Pathophysiology of seizures and epilepsy

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Official reprint from UpToDate

www.uptodate.com 2014 UpToDate
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: Oct 2014. | This topic last updated: Jul 30, 2014.
INTRODUCTION An epileptic seizure is an episode of neurologic dysfunction in which abnormal
neuronal firing is manifest clinically by changes in motor control, sensory perception, behavior, and/or
autonomic function. Epilepsy is the condition of recurrent spontaneous seizures arising from aberrant
electrical activity within the brain. While anyone can experience a seizure under the appropriate
pathophysiological conditions, epilepsy suggests an enduring alteration of brain function that
facilitates seizure recurrence. Epileptogenesis is the process by which the normal brain becomes
prone to epilepsy [1].
The aberrant electrical activity that underlies epilepsy is the result of biochemical processes at the
cellular level promoting neuronal hyperexcitability and neuronal hypersynchrony. However, a single
neuron, discharging abnormally, is insufficient to produce a clinical seizure, which occurs only in the
context of large neuronal networks. Several key cortical and subcortical structures are involved in
generating a seizure.
This topic will review the cellular basis for focal and generalized seizure activity, with specific attention
to ion channels, the essential currency of neuronal excitability, and the hippocampus, one of the most
seizure-prone areas of the brain. The pharmacology of antiepileptic drugs and issues related to the
assessment and management of patients with epilepsy are discussed separately. (See "Overview of
antiepileptic drugs" and "Overview of the management of epilepsy in adults".)
CLASSIFICATION OF SEIZURES Epilepsy is not a singular disease, but is heterogeneous in
terms of clinical expression, underlying etiologies, and pathophysiology (table 1). As such, specific
mechanisms and pathways underlying specific seizure types may vary. Epileptic seizures are broadly
classified according to their site of origin and pattern of spread (figure 1).
Focal seizures arise from a localized region of the brain and have clinical manifestations that
reflect that area of brain. Focal discharges can remain localized or they can spread to nearby
cortical areas, to subcortical structures and/or transmit through commissural pathways to involve
the whole cortex. The latter sequence describes the secondary generalization of focal seizures.
As an example, a seizure arising from the left motor cortex may cause jerking movements of the
right upper extremity. If epileptiform discharges spread to adjacent areas and then the entire
brain, a secondary generalized tonic-clonic seizure ensues.
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 seizures, it is
useful to view any seizure as the result of a perturbation in the normal balance between inhibition and
excitation in a localized region or throughout the brain [2-4].

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

an imbalance between excitatory and inhibitory currents within neural circuits of the brain [2-5].
Neuronal circuits are composed of excitatory and inhibitory neurons and their dendrites and axons,
synapses, and glial cells. All of the following circuit components function via ion channels:
Neuronal dendrites and somata, which convert incoming synaptic current into propagated
electrical activity which is integrated at the axon initial segment,
Axons, which propagate action potentials along the neuronal axon, and
Synapses the site of chemical neurotransmission 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 that maintains the resting membrane potential in a
polarized state (about -70 mV) (figure 2). When an ion channel opens, the ion moves passively into or
out of the cell along its electrochemical gradient.
Two major types of ion channels are responsible for inhibitory and excitatory activity:
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 gammaaminobutyric 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).
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 [6]. Augmentation of noninactivating sodium channel
activity may promote burst firing in neurons [7].
Each sodium channel exists as a complex of polypeptide subunits; there is a major alpha subunit
and one or more smaller beta subunits, which influence the kinetic properties of the alpha
subunit. The shape of action potentials is determined by the types of alpha and beta subunits
present in an individual neuron [8]. Genetic alterations in the structure of sodium channels
underlie the syndrome of generalized epilepsy with febrile seizures plus (GEFS+) and Dravet
syndrome, a severe myoclonic epilepsy of infancy as well as other epilepsy syndromes [9]. (See
"Epilepsy syndromes in children", section on 'Myoclonic epilepsy of infancy' and "Clinical
features and evaluation of febrile seizures", section on 'Genetic epilepsies with febrile seizures'.)

