Acta neurol. belg., 2000, 100, 201-213
Review article
Pathophysiology of epilepsy
S. ENGELBORGHS, R. D’HOOGE, P. P. DE DEYN
Department of Neurology, A.Z. Middelheim, Antwerp, and Department of Neurology, Laboratory of Neurochemistry and Behavior,
Born-Bunge Foundation, University of Antwerp, Antwerp, Belgium
————
Abstract
This work reviews the current knowledge on epileptogenesis and pathophysiology of epilepsy. Recently, gene
defects underlying four monogenic epilepsies (generalized epilepsy with febrile seizures, autosomal dominant
nocturnal frontal lobe epilepsy, benign familial neonatal
convulsions and episodic ataxia type 1 with partial
seizures) have been identified, shedding new light on the
pathophysiology of epilepsy as these diseases are
caused by ion channel mutations. Although epileptic
syndromes differ pathophysiologically, common ictogenesis-related characteristics as increased neuronal
excitability and synchronicity are shared as well as
mechanisms involved in interictal-ictal transition.
Emerging insights point to alterations of synaptic functions and intrinsic properties of neurons as common
mechanisms underlying hyperexcitability. This work
also reviews the neurochemical mechanisms of epilepsy.
An imbalance between glutamate and g-aminobutyric
acid neurotransmitter systems can lead to hyperexcitability but catecholaminergic neurotransmitter systems and opioid peptides were shown to play a role in
epileptogenesis as well. An overview of currently available anti-epileptic drugs and their presumed mechanisms of action is given as an illustration of the neurochemistry of epileptogenesis. Most anti-epileptic drugs
exert their anti-epileptic properties through only a few
neurochemical mechanisms that are meanwhile basic
pathophysiological mechanisms thought to cause
seizures.
Key words : Epilepsy ; pathophysiology ; epileptogenesis ; ictogenesis ; neurochemistry ; anti-epileptic drugs.
1. Introduction
Several decades have been devoted to the study
of the pathophysiology of epilepsy. Increasing
knowledge in the field only contributed to a partial
understanding of the underlying mechanisms.
Nevertheless, insight in the pathophysiology of
epilepsy and its underlying histological and neurochemical alterations has contributed to rational
development strategies of new anti-epileptic drugs
(AEDs).
Although various epileptic syndromes were
shown to differ pathophysiologically, they appar-
ently share common ictogenesis-related characteristics such as increased neuronal excitability and
synchronicity. Emerging insights point to alterations of synaptic functions and intrinsic properties
of neurons as common mechanisms underlying
hyperexcitability. Progress in the field of molecular
genetics revealed arguments in favor of this
hypothesis as mutations of genes encoding ion
channels were recently discovered in some forms
of human epilepsy.
This work reviews the current knowledge on the
pathophysiology of epilepsy with special emphasis
on ictogenesis, mechanisms of interictal-ictal transition and neurochemical mechanisms underlying
epilepsy. Where possible, examples concerning
pathophysiological mechanisms underlying distinct epileptic syndromes will be given.
2. Pathophysiology of epilepsy
Epileptic seizures arise from an excessively synchronous and sustained discharge of a group of
neurons. The single feature of all epileptic syndromes is a persistent increase of neuronal
excitability. Abnormal cellular discharges may be
associated with a variety of causative factors such
as trauma, oxygen deprivation, tumors, infection,
and metabolic derangements. However, no specific
causative factors are found in about half of the
patients suffering from epilepsy.
Underlying causes and pathophysiological
mechanisms are (partially) understood for some
forms of epilepsy, e.g. epilepsies caused by disorders of neuronal migration and monogenic epilepsies. For several other types of epilepsy, current
knowledge is only fragmentary.
2.1. DISORDERS OF NEURONAL MIGRATION
The major developmental disorders giving rise
to epilepsy are disorders of neuronal migration that
may have genetic or intrauterine causes (Meldrum,
1994). Abnormal patterns of neuronal migration
lead to various forms of agyria or pachygyria
whereas lesser degrees of failure of neuronal
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migration induce neuronal heterotopia in the subcortical white matter. Recent experimental data
suggest that cortical malformations can both form
epileptogenic foci and alter brain development in a
manner that diffuse hyperexcitability of the cortical
network occurs (Chevassus au Louis et al., 1999).
Other studies revealed increases in postsynaptic
glutamate receptors and decreases in g-aminobutyric acid (GABA) (A) receptors in microgyric cortex which could promote epileptogenesis (Jacobs et
al., 1999).
Tuberous sclerosis is a developmental disorder
with autosomal dominant inheritance in which disordered neuronal migration and epilepsy are commonly found. Periventricular heterotopia is an Xlinked dominant disorder of cerebral cortical development. Fox et al. (1998) showed that mutations in
the filamin 1 gene prevent migration of cerebral
cortical neurons causing periventricular heterotopia. Affected females present with epilepsy
whereas affected males die embryonically.
Recently, however, a male patient with bilateral
periventricular and subcortical heterotopia was
described which raises the possibility of a novel
gene involved in brain formation (Sisodiya et al.,
2000). X-linked lissencephaly and double cortex
syndrome is another disorder of neuronal migration. Double cortex or subcortical band heterotopia
often occurs in females whereas more severe
lissencephaly is found in affected males. A causal
mutation in a gene called doublecortin was recently identified (Gleeson et al., 1998). It was suggested that doublecortin acts as an intracellular signaling molecule critical for the migration of developing neurons (Allen and Walsh, 1999).
