Pathophysiology of Seizures and Epilepsy

13.07.
2015 Pathophysiology of seizures and epilepsy
Official reprint from UpToDate®
www.uptodate.com ©2015 UpToDate®
Pathophysiology of seizures and epilepsy
Authors Section Editor Deputy Editor

Carl E Stafstrom, MD, Timothy A Pedley, MD April F Eichler, MD, MPH
PhD
Jong M Rho, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2015. | 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 seizureprone
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 "Antiepileptic drugs: Mechanism of
action, pharmacology, and adverse effects" 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 tonicclonic 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 [24].
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 [25]. 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:
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13.07.2015 Pathophysiology of seizures and epilepsy
● 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 membranespanning 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 ATPdependent
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:
● Voltagegated channels are activated by changes in the membrane potential that alter the conformational
state of the channel, allowing selective passage of charged ions. Voltagegated sodium and calcium
channels function to depolarize the cell membrane toward action potential threshold and are excitatory.
Voltagegated potassium channels largely function to hyperpolarize the cell membrane away from the
action potential threshold and are inhibitory.
● Ligandgated 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 membranebound 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 voltagegated and ligandgated channels results in either depolarization (eg,
inward flux of cations) or hyperpolarization (eg, inward flux of anions or outward flux of cations).
Voltagedependent conductances
Depolarizing conductances — Depolarizing conductances are excitatory and are mediated by inward
sodium and calcium currents.
● Inward sodium conductances include the rapidlyinactivating 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'.)
Many anticonvulsants act in part through interactions with voltagedependent sodium channels [10].
Examples include phenytoin, carbamazepine, and lacosamide. (See "Antiepileptic drugs: Mechanism of
action, pharmacology, and adverse effects", section on 'Drugs that affect voltagedependent sodium
channels'.)
● Activation of voltagedependent 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 voltagegated calcium channels are heterooligomeric 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 voltagedependent 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 voltagegated potassium channel is composed of four membranespanning
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 Acurrent, which helps determine
interspike interval and thus affects the rate of cell firing; an Mcurrent, 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 voltagegated potassium channels [13]. (See "Antiepileptic drugs: Mechanism of
action, pharmacology, and adverse effects".)
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 [1416]. (See "Neonatal epileptic syndromes",
section on 'Benign familial neonatal convulsions' and "Benign focal 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 activitydependent synaptic plasticity [17]. Ionotropic
glutamate receptors are broadly divided into NmethylDaspartate (NMDA) and nonNMDA 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.
● The NMDA receptor contains a binding site for glutamate (or NMDA), and a recognition site for a variety
of modulators (eg, glycine, polyamines, MK801, zinc). A voltagedependent 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 longlasting excitatory postsynaptic 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.
● NonNMDA ionotropic receptors are αamino3hydroxy5methyl4isoxazoleproprionic 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 fastrising, 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 "Antiepileptic drugs: Mechanism of action, pharmacology, and adverse effects", section on
'Perampanel'.)
● Metabotropic glutamate receptors (those not directly coupled to ion channels) represent a large,
heterogeneous family of Gprotein coupled receptors. Gproteins activate various transduction pathways
and are important modulators of voltagedependent potassium and calcium channels, nonselective cation
currents, ligandgated 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 glutamateactivated 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 [2628]. 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:
● Feedforward 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 negativefeedback loop, controlling repetitive
firing and limiting recruitment of surrounding neurons (ie, inhibitory surround).
Both of these inhibitory circuits utilize gammaaminobutyric acid (GABA), a neutral amino acid, as the
neurotransmitter. After release from axon terminals, GABA binds to at least two classes of receptors, GABAA
and GABAB receptors, which are found on almost all cortical neurons. GABAA receptors are also found on
glia, although their functional significance on these cells is unclear.
● GABAA 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 GABAA 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 "Antiepileptic drugs: Mechanism of action,
pharmacology, and adverse effects", section on 'Drugs that affect GABA activity'.)
Activation of GABAA 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 [31
33]. This reversal of the conventional GABAA 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 GABAA channels also contributes to the depolarization. (See 'Susceptibility of the immature
brain' below.)
● GABAB 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 GTPbinding proteins. Whereas
GABAA receptors generate fast highconductance inhibitory postsynaptic potentials (IPSPs) close to the
cell body, GABAB receptors on the postsynaptic membrane mediate slow longlasting lowconductance