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Many anticonvulsants act in part through interactions with voltage-dependent sodium channels
[10]. Examples include phenytoin, carbamazepine, and lacosamide. (See "Overview of
antiepileptic drugs", section on 'Drugs that affect voltage-dependent sodium channels'.)
Activation of voltage-dependent calcium channels contributes to the depolarizing phase of the
action potential. Calcium influx can also affect neurotransmitter release, gene expression, and
neuronal firing patterns. There are several subtypes of calcium channels, with distinct
electrophysiological properties, pharmacological profiles, molecular structures, and cellular
localization [11]. Similar to sodium channels, the molecular structures of voltage-gated calcium
channels are hetero-oligomeric complexes which form the pore as well as other subunits that
can modulate the kinetic properties of the channel.
Calcium currents in hippocampal CA3 pyramidal cells underlie burst discharges in these cells
and may contribute to epileptic synchronization. Alteration in calcium channels also play a role in
childhood absence epilepsy. (See 'Primary generalized epilepsy: Absence epilepsy' below.)
Hyperpolarizing conductances An array of voltage-dependent hyperpolarizing currents,
mediated primarily by potassium channels, counter balance depolarizing currents and function to
inhibit or decrease excitation in the nervous system. Potassium channels represent the largest and
most diverse family of voltage-gated ion channels. The prototypic voltage-gated potassium channel is
composed of four membrane-spanning alpha subunits and four regulatory beta subunits that are
assembled in an octameric complex to form an ion selective pore.
In hippocampal neurons, potassium conductances include a leak conductance, which is a major
determinant of the resting membrane potential, and an inward rectifier (involving the flux of other
ions), which is activated by hyperpolarization. (Rectification refers to a situation in which the direction
of ion flow through a channel changes according to voltage; rectification can also be secondary to
"blocking" of the pore by other ions.) Other potassium conductances include several delayed rectifiers
that are involved in the termination of action potentials and repolarization of the neuron's membrane
potential; a dendritic A-current, which helps determine interspike interval and thus affects the rate of
cell firing; an M-current, which is inhibited by activation of cholinergic muscarinic agonists and
hyperpolarizes the membrane potential, reducing the rate of cell firing [12]; and a set of calciumactivated potassium conductances, which are sensitive to intracellular calcium concentration and
affect cell firing rate and interburst interval.
Facilitation of hyperpolarizing conductances may be anticonvulsant. Part of the anticonvulsant
properties of topiramate and levetiracetam may include actions on potassium channels. The
anticonvulsant retigabine acts by opening and activating voltage-gated potassium channels [13]. (See
"Overview of antiepileptic drugs".)
Mutations in the KCNQ2 and KCNQ3 genes encoding the potassium channels responsible for the Mcurrent have been linked to a rare form of inherited epilepsy, benign familial neonatal convulsions as
well as to families with benign partial epilepsy and idiopathic generalized epilepsy [14-16]. (See
"Neonatal epileptic syndromes", section on 'Benign familial neonatal convulsions' and "Benign partial
epilepsies of childhood", section on 'Benign epilepsy with centrotemporal spikes'.)
Synaptic transmission
Excitatory transmission The amino acid glutamate is the principal excitatory neurotransmitter
of the central nervous system. Glutamatergic pathways are widespread throughout the brain, and
excitatory amino acid activity is critical to normal brain development and activity-dependent synaptic
plasticity [17]. Ionotropic glutamate receptors are broadly divided into N-methyl-D-aspartate (NMDA)
and non-NMDA receptors, based on biophysical properties and pharmacological profiles. Each
subtype of glutamate receptor consists of a multimeric assembly of subunits that determine its distinct

