes. Neurology 2008; 71:177.

18. Simeone TA, Sanchez RM, Rho JM. Molecular biology and ontogeny of glutamate receptors in themammalian central nervous system. J Child Neurol 2004; 19:343.

19. Mori H, Mishina M. Structure and function of the NMDA receptor channel. Neuropharmacology 1995;34:1219.

20. Kalia LV, Kalia SK, Salter MW. NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol2008; 7:742.

21. Avanzini G, Franceschetti S. Cellular biology of epileptogenesis. Lancet Neurol 2003; 2:33.

22. Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev 1999;51:7.

23. Conn PJ. Physiological roles and therapeutic potential of metabotropic glutamate receptors. Ann N Y AcadSci 2003; 1003:12.

24. Ure J, Baudry M, Perassolo M. Metabotropic glutamate receptors and epilepsy. J Neurol Sci 2006; 247:1.

25. Rakhade SN, Loeb JA. Focal reduction of neuronal glutamate transporters in human neocortical epilepsy.Epilepsia 2008; 49:226.

26. Pleasure D. Diagnostic and pathogenic significance of glutamate receptor autoantibodies. Arch Neurol 2008;65:589.

27. van der Hel WS, Verlinde SA, Meijer DH, et al. Hippocampal distribution of vesicular glutamate transporter 1in patients with temporal lobe epilepsy. Epilepsia 2009; 50:1717.

28. Macdonald RL, Olsen RW. GABAA receptor channels. Annu Rev Neurosci 1994; 17:569.

29. Ben-Ari Y. Excitatory actions of gaba during development: the nature of the nurture. Nat Rev Neurosci 2002;3:728.

30. Staley KJ. Wrong-way chloride transport: is it a treatable cause of some intractable seizures? Epilepsy Curr

Page 12: Pathophysiology of Seizures and Epilepsy

5/27/2014 Pathophysiology of seizures and epilepsy

http://www.uptodate.com/contents/pathophysiology-of-seizures-and-epilepsy?topicKey=NEURO%2F2232&elapsedTimeMs=0&source=search_result&search… 12/22

2006; 6:124.

31. Rivera C, Voipio J, Payne JA, et al. The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing duringneuronal maturation. Nature 1999; 397:251.

32. Staley KJ, Soldo BL, Proctor WR. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors.Science 1995; 269:977.

33. Simeone TA, Donevan SD, Rho JM. Molecular biology and ontogeny of gamma-aminobutyric acid (GABA)receptors in the mammalian central nervous system. J Child Neurol 2003; 18:39.

34. D'Ambrosio R. The role of glial membrane ion channels in seizures and epileptogenesis. Pharmacol Ther2004; 103:95.

35. Meldrum BS, Akbar MT, Chapman AG. Glutamate receptors and transporters in genetic and acquired modelsof epilepsy. Epilepsy Res 1999; 36:189.

36. Traynelis SF, Cull-Candy SG. Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons.Nature 1990; 345:347.

37. Tian GF, Azmi H, Takano T, et al. An astrocytic basis of epilepsy. Nat Med 2005; 11:973.

38. Vezzani A, Moneta D, Richichi C, et al. Functional role of proinflammatory and anti-inflammatory cytokines inseizures. Adv Exp Med Biol 2004; 548:123.

39. Schwartzkroin PA, Mueller AL. Electrophysiology of hippocampal neurons. In: Further Aspects of CorticalFunction, Including Hippocampus, Jones EG, Peters A. (Eds), Plenum Press, New York 1987. p.295.

40. Nadler JV. The recurrent mossy fiber pathway of the epileptic brain. Neurochem Res 2003; 28:1649.

41. Buzsáki G, Draguhn A. Neuronal oscillations in cortical networks. Science 2004; 304:1926.

42. Bouilleret V, Semah F, Chassoux F, et al. Basal ganglia involvement in temporal lobe epilepsy: a functionaland morphologic study. Neurology 2008; 70:177.

43. Cobb SR, Buhl EH, Halasy K, et al. Synchronization of neuronal activity in hippocampus by individualGABAergic interneurons. Nature 1995; 378:75.

44. Jefferys JG, Traub RD, Whittington MA. Neuronal networks for induced '40 Hz' rhythms. Trends Neurosci1996; 19:202.

45. Li J, Shen H, Naus CC, et al. Upregulation of gap junction connexin 32 with epileptiform activity in theisolated mouse hippocampus. Neuroscience 2001; 105:589.