Although these disorders are relatively rare,
studying the underlying pathophysiological mechanisms may shed light on the pathophysiology of
more common epileptic syndromes.
2.2. GENETICS OF HUMAN EPILEPSY
Epilepsies with complex inheritance
About 40% of patients suffering from epilepsy
have a genetic background that contributes to the
aetiology of epilepsy (Gardiner, 2000). Most familial epilepsies like juvenile myoclonic epilepsy,
childhood absence epilepsy, and benign childhood
epilepsy with centrotemporal spikes have a complex mode of inheritance resulting from the interaction of several loci together with environmental
factors (McNamara, 1999).
In patients with absence seizures (and their first
degree relatives), biochemical changes (e.g.
increased plasma glutamate levels) have been identified which can be related to a generalized increase
in cortical excitability (Van Gelder et al., 1980).
Probably, the genetic predisposition of absence
epilepsy is based on a gene-dependent biochemical
derangement leading to increased cortical
excitability. Genetic data generated by studies on
animal models of absence epilepsy show a relative
simple inheritance factor of one gene that determines being epileptic or not while other genes
determine number and duration of epileptic fits
(Renier and Coenen, 2000).
Monogenic epilepsies
Monogenic epileptic disorders are rare, accounting for no more than 1% of patients. Recent
advances in the genetics and molecular biology of
these diseases unravelled the underlying pathophysiology of some of these epileptic syndromes.
In 1996, Berkovic et al. described a new epileptic syndrome : familial temporal lobe epilepsy.
Simple partial seizures with psychic or autonomic
symptoms are frequently occurring seizure types
whereas complex partial fits are infrequent.
Pedigree analysis suggested autosomal dominant
inheritance with age-dependent penetrance
(Berkovic et al., 1996). Linkage to chromosome
10q has been reported in one family but the genetic defect remains to be elucidated (Berkovic and
Scheffer, 1997a).
Autosomal dominant partial epilepsy with auditory features is characterized by auditory hallucinations, although other sensory symptoms have been
reported as well (Winamer et al., 2000). Clinical
semiology points to a lateral temporal localization
which is supported by electroencephalogram
(EEG)-data that revealed inconstant focal abnormalities over both temporal regions (Michelucci et
al., 2000). In a single case, brain Magnetic
Resonance Imaging (MRI) showed atrophy with an
increased T2 signal in the lateral portion of the
right temporal lobe (Michelucci et al., 2000). This
epileptic syndrome was found to be linked to chromosome 10q22-24 (Winamer et al., 2000).
Gene defects underlying four other monogenic
epilepsies (generalized epilepsy with febrile
seizures, autosomal dominant nocturnal frontal
lobe epilepsy, benign familial neonatal convulsions
and episodic ataxia type 1 with partial seizures)
have recently been identified, shedding new light
on the pathophysiology of epilepsy as these diseases are caused by ion channel mutations
(Steinlein, 1998 ; Zuberi et al., 1999).
Generalized epilepsy with febrile seizures type I
is an autosomal dominant epileptic syndrome that
is caused by a point mutation in the b1-subunit of a
voltage-gated Na+ channel (Wallace et al., 1998)
whereas type II is caused by a point mutation in the
a1-subunit of a voltage-gated Na+ channel (Escayg
et al., 2000). These mutations cause distinct types
of epilepsy in different members of the same family, which may result from inheritance of the mutant
gene in the context of other susceptibility genes or
environmental factors (McNamara, 1999).
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203
Benign familial neonatal convulsions is a syndrome that is inherited in an autosomal dominant
pattern. Mutations of two distinct but related voltage-gated K+ channel genes have been identified
(Biervert et al., 1998). Although both genes
(KCNQ2 and KCNQ3) are located on different
chromosomes (20q and 8q respectively), their coexpression explains how these 2 different mutations cause an identical disease phenotype.
In some families, autosomal dominant nocturnal
frontal lobe epilepsy is caused by a point mutation
in a gene on chromosome 20q (CHRNA4), encoding the a4 subunit of the neuronal nicotinic acetylcholine (ACh) receptor (Steinlein et al., 1995). At
least some ACh receptors are located presynaptically, thus promoting the release of neurotransmitters as GABA. The mutant receptor causes a reduction of ACh-mediated Ca2+ flux, which results in
a decrease of GABA released from presynaptic
terminals leading to synaptic disinhibition
(McNamara, 1999). However, the majority of the
families with autosomal dominant nocturnal
frontal-lobe epilepsy are not linked to CHRNA4,
indicating the presence of genetic heterogeneity
(Gardiner, 2000).
Episodic ataxia type 1 is a rare autosomal dominant disorder, characterized by brief episodes of
ataxia associated with myokymia (Zuberi et al.,
1999). The patients suffering from this syndrome
also show partial epileptic fits. The syndrome is
associated with point mutations in the human voltage-gated potassium channel gene on chromosome
12p13 (Zuberi et al., 1999). As potassium channels
determine the excitability of neurons, it is suggested that this mutation is pathogenic (Zuberi et al.,
1999).