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functional properties. Glutamate receptor channel subunits are currently classified into several
subfamilies based on amino acid sequence homology.
The NMDA receptor contains a binding site for glutamate (or NMDA), and a recognition site for a
variety of modulators (eg, glycine, polyamines, MK-801, zinc). A voltage-dependent blockade of
the NMDA receptor by magnesium ions is reversed when the membrane is depolarized [18,19].
When this happens, the NMDA receptor is activated, resulting in an influx of calcium and sodium
ions and generation of relatively slow and long-lasting excitatory post-synaptic potentials
(EPSPs). Calcium entry also initiates a number of "second messenger" pathways.
These synaptic events can contribute to epileptiform burst discharges. Recurrent excitatory
circuits produced by mossy fiber sprouting in mesial temporal epilepsy are associated with
increased NMDA conductances [20]. (See 'Synchronizing mechanisms' below.) NMDA receptor
blockade attenuates bursting activity in many models of epileptiform activity.
Non-NMDA ionotropic receptors are -amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid
(AMPA) and kainate receptors, which are both coupled to sodium and potassium ion channels
[21] Activation of the postsynaptic AMPA receptor by glutamate is responsible for the fast-rising,
brief EPSP. In addition, the depolarization generated via AMPA receptors is necessary for
effective activation of NMDA receptors. Consequently, AMPA receptor antagonists block most
excitatory synaptic activity in pyramidal neurons. One AMPA receptor antagonist, perampanel, is
approved as a treatment for refractory focal seizures [22]. (See "Overview of antiepileptic drugs",
section on 'Perampanel'.)
Metabotropic glutamate receptors (those not directly coupled to ion channels) represent a large,
heterogeneous family of G-protein coupled receptors. G-proteins activate various transduction
pathways and are important modulators of voltage-dependent potassium and calcium channels,
non-selective cation currents, ligand-gated receptors (ie, GABA and glutamate receptors), and
can regulate glutamate release [23]. Different metabotropic glutamate receptor subtypes are
specific for different intracellular processes and are differentially localized within the brain.
Knowledge of the role of metabotropic glutamate receptors in epilepsy is expanding rapidly and
this receptor may eventually provide a therapeutic target [24].
Alterations in glutamate-activated channels may lead to their increased activation, as is observed in
animal models of epilepsy and in human epilepsy [25]. NMDA and other glutamate receptor agonists
induce epilepsy in animals. Glutamate receptor autoantibodies have been identified in Rasmussen
encephalitis and other focal epilepsies [26-28]. Upregulation of a vesicular glutamate transporter was
found in patients with temporal lobe epilepsy in one study [29].
Inhibitory transmission Synaptic inhibition in the hippocampus is mediated by two basic circuit
configurations:
Feed-forward inhibition occurs when a collateral projection from an axon of an excitatory
principal neuron synapses with and directly activates an inhibitory interneuron, which then
provides inhibitory input to the same target neuron which the primary neuron activates.
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.

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GABA-A receptors are macromolecular complexes consisting of an ion pore, as well as binding
sites for agonists and a variety of allosteric modulators, such as benzodiazepines and
barbiturates, each differentially affecting the kinetic properties of the receptor [30]. The ion
channel is selectively permeable to chloride (and bicarbonate) ions. At least seven different
polypeptide subunits have been described, each with one or more subtypes. In theory, several
thousand isoforms of these subunits are possible, however, a limited number of functional
combinations are thought to exist. The precise subunit composition of native GABA-A receptors
has yet to be identified. Because individual subunits may be differentially sensitive to
pharmacological agents, GABA receptor subunits represent potentially useful molecular targets
for new anticonvulsants. (See "Overview of antiepileptic drugs", section on 'Drugs that affect
GABA activity'.)
Activation of GABA-A receptors on the soma of a mature cortical neuron generally results in
influx of chloride ions and membrane hyperpolarization, thus inhibiting cell discharge. However,
in immature neurons, GABA-A receptor activation causes depolarization of the postsynaptic
membrane instead [31-33]. This reversal of the conventional GABA-A effect is thought to reflect
a reversed chloride electrochemical gradient, a consequence of the immature expression of the
potassium/chloride cotransporter, KCC2, which ordinarily renders GABA hyperpolarizing [34].
Outward flux of bicarbonate through GABA-A channels also contributes to the depolarization.
(See 'Susceptibility of the immature brain' below.)
GABA-B receptors are located on both the postsynaptic membrane and on presynaptic
terminals. These so-called metabotropic receptors do not form an ion pore as ionotropic
receptors do. Rather, they act to control calcium or potassium conductances through second
messenger GTP-binding proteins. Whereas GABA-A receptors generate fast high-conductance
inhibitory postsynaptic potentials (IPSPs) close to the cell body, GABA-B receptors on the
postsynaptic membrane mediate slow long-lasting low-conductance IPSPs, primarily in
hippocampal pyramidal cell dendrites. Perhaps of more functional significance, activation of
GABA-B receptors on the presynaptic terminal blocks the synaptic release of neurotransmitter. It
is thought that some GABA-B receptors are associated with terminals that release GABA onto
postsynaptic GABA-A receptors. In such cases, activation of GABA-B receptors reduces the
amount of GABA released, resulting in disinhibition [35].
The summation of individual GABA receptor mediated activation produces a largely chloride-mediated
membrane hyperpolarization that counterbalances the depolarization generated by the summation of
EPSPs. Impairment of this inhibitory activity can lead to seizures. As an example, drugs such as
picrotoxin and bicuculline bind to the GABA-A receptor and block chloride channels and are
proconvulsant. Infants deficient in pyridoxine, a coenzyme required for GABA synthesis, are prone to
seizures [36]. (See "Etiology and prognosis of neonatal seizures".) Angelman syndrome, which
includes severe epilepsy, is associated with a genetic defect involving a GABA-A receptor subunit.
(See "Congenital cytogenetic abnormalities".)
Conversely, enhanced GABA-mediated inhibition is an important mechanism of antiepileptic drugs
such as phenobarbital and the benzodiazepines. (See "Overview of antiepileptic drugs", section on
'Drugs that affect GABA activity'.)
Role of glia The contribution of glia to the regulation of epileptiform discharges is increasingly
appreciated [37]. Among other functions, glia play an important part in maintaining extracellular levels
of membrane permeant ions and neurotransmitters.
One important role for glia is the restoration of ionic homeostasis after neuronal activity, particularly
extracellular potassium levels. A variety of inwardly-rectifying potassium channels mediate potassium
uptake. The location of glial end-feet on brain microvasculature provides a convenient "sink" for
potassium release. Glial membrane potential changes are directly correlated with changes in

