Pathophysiology of Seizures and Epilepsy

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5/27/2014

Pathophysiology of seizures and epilepsy

Official reprint from UpToDate®
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Pathophysiology of seizures and epilepsy
Authors
Carl E Stafstrom, MD, PhD
Jong M Rho, MD

Section Editor
Timothy A Pedley, MD

Deputy Editor
April F Eichler, MD, MPH

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, GABAA 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 socalled 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 forwardprojecting 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 cm2. 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
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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 Ttype 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 'Voltagedependent 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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Topic 2232 Version 6.0

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GRAPHICS
Examples of specific pathophysiological defects leading to epilepsy
Level of brain

Condition

function
Neuronal network

Pathophysiologic mechanism

Cerebral dysgenesis, post-

Altered neuronal circuits: Formation

traumatic scar, mesial temporal
sclerosis (in TLE)

of aberrant excitatory connections
("sprouting")

Down syndrome and possibly
other syndromes with mental

Abnormal structure of dendrites
and dendritic spines: Altered

retardation and seizures

current flow in neuron

Neurotransmitter
synthesis

Pyridoxine (vitamin B 6 )
dependency

Decreased GABA synthesis: B 6 , 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

Benign familial neonatal

Potassium channel mutations:

("channelopathies")

convulsions

Impaired repolarization

Neuron structure

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

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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 SpringerVerlag.
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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Pathophysiology of seizures and epilepsy

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

Longer action potentials, shorter
refractory periods, increased neuron

potassium channels

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

Favor relative hyperexcitability

subunits: NR2B/NR2A ratio favors prolonged
depolarizing responses; NR2D relative over
expression reduces Mg ++ block
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 A receptor function
and Cl - gradient

GABA is depolarizing early in life,

Developmental changes in GABA A 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 A 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

enhancing excitability

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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Disclosures
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). Tim othy 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 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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