These recent discoveries illustrate that ion channel dysfunctions can play a crucial role in the
pathophysiology of epilepsy. As several AEDs act
on ion channels, these findings are relevant to other
epileptic syndromes in man.
metabolism at the medial thalamic nucleus (Juhász
et al., 1999). These findings are common and have
strong lateralization value for the seizure focus in
human temporal lobe epilepsy. The decreased benzodiazepine receptor binding possibly reflects neuronal loss but may also indicate decreased benzodiazepine receptor density in the medial thalamic
nucleus which remains to be elucidated. This structure may indeed play an important role in temporal
lobe epilepsy as the nucleus medialis thamali has
strong reciprocal connections with other parts of
the limbic system (Engelborghs et al., 1998b ;
Juhász et al., 1999). Interictal PET studies revealed
increased glucose metabolism and FMZ binding in
the lateral thalamus of patients with temporal lobe
epilepsy, possibly reflecting an upregulation of
GABA-mediated inhibitory circuits (Juhász et al.,
1999).
A recent study investigated expression and distribution of GABA(A)-receptors in the hippocampus of pilocarpine-treated rats (Fritschy et al.,
1999). A loss of a critical number of interneurons
in the gyrus dentatus was noticed, which might
play a role in seizure initiation (Fritschy et al.,
1999). Meanwhile, long-lasting upregulation of
GABA(A)-receptors in granule cells was found,
which might represent a compensatory response to
seizure activity (Fritschy et al., 1999). Central benzodiazepine receptor density in the CA1 region was
shown to be significantly reduced by means of
autoradiography in post-mortem samples of
patients with hippocampal sclerosis (Hand et al.,
1997). On the other hand, affinity for FM2 was
increased in subiculum and gyrus dentatus (Hand et
al., 1997). Other publications suggest that enhanced sensitivity to glutamate may be an important element in the pathophysiology of temporal
lobe epilepsy as a quantitative autoradiographic
analysis of ionotropic glutamate receptor subtypes
revealed an upregulation in the reorganized human
epileptogenic hippocampus (Brines et al., 1997).
2.3. PATHOPHYSIOLOGY OF DISTINCT TYPES OF EPILEPSY
Gelastic epilepsy
Mesial temporal lobe epilepsy
Mesial temporal lobe epilepsy is characterized
by recurrent complex partial seizures and hippocampal sclerosis. Ipsilateral to the epileptogenic
focus, hippocampal neuronal loss results in significantly reduced hippocampal volumes as measured
by means of MRI (Jokeit et al., 1999). Besides hippocampal volumetry, MR proton spectroscopy was
shown to be a valuable tool to correctly lateralize
patients with mesial temporal lobe epilepsy
(Kuzniecky et al., 1998). In patients with
intractable temporal lobe epilepsy, interictal
Positron Emission Tomography (PET) studies
found decreased [11C]flumazenil (FMZ) binding
(benzodiazepine receptor binding) and glucose
Gelastic seizures are frequently caused by hypothalamic hamartomas (Engelborghs et al., 2000). In
a series of 9 patients with gelastic seizures, 4 had
hypothalamic hamartoma (Striano et al., 1999).
Hypothalamic hamartomas are rare congenital malformations and often present as a clinical syndrome, characterized by pubertas praecox, mental
retardation, and gelastic seizures. Later, refractory
epilepsy with multiple seizure types develops.
Patients with hypothalamic hamartoma may as well
have focal epileptiform discharges in the anterior
temporal or frontal lobe on ictal electrocorticographic recordings but focal cortical resection was
shown not to affect seizure frequency (Cascino et
al., 1993). According to depth electrode data showing ictal onset from the lesion, seizures seem to
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begin in the intrinsically epileptogenic hamartoma
(Munari et al., 1995 ; Kuzniecky et al., 1997). Ictal
single-photon emission computed tomography performed during typical gelastic seizures demonstrated hyperperfusion in the hamartoma and the hypothalamic region (Kuzniecky et al., 1997). Moreover, complete surgical extirpation or a gamma
knife radiosurgical treatment of the hypothalamic
hamartoma results in seizure remission (Kuzniecky
et al., 1997 ; Georgakoulias et al., 1998 ; Unger et
al., 2000). It therefore seems probable that epileptic discharges arise in the hypothalamus and spread
via hypothalamic-amygdala connections to produce focal temporal lobe ictal discharges (Saper,
1990 ; Berkovic et al., 1997b).
Rasmussen encephalitis
Rasmussen encephalitis is a rare, progressive,
neurodegenerative illness of unknown cause that
typically affects children in the first decade of life
(Rasmussen et al., 1958). Severe seizures that are
refractory to anti-epileptic medication, hemispheric atrophy, and dementia are cardinal features of
this disease. Rabbits immunized with glutamate
receptor subunit 3 (GluR3) protein developed
epilepsy and cerebral histopathological changes
characteristic of Rasmussen encephalitis (Rogers et
al., 1994). This led to the discovery of anti-GluR3
antibodies in serum of patients with Rasmussen
encephalitis (Rogers et al., 1994). Effectiveness of
plasma exchanges or intravenous immunoglobin
therapy as treatment of Rasmussen encephalitis
was demonstrated in a series of patients (Andrews
et al., 1996 ; Topcu et al., 1999), which further
proves the auto-immune pathogenesis of Rasmussen encephalitis.