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

hyperexcitability.
Transport of glutamate out of the extracellular space may be an important role for glia in the
maintenance of neuronal excitability. Glial cells have powerful glutamate transport molecules in their
membranes. Rapid and efficient removal of extracellular glutamate is essential in normal brain tissue
since residual glutamate would continue to excite surrounding neurons. Blockade of glutamate
transporters or "knockout" of the genes for these transport proteins results in epilepsy or excitotoxicity
[38].
Glia can modulate neuronal excitability in a number of other ways [39]. First, glia play a critical role in
regulating extracellular pH, via a proton exchanger and bicarbonate transporter mechanisms. Even
low levels of neuronal activity create significant pH transients. Furthermore, pH modulates receptor
function, particularly the NMDA receptor, which plays an important role in epileptic discharge. Second,
glia are also now thought to release powerful neuroactive agents into the extracellular space.
Glutamate released from glia can excite neighboring neurons [40]. Other glia-related factors, such as
the cytokine, IL-1beta, can have profound anticonvulsant efficacy [41].
PATHOPHYSIOLOGY OF EPILEPSY In an epileptic seizure, neurons transition from their normal
firing pattern to interictal epileptiform bursts, and then to an ictal state. Each of these stages in the
evolution of a seizure is governed by distinct electrophysiological mechanisms. Much of our
understanding of the mechanisms regulating each stage comes from cellular electrophysiological
studies in which microelectrodes record intracellular potential changes from individual neurons.
Focal epilepsy: Mesial temporal lobe epilepsy The most prevalent form of focal epilepsy is
mesial temporal lobe epilepsy. Ictal onset in the mesial temporal lobe can produce a seizure aura,
such as an olfactory hallucination, an epigastric sensation, or a psychic symptom. Progression of the
seizure is often associated with loss of awareness and motor automatisms. (See "Localization-related
(focal) epilepsy: Causes and clinical features", section on 'Mesial temporal lobe epilepsy'.) As a
consequence, hippocampal pyramidal cells have become one of the most intensively studied cell
types in the central nervous system.
The hippocampal formation consists of the dentate gyrus, the hippocampus proper (Ammon's horn)
(with subregions CA1, CA2, and CA3), the subiculum, and the entorhinal cortex (figure 3). These four
regions are linked by excitatory, largely unidirectional, feed-forward connections. Backwards
projections include those from the entorhinal cortex to Ammon's horn and those from the CA3 field to
the dentate gyrus. The predominant forward-projecting circuit begins with neurons in layer II of the
entorhinal cortex that project axons to the dentate gyrus along the perforant pathway where they
synapse on granule cell (and interneuron) dendrites. Granule cells send their axons, called mossy
fibers, to synapse on cells in the hilus and in the CA3 field of Ammon's horn. CA3 pyramidal cells, in
turn, project to other CA3 pyramidal cells via local collaterals, to the CA1 field of Ammon's horn via
Schaffer collaterals, and to the contralateral hippocampus. CA1 pyramidal cell axons project onto the
subicular complex, and neurons of the subicular complex project to the entorhinal cortex, as well as to
other cortical and subcortical targets.
In hippocampal sclerosis, the pathologic hallmark of mesial temporal lobe epilepsy, there is a pattern
of gliosis and neuronal loss primarily in the hilar polymorphic and CA1 pyramidal regions with relative
sparing of the CA2 pyramidal region, and an intermediate degree of cell loss in the CA3 pyramidal
region and dentate gyrus. A form of synaptic reorganization known as mossy fiber sprouting results
from denervation of dentate granule cells; axons of dentate granule cells then innervate neurons of
the dentate gyrus rather than CA3 and hilus, causing a form of recurrent hyperexcitability (see
'Synchronizing mechanisms' below). It is not known whether these pathologic findings are primarily
the cause or the result of epileptic activity.