IPSPs, primarily in hippocampal pyramidal cell dendrites. Perhaps of more functional significance,
activation of GABAB receptors on the presynaptic terminal blocks the synaptic release of
neurotransmitter. It is thought that some GABAB receptors are associated with terminals that release
GABA onto postsynaptic GABAA receptors. In such cases, activation of GABAB receptors reduces the
amount of GABA released, resulting in disinhibition [35].
The summation of individual GABA receptor mediated activation produces a largely chloridemediated
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 GABAA 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 GABAA receptor subunit. (See "Congenital cytogenetic abnormalities".)
Conversely, enhanced GABAmediated inhibition is an important mechanism of antiepileptic drugs such as
phenobarbital and the benzodiazepines. (See "Antiepileptic drugs: Mechanism of action, pharmacology, and
adverse effects", 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 inwardlyrectifying potassium channels mediate potassium uptake.
The location of glial endfeet 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 gliaselective 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 gliarelated factors, such as the cytokine, IL1beta, 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 "Localizationrelated (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, feedforward 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 results from denervation of dentate granule
cells; axons of dentate granule cells then innervate neurons of the dentate gyrus rather than CA3 and hilus,
causing a form of recurrent hyperexcitability (see 'Synchronizing mechanisms' below). It is not known whether
these pathologic findings are primarily the cause or the result of epileptic activity.
A wide variety of brain injuries can increase the propensity for seizures to develop. Examples of insults to the
brain that are associated with the development of epilepsy include physical trauma to the brain, hypoxia,
prolonged fever (in young children), central nervous system infection, and stroke. Mechanisms of
epileptogenesis in these circumstances can involve any of the physiologic factors previously discussed that
increase excitation or decrease inhibition. As an example, mossy fiber sprouting can result from numerous
initiating brain insults, confirming a similar response of neural circuits to a wide variety of epileptogenic stimuli
[42].
Paroxysmal depolarization shift — The neurophysiologic hallmark of a partial seizure is the interictal
epileptiform discharge on EEG. The cellular correlate of the focal interictal epileptiform discharge is known as
the paroxysmal depolarization shift (PDS) (figure 4).
A PDS is characterized by an initial rapid and prolonged depolarization of the membrane potential, followed by
a burst of repetitive action potentials lasting several hundred milliseconds. The initial depolarization is mediated
by AMPA receptors, while the sustained depolarization is a consequence of NMDA receptor activation. The
PDS terminates with a prolonged hyperpolarization phase that is mediated primarily by inhibitory potassium and
chloride conductances, carried by voltagegated 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 PDSlike 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
interneuronmediated 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 GABAAreceptormediated
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 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 upregulated 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 longterm 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 epilepsyrelated adverse psychosocial challenges are referred to as "comorbidities" [54].
Therefore, the consequences of epilepsy are both multiple and multifactorial. (See "Evaluation and
management of drugresistant 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 spikewave 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 GABAergic 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 spikewave 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.
● Ttype calcium channel. A subtype of voltagegated calcium channel is known as the lowthreshold or T
type calcium channel, sonamed 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 spikewave discharge.
Genetic alterations in the Ttype 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 Ttype calcium
currents, although it is uncertain as to whether this is the primary mechanism of their action [61,62].
● HCN channels and hcurrents. The second important ion channel involved in the regulation of
thalamocortical rhythmicity is the hyperpolarizationactivated cation channel (HCN channel), responsible
for the socalled Ih or hcurrent. 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 voltagegated 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 hcurrents 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 GABAB receptors and agonists of dopamine receptors can
also interrupt abnormal thalamocortical discharges in experimental absence epilepsy models [67]. GABA
B receptors mediate longlasting 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) [6,6971]. Each factor alters the brain excitatoryinhibitory 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 [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 ATPdependent 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.)
• Voltagegated 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.)
• Ligandgated 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
gammaaminobutyric 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 7.0
GRAPHICS
Examples of specific pathophysiologic defects leading to epilepsy
Level of brain Pathophysiologic
Condition
function mechanism
Neuronal network Cerebral dysgenesis, post Altered neuronal circuits:
traumatic scar, mesial temporal Formation of aberrant excitatory
sclerosis (in TLE) connections ("sprouting")
Neuron structure Down syndrome and possibly other Abnormal structure of dendrites