Insights gained from the study of Rasmussen
encephalitis may help to increase our knowledge
about more common forms of epilepsy. Some
patients undergoing temporal lobectomy for refractory epilepsy show localized inflammatory histopathological changes and increased auto-antibodies
in serum (Dambinova et al., 1997 ; Peltola et al.,
2000) ; whether or not this is caused by an autoimmune pathogenesis remains to be elucidated
(McNamara, 1999).
3. Kindling and epileptogenesis
Goddard (1967) was the first to describe that
periodic stimulation of neural pathways progressively leads to recurrent behavioral and electrographic seizures. Kindling procedures have provided a substrate for the study of the role of enhanced
synaptic efficacy in seizure disorders. It is now
considered to be a first choice experimental procedure in the study of the potential mechanisms of
epileptogenesis. The phenomenon can be evoked in
various brain regions, but amygdala kindling is
most frequently used in epilepsy research as a
model for complex partial seizures (Fisher, 1989).
Although kindling has been shown to be phenomenologically different from other types of plastic
changes in the central nervous system (Sutula,
1991), there are many points of similarity between
kindling and the process of long-term potentiation.
Kindling has been shown to depend upon functional as well as structural changes in glutamatergic
synapses. The anticonvulsant effects of glutamate
receptor blocking agents like NMDA antagonists
seem to be at least partly due to their inhibitory
effects on in vitro kindling.
4. Ictogenesis
Excitability is a key feature of ictogenesis that
may originate from individual neurons, neuronal
environment or a population of neurons (Traub et
al., 1996). Excitability arising from single neurons
may be caused by alterations in membrane or metabolic properties of individual neurons. When regulation of environmental, extracellular concentrations of ions or neurotransmitters is suboptimal, the
resulting imbalance might enhance neuronal excitation. Collective anatomic or physiologic neuronal
alterations may convert neurons into a hyperexcitable neuronal population. In reality, these three
theoretical mechanisms are thought to interact during specific ictal episodes. Each epileptic focus is
unique as the differential contribution of these three
concepts leading to ictal events is thought to differ
from focus to focus.
4.1. EXCITABILITY ARISING FROM INDIVIDUAL NEURONS
Functional and perhaps structural changes occur
in the postsynaptic membrane, thus altering the
character of receptor protein - conductance channels, thereby favoring development of paroxysmal
depolarizing shift (PDS) and enhanced excitability.
Epileptic neurons appear to have increased Ca2+
conductance. It may be that latent Ca2+ channels are
used, that the efficacy of Ca2+ channels is increased
or that the number of Ca2+ channels is chronically
elevated. However, development of burst activity
depends on the net inward current and not on the
absolute magnitude of the inward current. When
extracellular K+ concentrations are increased (as
during seizure activity), the K+ equilibrium across
the neuronal membrane is reduced, resulting in
reduced outward K+ currents. The net current will
become inward, depolarizing the neuron to the
extent that Ca2+ currents will be triggered. This
results in a PDS and a burst of spikes (Fig. 1)
(Dichter, 1997).
4.2. EXCITABILITY
ARISING FROM NEURONAL MICRO-
ENVIRONMENT
Both functional and structural alterations occur
in epileptic foci. The functional changes involve
PATHOPHYSIOLOGY OF EPILEPSY
205
MFS was demonstrated in patients with refractory temporal lobe epilepsy with hippocampal sclerosis on neuroimaging as well as in numerous animal
models of temporal lobe epilepsy (Sutula et al.,
1988 ; Sutula et al., 1989). In normal conditions,
the dentate granule cells limit seizure propagation
through the hippocampal network. However, the
formation of recurrent excitatory synapses between
dentate granule cells, as is thought to occur after
MFS, may transform the dentate granule cells into
an epileptogenic population of neurons (Figure 2)
(McNamara et al., 1999). Possibly, a vicious circle
develops : seizures cause neuronal death which
results in MFS which in turn increases seizure frequency.
FIG. 1. — The hallmark of a discharge is the paroxysmal
depolarization shift. The ability to record such events at the
scalp suggests that numerous neurons are firing in synchrony
(From : Browne T.R., Feldman R.G., eds. Epilepsy : Diagnosis
and Management. Boston : Little, Brown and Company, 1983,
p.12).
concentrations of cations and anions, metabolic
alterations, and changes in neurotransmitter levels.
The structural changes involve both neurons and
glia. Excessive extracellular K+ depolarizes neurons and leads to spike discharge. During seizures,
changes in extracellular Ca2+ (a decrease of 85%)
precede those of K+ by milliseconds and Ca2+ levels
return to normal more quickly than K+.
Glia are able to clear neurotransmitters from the
extracellular space and to buffer K+ thus correcting
the increased extracellular K+ concentrations that
occur during seizures. Epileptic foci may show proliferation of glia that differ however in morphological and physiological properties (Bordey and
Sontheimer, 1998). Gliosis will affect glial K+
buffering capacity and hence may contribute to
seizure generation (Grisar et al., 1999).
4.3. THE EPILEPTIC CELL POPULATION
Collective anatomic or physiologic neuronal
alterations might produce progressive, networkdependent facilitation of excitability, perhaps coupled with a decrease of inhibitory influences, e.g.
due to selective loss of inhibitory neurons. Mossy
fiber sprouting (MFS) is an example of neuronal
alterations leading to increased excitability
(Cavazos et al., 1991).