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A wide variety of brain injuries can increase the propensity for seizures to develop. Examples of
insults to the brain that are associated with the development of epilepsy include physical trauma to the
brain, hypoxia, prolonged fever (in young children), central nervous system infection, and stroke.
Mechanisms of epileptogenesis in these circumstances can involve any of the physiologic factors
previously discussed that increase excitation or decrease inhibition. As an example, mossy fiber
sprouting can result from numerous initiating brain insults, confirming a similar response of neural
circuits to a wide variety of epileptogenic stimuli [42].
Paroxysmal depolarization shift The neurophysiologic hallmark of a partial seizure is the
interictal epileptiform discharge on EEG. The cellular correlate of the focal interictal epileptiform
discharge is known as the paroxysmal depolarization shift (PDS) (figure 4).
A PDS is characterized by an initial rapid and prolonged depolarization of the membrane potential,
followed by a burst of repetitive action potentials lasting several hundred milliseconds. The initial
depolarization is mediated by AMPA receptors, while the sustained depolarization is a consequence
of NMDA receptor activation. The PDS terminates with a prolonged hyperpolarization phase that is
mediated primarily by inhibitory potassium and chloride conductances, carried by voltage-gated
potassium channels and GABA receptors, respectively. This constitutes a refractory period (figure 4).
Experimental techniques used to promote epileptogenesis, such as blockade of GABA inhibition
and/or potentiation of excitatory transmission, such as with NMDA, can induce PDS-like activity in
cortical neurons [20].
A PDS is an event occurring in a single neuron. An interictal epileptiform discharge represents
synchronously occurring PDS in several million neurons, involving an area of cortex of at least 6 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. In various regions of the hippocampus, sharp waves, dentate spikes,
theta activity (range 8 to 13 Hz), 40 Hz oscillations, and 200 Hz oscillations are all forms of neuronal
synchronization that can be recorded [43].
Neuronal synchronization is also a hallmark of epilepsy. This may result from exaggerated synchrony
among hippocampal neurons. Alternatively, or in addition, normal forms of synchronized activity may
become epileptogenic in a hippocampus that has undergone selective neuronal loss, synaptic
reorganization, or changes in expression of specific receptor subtypes.
In the hippocampus, synchronizing mechanisms include input from subcortical nuclei as well as
intrinsic interneuron-mediated synchronization [44]. As an example, high amplitude theta activity
represents synchronized activity of hippocampal neurons that is largely dependent on input from the
septum [43]. Subcortical nuclei, such as the septum, have divergent inputs that target hippocampal
interneurons. In turn, the divergent axon projections of interneurons, and the powerful effect of the
GABA-A-receptor-mediated conductances that they produce, enable interneurons to entrain the
activity of large populations of principal cells. These characteristics make interneurons an effective
target for subcortical modulation of hippocampal principal cell activity. In addition, mutual inhibitory
interactions among hippocampal interneurons can produce synchronized discharges [45].
Recurrent excitatory circuits are another mode by which neuronal synchronization occurs in the
hippocampus. Recurrent excitatory collaterals are a normal feature of the CA3 region; CA3 pyramidal
cells form direct, monosynaptic connections with other CA3 pyramidal cells and contribute to the
synchronized burst discharges that characterize this region. In the epileptic temporal lobe, synaptic
reorganization and axonal sprouting might lead to aberrant recurrent excitation, providing a
synchronizing mechanism in other parts of the hippocampal formation (figure 5). As an example, while
granule cells in the dentate gyrus normally form few, if any monosynaptic contacts with neighboring