syndromes with mental and dendritic spines: Altered
retardation and seizures current flow in neuron
Neurotransmitter Pyridoxine (vitamin B 6 ) Decreased GABA synthesis: B 6 , a

synthesis dependency cofactor for GAD
Neurotransmitter Angelman syndrome, juvenile Abnormal GABA receptor subunit(s)

receptors: myoclonic epilepsy
Inhibitory
Neurotransmitter Nonketotic hyperglycinemia Excess glycine leads to activation of

receptors: NMDA receptors
Excitatory
Synapse Neonatal seizures Many possible mechanisms,

development including the depolarizing action of
GABA early in development
Ion channels Benign familial neonatal Potassium channel mutations:

("channelopathies") convulsions Impaired repolarization
TLE: temporal lobe epilepsy; GABA: gammaaminobutyric 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
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 14. 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 spikewave 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 spikewaves on EEG.
CC: corpus callosum; EEG: electroencephalogram; GABA: gammaaminobutyric acid.
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.6. Copyright © 2004 SpringerVerlag.
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 voltagegated Na+ and K+ channels; the direction of ion fluxes during
excitatory activation is shown. After firing, the membranebound Na+ –K+ pump and star
shaped astroglial cells restore ionic balance.
AHP: afterhyperpolarization; EPSP: exciatory postsynaptic potential; IPSP: inhibitory postsynaptic
potential; mV: millivolts.
Reproduced with permission from: Stafstrom CE. An introduction to seizures and epilepsy: cellular
mechanisms underlying classification and treatment. In: Epilepsy and the Ketogenic Diet, Stafstrom
CE, Rho JM (Eds), Humana Press, Totowa, New Jersey 2004. p.11. Copyright © 2004 Springer
Verlag.
Hippocampal trisynaptic pathway
The hippocampal trisynaptic pathway begins with neurons in layer II of the
entorhinal cortex (EC), which project axons to the dentate gyrus (DG) along the
perforant path (PP) (1), where they synapse on granule cell dendrites. Next,
dentate granule cells send their axons (called mossy fibers [MF]) to synapse on
cells in the hilus and in the CA3 field of Ammon’s horn (2). CA3 pyramidal cells,
in turn, project to the CA1 field of Ammon’s horn via Schaffer collaterals (SC) (3).
Finally, CA1 neurons send projections outward through the fornix to other brain
regions, as well as back to the subiculum. For simplicity, only the classic "feed
forward" projections of the trisynaptic pathway are shown. The known "backward"
projections and local circuit interactions are omitted here for simplicity.
DG: dentate gyrus; EC: entorhinal cortex; MF: mossy fiber; PP: perforant path; SC: Shaffer
collaterals; Subic: subiculum.
Courtesy of Carl E Stafstrom, MD, PhD.
Abnormal neuronal firing in epilepsy
Abnormal neuronal firing at the levels of (A) the brain and (B) a simplified neuronal
network, consisting of two excitatory neurons (1 and 2) and an inhibitory interneuron (filled
black circle, 3). EEG (top set of traces) and intracellular recordings (bottom set of traces)
are shown for the normal (left column), interictal (middle column), and ictal conditions
(right column). Numbered traces refer to likenumbered 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 nonNMDAmediated
fast EPSP (shaded area), and is maintained by a longer, larger NMDAmediated EPSP. The
postPDS hyperpolarization (*) temporarily stabilizes the neuron. If this postPDS
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: NmethylD
aspartate; PDS: paroxysmal depolarization shift.
Reproduced with permission from: Stafstrom CE. An introduction to seizures and epilepsy: cellular
mechanisms underlying classification and treatment. In: Epilepsy and the Ketogenic Diet, Stafstrom
CE, Rho JM (Eds), Humana Press, Totowa, New Jersey 2004. p.18. Copyright © 2004 SpringerVerlag.
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.
Factors promoting increased seizure susceptibility in the
developing brain
Factor Consequence
Input resistance and time constant: Increased Small inputs result in relatively large voltage
in immature neurons changes
Voltagegated ion channels: Earlier maturation Longer action potentials, shorter refractory
of sodium and calcium channels, delayed periods, increased neuron firing
development of potassium channels
Synapse development: Excitatory synapses Relative predominance of excitation over
appear before inhibitory synapses inhibition early in development
Synapse development: Over expression of Corresponds to window of heightened seizure
excitatory synapses during critical period 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 Along with other factors favoring excitation,
synapses contributes to neuronal excitatory drive and
lack of functional inhibition
Developmental changes in GABA A receptor GABA is depolarizing early in life, enhancing