FIG. 2. — Many central neurons burst, but rarely in a prolonged manner (panel A). In an epileptic focus, neurons burst
spontaneously and for prolonged periods (note the paroxysmal
depolarization shift) (panel B).
5. Mechanisms of interictal-ictal transition
Mechanisms producing signal amplification,
synchronicity, and spread of activity are likely to be
involved in interictal-ictal transitions. Different
theoretical mechanisms of interictal-ictal transition
are summarized in table 1 and discussed in the following section. In vivo, interictal-ictal transition
can seldom be attributed to one theoretical mechanism, but often results from the interaction of different mechanisms.
5.1. NONSYNAPTIC MECHANISMS
Alterations in ionic microenvironment
Repetitive ictal and interictal activity causes
increases in extracellular K+ leading to increased
neuronal excitability (Moody et al., 1974). Some
neurons are very sensitive to changes in membrane
K+ currents, e.g. pyramidal cells in the CA1 region
of the hippocampus (Rutecki et al., 1985).
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Table 1
Summary of mechanisms of interictal-ictal transition
Nonsynaptic mechanisms
1. Alterations in ionic microenvironment ; e.g. increased
extracellular K+, decreased extracellular Ca++
2. Decreases in size of extracellular space
3. Failure of ion transport : Na+-K+ pump or Cl--K+ co-transport
4. Presynaptic terminal bursting
5. Ephaptic interactions
Synaptic mechanisms
1.
2.
3.
4.
Depression of GABA-ergic inhibition
NMDA receptor activation ; voltage-dependent EPSPs
Frequency potentiation of EPSPs
Actions of modulators
Active ion transport
Activation of the Na+-K+ pump is important for
regulation of neuronal excitability during excessive
neuronal discharges (Ayala et al., 1970). Substances like ouabain that block the Na+-K+ pump
can induce epileptogenesis in animal models.
Hypoxia or ischemia can result in Na+-K+ pump
failure thus promoting interictal-ictal transition.
A Cl--K+ co-transport mechanism controls the
intracellular Cl- concentration and the Cl- gradient
across the cell membrane which regulates effectiveness of GABA-activated inhibitory Cl- currents.
Interference with this process could cause a progressive decrease in the effectiveness of GABAergic inhibition leading to increased excitability
(Prince, 1988).
Presynaptic terminal bursting
The amount of transmitter released is related to
depolarization of presynaptic terminals. Changes in
axon terminal excitability will have effects on
synaptic excitation (Prince, 1988).
Abnormal bursts of action potentials occur in the
axonal arborizations of thalamocortical relay cells
during epileptogenesis. Since one thalamocortical
relay cell ends on a large number of cortical neurons, synchronization can occur which might play
an important role in interictal-ictal transition
(Engelborghs et al., 1998b).
Ephaptic interaction
Ephaptic interactions are produced when currents from activated neurons excite adjacent neurons in the absence of synaptic connections.
Ephaptic effects are strongly dependent on the size
of the extracellular space. When extracellular space
is small, ephaptic interactions are promoted (Traub
et al., 1985).
5.2. SYNAPTIC MECHANISMS
Two theoretical mechanisms can occur :
decreased effectiveness of inhibitory synaptic
mechanisms or facilitation of excitatory synaptic
events. Both mechanisms will be discussed in the
following section.
6. Neurochemical mechanisms underlying
epilepsy
6.1. GABA
The GABA hypothesis of epilepsy implies that a
reduction of GABA-ergic inhibition results in
epilepsy whereas an enhancement of GABA-ergic
inhibition results in an anti-epileptic effect (De
Deyn et al., 1990). Inhibitory postsynaptic potentials (IPSPs) gradually decrease in amplitude during repetitive activation of cortical circuits. This
phenomenon might be caused by decreases in
GABA release from terminals, desensitization of
GABA receptors that are coupled to increases in Clconductance or alterations in the ionic gradient
because of intracellular accumulation of Cl- (Wong
and Watkins, 1982). In case of intracellular accumulation of Cl-, passive redistribution is ineffective.
Moreover, Cl--K+ co-transport becomes less effective during seizures as it depends on the K+ gradient. As Cl--K+ co-transport depends on metabolic
processes, its effectiveness may be affected by
hypoxia or ischemia as well. These mechanisms
may play a critical role in ictogenesis and interictal-ictal transition.
Several studies have shown that GABA is
involved in pathophysiology of epilepsy in both
animal models and patients suffering from epilepsy. GABA levels and glutamic acid decarboxylase
(GAD) activity were shown to be reduced in
epileptic foci surgically excised from patients with
intractable epilepsy and in CSF of patients with
certain types of epilepsy (De Deyn et al., 1990). In
stiff-man syndrome, a disease associated with
epilepsy and diabetes mellitus, auto-antibodies to
GAD were demonstrated (Solimena et al., 1988). A
reduction of 3H-GABA binding has been reported
in human brain tissue from epileptic patients
whereas PET studies demonstrated reduced benzodiazepine receptor binding in human epileptic foci
(Savic et al., 1996). The degree of benzodiazepine
receptor reduction showed a positive correlation
with seizure frequency.