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granule cells, the mossy fiber sprouting seen in mesial temporal sclerosis results in direct excitatory
interactions among granule cells that lower the threshold for synchronization [42].
Finally, mechanisms independent of chemical synaptic transmission might synchronize neuronal firing
under some circumstances. Such mechanisms include:
Gap junctions that allow electrical signals to pass directly between cells. Studies suggest that
gap junctions are up-regulated in epileptic brain tissue, and that blockade of gap junctions
significantly affects the duration of seizure activity [46].
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 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
depend on many factors, including the etiology, epilepsy syndrome, age at the time of seizure onset,
and seizure type, frequency, duration, and severity.
The longer a seizure, the more serious the potential consequences. As an example, status epilepticus
causes damage to neurons even when systemic factors (eg, blood pressure, oxygen level) and
underlying etiology are controlled. This can lead to increased risk for recurrent seizures and disabling
neurologic deficits. (See "Convulsive status epilepticus in adults: Treatment and prognosis", section
on 'Complications and outcome'.)
Brief seizures, if recurrent, can also lead to long-term changes in both brain structure and function.
The process by which a normal brain gradually becomes epileptic as a result of repeated seizures, or
even subclinical synchronous neuronal discharges, is known as kindling [51,52]. There is growing
evidence that temporal lobe epilepsy can be a progressive disorder with an underlying mechanism
akin to kindling [53]. Such considerations emphasize the need to suppress seizure occurrence.
Further considerations depend on how "brain damage" is defined, ie, structural brain changes versus
a wider spectrum of cognitive, behavioral, and neurologic disabilities. Persons with epilepsy face
numerous psychosocial and medical challenges, including intellectual impairment, mood disorders,
psychological adjustment to the chronic nature of the disorder and to the unpredictability of seizures,
the need to take antiepileptic drugs with their attendant side effects, and the dependence on others for
certain daily tasks. Together, these epilepsy-related adverse psychosocial challenges are referred to
as "comorbidities" [54]. Therefore, the consequences of epilepsy are both multiple and multifactorial.
(See "Evaluation and management of drug-resistant epilepsy".)
Primary generalized epilepsy: Absence epilepsy Childhood absence epilepsy is a subtype of
generalized epilepsy with a distinct pathophysiological substrate. Seizures are characterized by a
temporary loss of awareness and responsiveness, usually with a sudden cessation of motor activity
without falling, and total amnesia for the event. These seizures are generally brief (most last less than
20 seconds), do not include an aura, and end abruptly without postictal changes. (See "Childhood
absence epilepsy".)
The generalized spike-wave discharges seen on EEG during an absence seizure reflect widespread,
phase-locked oscillations between excitation and inhibition in thalamocortical networks [2,55]. This
network includes excitatory projections from pyramidal neurons in layer VI of the neocortex to thalamic

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relay (TR) neurons as well as to inhibitory GABA-ergic neurons comprising the nucleus reticularis
thalami (NRT). In turn, excitatory outputs of the TR neurons activate layer VI pyramidal neurons in
neocortex. This thalamocortical circuit is a critical substrate for the generation of cortical rhythms and
is responsible in large part for normal EEG oscillations during wake and sleep states. It is influenced
by sensory input as well as several brainstem nuclei.
In absence seizures, hyperactivity of this circuit causes rhythmic activation of the cortex, generating
generalized spike-wave discharges. Involvement of this circuit is also implicated in other idiopathic
generalized epilepsies, including juvenile myoclonic epilepsy [56,57].
Although multiple ionic conductances are involved in these pacemaking rhythms, two specific
channels are believed to play a key role in regulating thalamocortical activity.
T-type calcium channel. A subtype of voltage-gated calcium channel is known as the lowthreshold 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 lowthreshold spikes, which in turn activate a burst of action potentials [58]. Such an excitatory burst
is believed to underlie the spike portion of a generalized spike-wave discharge.
Genetic alterations in the T-type calcium channel have been associated with childhood absence
epilepsy as well as other generalized epilepsy syndromes [59,60]. Moreover, anticonvulsants
known to be clinically effective against absence seizures (eg, ethosuximide and valproic acid)
block T-type calcium currents, although it is uncertain as to whether this is the primary
mechanism of their action [61,62].
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, hcurrents are both inhibitory and excitatory [65,66]. HCN channels possess an inherent negativefeedback property; hyperpolarization activates them, which then leads to depolarization that
deactivates them. The net effect of HCN channel activation is a decrease in the voltage change
produced by a given synaptic current. H-currents tend to stabilize a neuron's membrane potential
toward the resting potential against both hyperpolarizing and depolarizing inputs.
The relevance of HCN channels in the pathogenesis of absence seizures is supported by the
demonstration that lamotrigine, an AED effective against absence seizures, enhances activation
of dendritic h-currents in hippocampal pyramidal neurons, and by the experimental finding that
deletion of a specific HCN isoform results in absence epilepsy in mice [65].
Other synaptic influences. Antagonists of GABA-B receptors and agonists of dopamine receptors
can also interrupt abnormal thalamocortical discharges in experimental absence epilepsy models
[67]. GABA-B receptors mediate long-lasting thalamic IPSPs involved in the generation of normal
thalamocortical rhythms, while brainstem monoaminergic projections disrupt these rhythms.
Susceptibility of the immature brain Seizure incidence is highest during the first decade of life,
especially during the first year [68]. Multiple physiological factors contribute to the increased
susceptibility of the developing brain to seizures (table 2) [6,69-71]. Each factor alters the brain
excitatory-inhibitory balance in favor of enhanced excitation. Examples include:

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Ion channels that mediate depolarization develop earlier than those that mediate repolarization.
Excitatory neurotransmitters develop before inhibitory ones [17,72,73].
As discussed above, early in development, GABA exerts an excitatory action, rather than the
inhibitory effect seen later in life [31]. (See 'Inhibitory transmission' above.)
Electrical synapses appear to be more prevalent in the developing brain than in the mature brain;
fast-acting electrical transmission can facilitate rapid synchrony of the neuronal network and
precipitate seizures [74,75].
Structural factors also play a role. During the second week of life in the rat, the hippocampal CA3
region is characterized by an abundance of excitatory connections between pyramidal cells that
cause regional heightened excitability and epileptiform activity [76]. As part of development,
these connections are pruned and excessive excitation is stabilized.
The ability of glia to buffer extracellular potassium also varies with age and the expression of the
neuronal membrane ATP-dependent sodium/potassium pump follows a developmental time
course [77].
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.)

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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 7.0

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

Condition

function

Pathophysiologic
mechanism

Neuronal network

Cerebral dysgenesis, posttraumatic 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 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
("channelopathies")

Benign familial neonatal

convulsions

Potassium channel mutations:

Impaired repolarization

TLE: temporal lobe epilepsy; GABA: gamma-aminobutyric acid; GAD: glutamic acid
decarboxylase.
Reproduced with permission from: Rho JM, Stafstrom CE. Neurophysiology of epilepsy. In:
Pediatric Neurology: Principles and Practice, 4th ed, Swaiman KF, Ashwal S, Ferreiro DM
(Eds). Mosby Elsevier. Philadelphia 2006. Copyright 2006.
Graphic 75633 Version 2.0

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Pathophysiology of seizures and epilepsy

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Coronal brain sections depicting seizure types and

potential routes of seizure spread

A: Focal area of hyperexcitability (star under electrode 3) and spread to

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

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Pathophysiology of seizures and 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 2.0

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Pathophysiology of seizures and epilepsy

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Normal neuronal firing

Schematic of neuron with one excitatory (E) and one inhibitory (I) input. Right tracing shows
membrane potential, beginning at a typical resting potential (-70 mV). Activation of E leads
to graded excitatory postsynaptic potentials (EPSPs), the larger of which reaches threshold
(approximately -40 mV) for an action potential. The action potential is followed by an afterhyperpolarization (AHP), the magnitude and duration of which determine when the next
action potential can occur. Activation of I causes an inhibitory postsynaptic potential (IPSP),
which also keeps the membrane potential further from threshold for action potential
generation.
Inset (box) shows magnified portion of the neuronal membrane as a lipid bilayer with
interposed voltage-gated Na+ and K+ channels; the direction of ion fluxes during excitatory
activation is shown. After firing, the membrane-bound Na+ -K+ pump and star-shaped
astroglial cells restore ionic balance.
AHP: after-hyperpolarization; EPSP: exciatory postsynaptic potential; IPSP: inhibitory postsynaptic
potential; mV: millivolts.
Reproduced with permission from: Stafstrom, CE. An introduction to seizures and epilepsy: cellular
mechanisms underlying classification and treatment. In: Epilepsy and the Ketogenic Diet,
Stafstrom, CE, Rho, JM (Eds), Humana Press, Totowa, New Jersey 2004. p.11. Copyright 2004
Springer-Verlag.
Graphic 74749 Version 2.0

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Pathophysiology of seizures and epilepsy

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Hippocampal trisynaptic pathway

The hippocampal trisynaptic pathway begins with neurons in layer II of the

entorhinal cortex (EC), which project axons to the dentate gyrus (DG) along the
perforant path (PP) (1), where they synapse on granule cell dendrites. Next,
dentate granule cells send their axons (called mossy fibers [MF]) to synapse on
cells in the hilus and in the CA3 field of Ammons horn (2). CA3 pyramidal cells, in
turn, project to the CA1 field of Ammons horn via Schaffer collaterals (SC) (3).
Finally, CA1 neurons send projections outward through the fornix to other brain
regions, as well as back to the subiculum. For simplicity, only the classic "feedforward" projections of the trisynaptic pathway are shown. The known "backward"
projections and local circuit interactions are omitted here for simplicity.
DG: dentate gyrus; EC: entorhinal cortex; MF: mossy fiber; PP: perforant path; SC:
Shaffer collaterals; Subic: subiculum.
Courtesy of Carl E Stafstrom, MD, PhD.
Graphic 76895 Version 2.0

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Abnormal neuronal firing in epilepsy