function and Cl – gradient due to differential excitability
development of the K +/Cl – cotransporters
Developmental changes in GABA A receptor Partially accounts for developmental

subunits differences in inhibitory effectiveness and
benzodiazepine responsiveness
Developmental sensitivity to glutamate Less glutamateinduced excitotoxicity early in
toxicity development
Immature GABA A binding pattern in Proconvulsant effect

substantia nigra
Electrical synapses: More common early in Mechanism for enhanced synchrony of
development neuronal networks
Immature homeostatic mechanisms: NaK Prolonged exposure to elevated extracellular
ATPase, glial K + regulation, K +/Cl – co K + leads to further neuronal depolarization
transporters
GABA A : gammaaminobutyric acid A; NaKATPase: sodiumpotassium 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.
Disclosures
Disclosures: Carl E Stafstrom, MD, PhD Nothing to disclose. Jong M Rho, MD Speaker's Bureau:
Eisai Limited [Epilepsy (Rufinamide and perampanel)]. Consultant/Advisory Boards: Accera
[Alzheimer's (AC1202)]. Timothy A Pedley, MD Nothing to disclose. April F Eichler, MD, MPH
Equity Ownership/Stock Options: Johnson & Johnson [Dementia (galantamine), Epilepsy
(topiramate)].
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multilevel 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.
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Pathophysiology of Seizures and Epilepsy

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Authors Section Editor Deputy Editor

Neuron structure Down syndrome and possibly other Abnormal structure of dendrites

Neurotransmitter Pyridoxine (vitamin B 6 ) Decreased GABA synthesis: B 6 , a

Neurotransmitter Angelman syndrome, juvenile Abnormal GABA receptor subunit(s)

Neurotransmitter Nonketotic hyperglycinemia Excess glycine leads to activation of

Synapse Neonatal seizures Many possible mechanisms,

Ion channels Benign familial neonatal Potassium channel mutations:

Developmental changes in GABA A receptor GABA is depolarizing early in life, enhancing

Developmental changes in GABA A receptor Partially accounts for developmental

Immature GABA A binding pattern in Proconvulsant effect

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Pathophysiology of Seizures and Epilepsy

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Pathophysiology of Seizures and Epilepsy

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13.07.

Authors Section Editor Deputy Editor

Neuron structure Down syndrome and possibly other Abnormal structure of dendrites

Neurotransmitter Pyridoxine (vitamin B 6 ) Decreased GABA synthesis: B 6 , a

Neurotransmitter Angelman syndrome, juvenile Abnormal GABA receptor subunit(s)

Neurotransmitter Non­ketotic hyperglycinemia Excess glycine leads to activation of

Synapse Neonatal seizures Many possible mechanisms,

Ion channels Benign familial neonatal Potassium channel mutations:

Developmental changes in GABA A receptor GABA is depolarizing early in life, enhancing

Developmental changes in GABA A receptor Partially accounts for developmental

Immature GABA A binding pattern in Proconvulsant effect

Вам также может понравиться

Neurotransmitter Nonketotic hyperglycinemia Excess glycine leads to activation of