The GABA receptor complex is involved in various animal models of epilepsy as well. Low CSF
levels of GABA were revealed in dogs with epilepsy (Löscher and Swartz-Porsche, 1986). Reduced GAD levels were revealed in the substantia
nigra of amygdala-kindled rats (Löscher and
Schwark, 1985). Significant alterations in GABA
and benzodiazepine binding have been shown in
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the substantia nigra of genetically seizure-prone
gerbils (Olsen et al., 1985). Mice with a genetic
susceptibility to audiogenic seizures have a lower
number of GABA receptors than animals of the
same strain that are not seizure prone (Horton et
al., 1982).
Several endogenous (guanidino compounds) and
exogenous (e.g. bicuculline, picrotoxin, penicillin,
pilocarpine, pentylenetetrazol) convulsants inhibit
GABAergic transmission through inhibition of
GABA synthesis or through interaction with distinct sites at the postsynaptic GABA(A) receptor
(De Deyn and Macdonald, 1990 ; De Deyn et al.,
1992 ; D’Hooge et al. 1999). Convulsant agents
that block synaptic GABA-mediated inhibition,
amplify the dendritic spike-generating mechanism
that involves Ca2+ (Dichter and Ayala, 1987 ;
Fisher, 1989). Synaptic inputs are thought to trigger and synchronize this process throughout a population of cells which then might result in an
epileptic fit.
Several AEDs are GABA analogues, block
GABA metabolism (e.g. vigabatrin, tiagabine,
valproate) or facilitate postsynaptic effects of
GABA. However, a study evaluating dose-dependent behavioral effects of single doses of vigabatrin
in audiogenic sensitive rats, suggests that the antiepileptic properties of vigabatrin not only depend
on GABA-ergic neurotransmission but might also
be explained by decreased central nervous
system levels of excitatory amino acids or
increased glycine concentrations (Engelborghs et
al., 1998a).
6.2. GLUTAMATE
Glutamatergic synapses play a critical role in all
epileptic phenomena. Activation of both ionotropic
and metabotropic postsynaptic glutamate receptors
is proconvulsant. Antagonists of N-methyl-Daspartate (NMDA) receptors are powerful anti-convulsants in many animal models of epilepsy.
Several genetic alterations have been shown to be
epileptogenic in animal models but no specific
mutation relating to glutamatergic function has yet
been linked to a human epilepsy syndrome.
Nevertheless, there is evidence for altered NMDA
receptor function in acquired epilepsy in animal
models and in men. An increased sensitivity to the
action of glutamate at NMDA receptors is seen in
hippocampal slices from kindled rats and in cortical slices from cortical foci in human epilepsy
(Hwa and Avoli, 1992). This results in an enhanced
entry of Ca2+ into neurons during synaptic activity
(Louvel and Pumain, 1992). Changes in
metabotropic glutamate receptor function may also
play a key role in epileptogenesis (Chapman,
1998).
Epileptic seizures and epilepsy form frequent
complications of uremia. As a possible underlying
mechanism, we have demonstrated the accumulation of a series of uremic guanidino compounds
which were shown to inhibit GABA-ergic neurotransmission (De Deyn and Macdonald, 1990). One
of these endogenous agents was in addition shown
to be an agonist at the excitatory NMDA receptor
(D’Hooge et al., 1996 ; De Deyn et al., in press
(a)).
In patients with absence seizures, plasma glutamate levels were found to be significantly
increased (Van Gelder et al., 1980). Neuronal
membranes are exposed to increased amounts of
extracellular glutamate thus increasing neuronal
excitability. A recent study on a genetic rat model
of epilepsy (WAG/RIJ rats ; spontaneous spikewave (SW) discharges accompanied by behavioral
abnormalities) provides evidence for an interaction
of glutamatergic and serotonergic mechanisms in
the triggering and maintenance of epilepsy
(Filakovszky et al., 1999). Intracerebroventricular
injection of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5HT1A receptor agonist,
caused marked increase of the cumulative duration
and number of SW discharges whereas dizocilpine
(MK-801), a NMDA receptor antagonist, decreases
SW discharges (Gerber et al., 1998). Both substances opposed each other’s effects in this rat
model of epilepsy.
6.3. CATECHOLAMINES
Abnormalities of CNS catecholamines have
been reported in several genetic models of epilepsy. In spontaneous epileptic rat, dopamine was
decreased in the nucleus caudatus whereas noradrenaline was increased in midbrain and brainstem
(Hara et al., 1993). Decreased levels of dopamine
have been found in epileptic foci of epilepsy
patients (Mori et al., 1987). In animal models of
absence epilepsy, seizures are exacerbated by
dopamine antagonists while fits are alleviated by
dopamine agonists (Snead, 1995). These results
suggest that decreased dopamine facilitates appearance of seizures by lowering the threshold triggering such seizures.
Tottering mice have an absence-like syndrome
that is characterized by episodes of behavioral
arrest associated with 6 to 7 Hz cortical SW EEG
discharges. Selective destruction of the ascending
noradrenergic system at birth prevents the onset of
the syndrome. Therefore, it has been suggested that
the syndrome is caused by a noradrenergic hyperinnervation of the forebrain (Meldrum, 1994).
Recent data indicate that the serotonergic system
regulates epileptiform activity in a genetic rat
model of absence epilepsy as intraperitoneal or
intracerebroventricular administration of 8-OHDPAT caused marked and dose-dependent increases in number and duration of SW discharges
(Gerber et al., 1998).