Abnormal neuronal firing at the levels of (A) the brain and (B) a simplified neuronal network,
consisting of two excitatory neurons (1 and 2) and an inhibitory interneuron (filled black circle,
3). EEG (top set of traces) and intracellular recordings (bottom set of traces) are shown for
the normal (left column), interictal (middle column), and ictal conditions (right column).
Numbered traces refer to like-numbered recording sites. Note time scale differences in
different traces.
A. Three EEG electrodes record activity from superficial neocortical neurons. In the normal
case, activity is low voltage and desynchronized (neurons are not firing together in
synchrony). In the interictal condition, large spikes are seen focally at electrode 2 (and to a
lesser extent at electrode 1, where they might be termed sharp waves), representing
synchronized firing of a large population of hyperexcitable neurons (expanded in time below).
The ictal state is characterized by a long run of spikes.
B. At the neuronal network level, the intracellular correlate of the interictal EEG spike is the
paroxysmal depolarization shift (PDS). The PDS is initiated by a non-NMDA-mediated fast
EPSP (shaded area), and is maintained by a longer, larger NMDA-mediated EPSP. The postPDS hyperpolarization (*) temporarily stabilizes the neuron. If this post-PDS hyperpolarization
fails (right column, thick arrow), ictal discharge can occur. The lowermost traces, recordings
from neuron 2, show activity similar to that recorded in neuron 1, with some delay (doubleheaded horizontal arrow). Activation of inhibitory neuron 3 by firing of neuron 1 prevents
neuron 2 from generating an action potential (the IPSP counters the depolarization caused by
the EPSP). If neuron 2 reaches firing threshold, additional neurons will be recruited, leading to
an entire network firing in synchrony (seizure).
EPSP: excitatory postsynaptic potential; IPSP: inhibitory postsynaptic potential; NMDA: N-methyl-Daspartate; PDS: paroxysmal depolarization shift.
Reproduced with permission from: Stafstrom, CE. An introduction to seizures and epilepsy: cellular
mechanisms underlying classification and treatment. In: Epilepsy and the Ketogenic Diet, Stafstrom,
CE, Rho, JM (Eds), Humana Press, Totowa, New Jersey 2004. p.18. Copyright 2004 SpringerVerlag.
Graphic 76134 Version 3.0

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Pathophysiology of seizures and epilepsy

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Hippocampal axonal sprouting and hyperexcitability

in epilepsy

A. Normal situation. Left: Dentate granule neurons (1, 2) make excitatory

synapses (E) onto dendrites of hippocampal pyramidal neurons (3,
4). Right: Activation of dentate neuron 2 causes single action potential in
pyramidal neuron 3.
B. As a consequence of status epilepticus, many pyramidal neurons die
(eg, 4, dashed lines), leaving axons of dentate neuron 1 without a
postsynaptic target. Those axons then sprout and innervate the
dendrites of granule neurons (thick curved arrow), creating the substrate
for a hyperexcitable circuit. Now, when dentate granule neuron 1 is
activated, multiple action potentials are fired in neurons 2 and 3, which
fire repetitively, a manifestation of their hyperexcitability.
This diagram represents a simplification; in fact, neurons of numerous
types in the dentate hilus (labeled H) may die as a consequence of status
epilepticus and the surviving neurons may become involved in seizureinduced synaptic plasticity. The resultant circuit function will depend upon
the balance of excitation and inhibition in the reorganized neuronal
network.
Reproduced with permission from: Stafstrom, CE. An introduction to seizures
and epilepsy: cellular mechanisms underlying classification and treatment. In:
Epilepsy and the Ketogenic Diet, Stafstrom, CE, Rho, JM (Eds), Humana Press,
Totowa, New Jersey 2004. Copyright 2004 Springer Science and Business
Media.
Graphic 56930 Version 4.0

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Pathophysiology of seizures and epilepsy

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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

Along with other factors favoring

synapses

excitation, contributes to neuronal

excitatory drive and lack of functional
inhibition

Developmental changes in GABA A

receptor function and Cl gradient due to
differential development of the K +/Cl cotransporters

GABA is depolarizing early in life,

enhancing excitability

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: NaKATPase, glial K + regulation, K +/Cl cotransporters

Prolonged exposure to elevated

extracellular K + leads to further neuronal
depolarization

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

triphosphatase.
Reproduced with permission from: Rho JM, Stafstrom CE. Neurophysiology of epilepsy. In:
Pediatric Neurology: Principles and Practice, 4th ed, Swaiman KF, Ashwal S, Ferreiro DM
(Eds). Mosby Elsevier. Philadelphia 2006. Copyright 2006.
Graphic 52092 Version 2.0

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