46. Köhling R, Gladwell SJ, Bracci E, et al. Prolonged epileptiform bursting induced by 0-Mg(2+) in rathippocampal slices depends on gap junctional coupling. Neuroscience 2001; 105:579.

47. Hochman DW, Baraban SC, Owens JW, Schwartzkroin PA. Dissociation of synchronization and excitabilityin furosemide blockade of epileptiform activity. Science 1995; 270:99.

48. Gnatkovsky V, Librizzi L, Trombin F, de Curtis M. Fast activity at seizure onset is mediated by inhibitorycircuits in the entorhinal cortex in vitro. Ann Neurol 2008; 64:674.

49. Emmi A, Wenzel HJ, Schwartzkroin PA, et al. Do glia have heart? Expression and functional role for ether-a-go-go currents in hippocampal astrocytes. J Neurosci 2000; 20:3915.

50. Sutula, T, Pitkänen, A. Do Seizures Damage the Brain? Elsevier, Amsterdam 2002.

51. Velísek L, Moshé SL. Effects of brief seizures during development. Prog Brain Res 2002; 135:355.

52. Bertram E. The relevance of kindling for human epilepsy. Epilepsia 2007; 48 Suppl 2:65.

53. Pitkänen A, Sutula TP. Is epilepsy a progressive disorder? Prospects for new therapeutic approaches intemporal-lobe epilepsy. Lancet Neurol 2002; 1:173.

54. Austin JK, Caplan R. Behavioral and psychiatric comorbidities in pediatric epilepsy: toward an integrativemodel. Epilepsia 2007; 48:1639.

55. Tyvaert L, Chassagnon S, Sadikot A, et al. Thalamic nuclei activity in idiopathic generalized epilepsy: anEEG-fMRI study. Neurology 2009; 73:2018.

56. Deppe M, Kellinghaus C, Duning T, et al. Nerve fiber impairment of anterior thalamocortical circuitry in juvenilemyoclonic epilepsy. Neurology 2008; 71:1981.

Page 13: Pathophysiology of Seizures and Epilepsy

5/27/2014 Pathophysiology of seizures and epilepsy

http://www.uptodate.com/contents/pathophysiology-of-seizures-and-epilepsy?topicKey=NEURO%2F2232&elapsedTimeMs=0&source=search_result&search… 13/22

57. Lin K, Carrete H Jr, Lin J, et al. Magnetic resonance spectroscopy reveals an epileptic network in juvenilemyoclonic epilepsy. Epilepsia 2009; 50:1191.

58. Perez-Reyes E. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 2003;83:117.

59. Heron SE, Khosravani H, Varela D, et al. Extended spectrum of idiopathic generalized epilepsies associatedwith CACNA1H functional variants. Ann Neurol 2007; 62:560.

60. Chen Y, Lu J, Pan H, et al. Association between genetic variation of CACNA1H and childhood absenceepilepsy. Ann Neurol 2003; 54:239.

61. Coulter DA, Huguenard JR, Prince DA. Specific petit mal anticonvulsants reduce calcium currents in thalamicneurons. Neurosci Lett 1989; 98:74.

62. Leresche N, Parri HR, Erdemli G, et al. On the action of the anti-absence drug ethosuximide in the rat andcat thalamus. J Neurosci 1998; 18:4842.

63. Robinson RB, Siegelbaum SA. Hyperpolarization-activated cation currents: from molecules to physiologicalfunction. Annu Rev Physiol 2003; 65:453.

64. Santoro B, Baram TZ. The multiple personalities of h-channels. Trends Neurosci 2003; 26:550.

65. Poolos NP. The h-channel: a potential channelopathy in epilepsy? Epilepsy Behav 2005; 7:51.

66. Dyhrfjeld-Johnsen J, Morgan RJ, Soltesz I. Double Trouble? Potential for Hyperexcitability Following BothChannelopathic up- and Downregulation of I(h) in Epilepsy. Front Neurosci 2009; 3:25.

67. Ludwig A, Budde T, Stieber J, et al. Absence epilepsy and sinus dysrhythmia in mice lacking the pacemakerchannel HCN2. EMBO J 2003; 22:216.