208
S. ENGELBORGHS ET AL.
6.4. OPIOID PEPTIDES
Established AEDs decrease neuronal membrane
excitability by interacting with ion channels or neurotransmitter receptor complexes. AEDs that
decrease membrane excitability through interaction
with ion channels act on sodium and calcium channels. Most AEDs that interact with neurotransmitter complexes promote inhibitory GABA-ergic
neurotransmission although some more recently
developed drugs act through inhibition of excitatory neurotransmission as well. The most frequently
used AEDs and their (presumed) mechanisms of
action are summarized in table 3.
Numerous AEDs interfere with ion channel
functioning. Both ethosuximide and valproate
block voltage-dependent Ca++ channels of the Ttype which explains their anti-epileptic efficacy in
generalized absence epilepsy (Stefani et al., 1997).
Carbamazepine, felbamate, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate and
zonisamide are known to reduce voltage-dependent
Na+ currents.
Several established AEDs promote inhibitory
neurotransmission. Vigabatrin is an enzymeactivated irreversible inhibitor of GABA-transaminase and has a weaker GABA uptake inhibitory
effect whereas tiagabine is a pure GABA uptake
inhibitor. Both AEDs thus increase the functional
pool of GABA. Benzodiazepines enhance GABAergic inhibition through interaction with the GABA
(A) receptor. Till present, progabide is the only
AED exerting GABA agonistic effects at both type
A and B sites. Several other AEDs have (weaker)
GABA-ergic properties but act on other mechanisms as well. The main mechanism underlying
phenobarbital’s anti-epileptic effects is attributed to
In experimental studies, opioids and opioid peptides had both convulsant and anticonvulsant properties (Meldrum, 1994). Kappa agonists suppress
SW discharges in an animal model of abscence
epilepsy (Przewlocka et al., 1995). Peptides with a
m agonist action induce hippocampal or limbic
seizures when administered intraventricularly possibly due to inhibition of inhibiting interneurons. In
patients with complex partial seizures, PET studies
pointed out that m receptor density is increased in
the temporal cortex (Mayberg et al., 1991).
7. Pathophysiology of epilepsy and mechanisms of action of AEDs
(Levy et al., 1995 ; Macdonald and Kelly, 1995 ;
Thomas, 1999)
Most of the presently used AEDs were discovered by screening without a rationale as to the
mechanism of action. As knowledge on the pathophysiology of epilepsy increases and the mechanisms of action of most AEDs are at least partially
unravelled, it becomes clear that most AEDs exert
their anti-epileptic properties through only a few
neurochemical mechanisms that are meanwhile
basic pathophysiological mechanisms thought to
cause epileptic fits (table 2). Thanks to increased
use of animal models of epilepsy, a better insight in
the pathophysiology of epilepsy and improved
knowledge on mechanisms of action of AEDs, several new more rationally designed AEDs were
developed and marketed during the past decade (De
Deyn et al., in press (b)).
Table 2
Correlation between mechanisms of epileptogenesis and mechanisms of action of AEDs
Mechanisms of epileptogenesis
GABA
●
●
●
●
●
Glu
●
●
●
Reduced GABA in microgyric cortex
Reduced benzodiazepine receptor binding in medial
thalamic nucleus (mesial temporal lobe epilepsy)
Reduced benzodiazepine receptor density in CA1 region
(hippocampal sclerosis)
Reduced GABA levels and GAD activity (epileptic foci)
Auto-antibodies to GAD (Stiff-man syndrome)
Upregulation of hippocampal ionotropic glutamate
receptors (temporal lobe epilepsy)
Anti-gluR3 antibodies (Rasmussen encephalitis)
Increased plasma glutamate levels (absence seizures)
Na+
●
Mutation voltage-gated Na+ channel (generalized
epilepsy with febrile seizures)
K+
●
Mutation voltage-gated K+ channel
(benign familial neonatal convulsions)
Ca++
●
Reduced ACh-mediated Ca flux
(nocturnal frontal lobe epilepsy)
→ Increased membrane excitability
Mechanisms of actions of AEDs
●
●
●
●
●
●
Increased functional pool of GABA (vigabatrin, tiagabine)
Enhanced GABA-ergic inhibition (benzodiazepines)
GABA agonistic effects (progabide)
(Weaker) GABA-ergic properties (phenobarbital,
gabapentin, topiramate, valproate, zonisamide)
Inhibition of glutamate release (lamotrigine)
Block of glycine site at NMDA receptor (felbamate)
●
Reduction of voltage-gated Na+ currents (carbamazepine,
felbamate, lamotrigine, oxcarbazepine, phenytoin,
topiramate, valproate, zonisamide)
●
Reduction of T-type Ca++ currents (ethosuximide, valproate)
→ Decreased membrane excitability
PATHOPHYSIOLOGY OF EPILEPSY
209
Table 3
Mechanisms of actions of anti-epileptic agents
Anti-epileptic agent
Mechanism(s) of action
Benzodiazepines
Enhances GABA action
Reduces sustained repetitive firing
Blocks voltage-dependent Na+ channels
Limitation of sustained repetitive firing
Reducing T-type Ca++ currents
Blocking synchronized thalamic firing
Inhibition of glutamatergic neurotransmission (reduces NMDA action, blocks glycine-site on
NMDA receptor)
GABA potentiation
Blocks voltage-dependent Na+ channels
Blocks L-type Ca++ channels
GABA analog but does not bind to GABA receptors
Increases synaptic GABA : activation of Glutamic Acid Decarboxylase ?
May block amino acid transporter
Binds to voltage-dependent Ca++channels Æ reduced intraneuronal concentration of Ca++
Possibly : inactivation of Na+ channels
Reduces glutamate release
Inhibits voltage-activated Ca++ currents, blocks voltage-dependent Na+ channels
Unknown mechanism of action
Increases seizure threshold and inhibits seizure spread in kindled rats
Inhibition of voltage-dependent Na+ channels
Inhibition of voltage-activated Ca++ currents
Enhances GABA action
Reduces sustained repetitive firing
Reduces voltage-dependent Ca++ currents
Blocks voltage-gated Na+ channels
Reduces Ca++ currents
Reduces sustained repetitive firing - blocks voltage-dependent Na+ currents
GABA agonist at A and B sites
NMDA receptor antagonist
Inactivation of Na+ channels
Neuronal and glial GABA-uptake inhibitor
Na+ channel block
Reduction of L-type Ca++ currents
Potentiation of GABA at the GABA(A) receptor : enhancement of Cl- flux
Inhibition of glutamatergic neurotransmission : weak block of AMPA/kainate receptors
Inhibition of carbonic anhydrase
Increases CNS GABA levels by increased synthesis and reduced catabolism
Blocks T-type Ca++ currents
Enhances Na+ channel inactivation
GABA-Transaminase inhibitor
Inhibits GABA uptake
Blocks Na+ channels
Blocks T-type Ca++ channels
Enhances GABA action
Inhibition of carbonic anhydrase
Carbamazepine
Ethosuximide
Felbamate
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Phenobarbital
Phenytoin
Primidone
Progabide
Remacemide
Tiagabine
Topiramate
Valproate
Vigabatrin
Zonisamide
the reduction of voltage-dependent Ca++ currents
although this drug enhances GABA-ergic neurotransmission as well. Gabapentin, topiramate, valproate and zonisamide are other examples of drugs
that have amongst others GABA-ergic properties.
Lamotrigine is currently the best example of a
drug acting through excitatory neurotransmission
as it inhibits the release excitatory amino acids,
especially glutamate. Although lamotrigine also
blocks ion channels, its effect on glutamate release
is thought to be primarily responsible for antiepileptic properties. Felbamate blocks the glycine
site at the NMDA receptor which is at least partially related to its anti-epileptic effects. Besides ion
channel inhibition and potentiation of GABA-ergic
neurotransmission, topiramate interferes with excitatory neurotransmission as it weakly blocks
amino-3-hydroxy-5-methyl-4-isoxazole propionic
acid (AMPA) receptors.
A link between from one side the preclinical
profile and mechanisms of action of AEDs and
from the other side clinical profile can be made. In
general, AEDs exerting anti-epileptic properties
through interaction with one single mechanism of
action, have a narrow clinical profile (e.g. ethosuximide). However, most AEDs interfere with a combination of basic mechanisms of anti-epileptic
action such as inhibitory neurotransmission and Na
210
S. ENGELBORGHS ET AL.
and/or Ca channel functioning (e.g. valproate).
The relative importance of basic mechanisms of
anti-epileptic action involved (partially) determines
the clinical profile of AEDs. Drugs effective
against myoclonic seizures generally enhance
GABA-ergic inhibition. Drugs effective against
generalized tonic-clonic and partial seizures appear
to reduce sustained high-frequency repetitive firing
by delaying recovery of Na+ channels from activation (e.g. carbamazepine, valproate). It has been
suggested that T-type Ca++ channels of thalamic
relay neurons play a critical role in the generation
of 3 Hz spike-and-wave discharges that characterize generalized absence epilepsy. Indeed, drugs that
block T-type Ca++ currents are effective against generalized absence seizures (ethosuximide, valproate).
Conclusions
Although different epileptic syndromes differ
pathophysiologically, ictogenesis-related mechanisms are often shared. The study of rare epileptic
syndromes as monogenic epilepsies shed new light
on ictogenesis and consequently substantially
increased our knowledge and understanding of the
pathophysiology of epilepsy. It now is generally
accepted that ictogenesis mainly results from neuronal membrane hyperexcitability. Both neurotransmitter systems and ion channels play a crucial
role in neuronal excitability.
Most of the presently used AEDs were discovered by screening without a rationale as to the
mechanism of action. As our knowledge on the
pathophysiology of epilepsy increases and the
mechanisms of action of most AEDs are at least
partially unravelled, it becomes clear that most
AEDs exert their anti-epileptic properties through
only a few neurochemical mechanisms leading to
decreased neuronal membrane excitability. At this
point, pathophysiological mechanisms of ictogenesis meet with mechanisms of action of AEDs. This
knowledge allowed linking preclinical mechanisms
of action with clinical profiles of AEDs. A more
detailed understanding of the pathophysiology of
epilepsy and epileptogenesis will thus further contribute to still more specific and efficacious pharmacological interactions in this field of clinical
neurology.
Acknowledgements
This work was supported by Born-Bunge Foundation,
University of Antwerp, Neurosearch Antwerp and Fund
for Scientific Research - Flanders (F.W.O. - Vlaanderen,
grant G.0027.97). S. E. is a Research Assistant and R. D.
is a post-doctoral fellow of the Fund for Scientific
Research - Flanders (F.W.O. - Vlaanderen).
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