68. Poolos NP, Migliore M, Johnston D. Pharmacological upregulation of h-channels reduces the excitability ofpyramidal neuron dendrites. Nat Neurosci 2002; 5:767.

69. Snead OC 3rd. Basic mechanisms of generalized absence seizures. Ann Neurol 1995; 37:146.

70. Hauser, W, Hersdorffer, D. Epilepsy: Frequency, Causes and Consequences. Demos, New York 1990.

71. Holmes GL. Epilepsy in the developing brain: lessons from the laboratory and clinic. Epilepsia 1997; 38:12.

72. Wong M. Advances in the pathophysiology of developmental epilepsies. Semin Pediatr Neurol 2005; 12:72.

73. Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol2009; 5:380.

74. Brooks-Kayal AR, Shumate MD, Jin H, et al. gamma-Aminobutyric acid(A) receptor subunit expressionpredicts functional changes in hippocampal dentate granule cells during postnatal development. J Neurochem2001; 77:1266.

75. Raol YH, Lund IV, Bandyopadhyay S, et al. Enhancing GABA(A) receptor alpha 1 subunit levels inhippocampal dentate gyrus inhibits epilepsy development in an animal model of temporal lobe epilepsy. JNeurosci 2006; 26:11342.

76. Perez Velazquez JL, Carlen PL. Gap junctions, synchrony and seizures. Trends Neurosci 2000; 23:68.

77. Margineanu DG. Epileptic hypersynchrony revisited. Neuroreport 2010; 21:963.

78. Swann JW, Hablitz JJ. Cellular abnormalities and synaptic plasticity in seizure disorders of the immaturenervous system. Ment Retard Dev Disabil Res Rev 2000; 6:258.

79. Haglund MM, Schwartzkroin PA. Role of Na-K pump potassium regulation and IPSPs in seizures andspreading depression in immature rabbit hippocampal slices. J Neurophysiol 1990; 63:225.

Topic 2232 Version 6.0

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GRAPHICS

Examples of specific pathophysiological defects leading to epilepsy

Level of brain

functionCondition Pathophysiologic 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: Γ-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 1.0

6 6

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Seizure types and potential routes of spread

Coronal brain sections depicting seizure types and potential routes of seizure

spread. Panel 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 traces). If a seizure secondarily generalizes,

activity may be seen synchronously at all electrodes, after a delay (right

traces). Panel 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 the rapid 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.

Reproduced with permission from: Stafstrom, CE. An introduction to seizures and

epilepsy: cellular mechanisms underlying classification and treatment. In: Epilepsy

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and the Ketogenic Diet, Stafstrom, CE, Rho, JM (Eds), Humana Press, Totowa, New

Jersey 2004. p.6. Copyright © 2004 Springer-Verlag.

Graphic 76510 Version 1.0

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Normal neuronal firing

Schematic of neuron with one excitatory (E) and one inhibitory (I) input. Right trace

shows membrane potential (in millivolts, mV), beginning at a typical resting potential (-70

mV). Activation of E leads to graded excitatory post-synaptic 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). 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.

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.

Graphic 74749 Version 1.0

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Hippocampal circuitry

Courtesy of Carl E Stafstrom, MD, PhD.

Graphic 76895 Version 1.0

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Abnormal neuronal firing in epilepsy

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.

Graphic 76134 Version 2.0

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Axonal sprouting and hyperexcitability in epilepsy

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.

Graphic 56930 Version 3.0

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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

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-transporter

Prolonged exposure to elevated

extracellular K leads to further

neuronal depolarization

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 52092 Version 1.0

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5/27/2014 Pathophysiology of seizures and epilepsy

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Disclosures: Carl E Stafstrom, MD, PhD Nothing to disclose. Jong M Rho, MD Speaker’s Bureau: Eisai Canada; UCB Pharma Canada(epilepsy). Consultant/Advisory Boards: Accera (Alzheimer’s disease, neuroprotection). Timothy A Pedley, MD Other Financial Interest:American Academy of Neurology (President). April F Eichler, MD, MPH Equity Ow nership/Stock Options: Johnson & Johnson [Dementia(galantamine), Epilepsy (topiramate)]; Employee of UpToDate, Inc.

Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are addressed by vetting througha multi-level review process, and through requirements for references to be provided to support the content. Appropriately referencedcontent is required of all authors and must conform to UpToDate standards of evidence.

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