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Pathophysiology of epilepsy

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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 ently share common ictogenesis-related character-


This work reviews the current knowledge on epilepto- istics such as increased neuronal excitability and
genesis and pathophysiology of epilepsy. Recently, gene synchronicity. Emerging insights point to alter-
defects underlying four monogenic epilepsies (general- ations of synaptic functions and intrinsic properties
ized epilepsy with febrile seizures, autosomal dominant of neurons as common mechanisms underlying
nocturnal frontal lobe epilepsy, benign familial neonatal hyperexcitability. Progress in the field of molecular
convulsions and episodic ataxia type 1 with partial genetics revealed arguments in favor of this
seizures) have been identified, shedding new light on the hypothesis as mutations of genes encoding ion
pathophysiology of epilepsy as these diseases are channels were recently discovered in some forms
caused by ion channel mutations. Although epileptic of human epilepsy.
syndromes differ pathophysiologically, common ictogen- This work reviews the current knowledge on the
esis-related characteristics as increased neuronal
excitability and synchronicity are shared as well as
pathophysiology of epilepsy with special emphasis
mechanisms involved in interictal-ictal transition. on ictogenesis, mechanisms of interictal-ictal tran-
Emerging insights point to alterations of synaptic func- sition and neurochemical mechanisms underlying
tions and intrinsic properties of neurons as common epilepsy. Where possible, examples concerning
mechanisms underlying hyperexcitability. This work pathophysiological mechanisms underlying dis-
also reviews the neurochemical mechanisms of epilepsy. tinct epileptic syndromes will be given.
An imbalance between glutamate and g-aminobutyric
acid neurotransmitter systems can lead to hyperex-
citability but catecholaminergic neurotransmitter sys- 2. Pathophysiology of epilepsy
tems and opioid peptides were shown to play a role in
epileptogenesis as well. An overview of currently avail- Epileptic seizures arise from an excessively syn-
able anti-epileptic drugs and their presumed mecha- chronous and sustained discharge of a group of
nisms of action is given as an illustration of the neuro- neurons. The single feature of all epileptic syn-
chemistry of epileptogenesis. Most anti-epileptic drugs dromes is a persistent increase of neuronal
exert their anti-epileptic properties through only a few excitability. Abnormal cellular discharges may be
neurochemical mechanisms that are meanwhile basic associated with a variety of causative factors such
pathophysiological mechanisms thought to cause as trauma, oxygen deprivation, tumors, infection,
seizures. and metabolic derangements. However, no specific
Key words : Epilepsy ; pathophysiology ; epileptogene- causative factors are found in about half of the
sis ; ictogenesis ; neurochemistry ; anti-epileptic drugs. patients suffering from epilepsy.
Underlying causes and pathophysiological
mechanisms are (partially) understood for some
1. Introduction forms of epilepsy, e.g. epilepsies caused by disor-
ders of neuronal migration and monogenic epilep-
Several decades have been devoted to the study sies. For several other types of epilepsy, current
of the pathophysiology of epilepsy. Increasing knowledge is only fragmentary.
knowledge in the field only contributed to a partial
understanding of the underlying mechanisms. 2.1. DISORDERS OF NEURONAL MIGRATION
Nevertheless, insight in the pathophysiology of
epilepsy and its underlying histological and neuro- The major developmental disorders giving rise
chemical alterations has contributed to rational to epilepsy are disorders of neuronal migration that
development strategies of new anti-epileptic drugs may have genetic or intrauterine causes (Meldrum,
(AEDs). 1994). Abnormal patterns of neuronal migration
Although various epileptic syndromes were lead to various forms of agyria or pachygyria
shown to differ pathophysiologically, they appar- whereas lesser degrees of failure of neuronal
202 S. ENGELBORGHS ET AL.

migration induce neuronal heterotopia in the sub- derangement leading to increased cortical
cortical white matter. Recent experimental data excitability. Genetic data generated by studies on
suggest that cortical malformations can both form animal models of absence epilepsy show a relative
epileptogenic foci and alter brain development in a simple inheritance factor of one gene that deter-
manner that diffuse hyperexcitability of the cortical mines being epileptic or not while other genes
network occurs (Chevassus au Louis et al., 1999). determine number and duration of epileptic fits
Other studies revealed increases in postsynaptic (Renier and Coenen, 2000).
glutamate receptors and decreases in g-aminobu-
tyric acid (GABA) (A) receptors in microgyric cor- Monogenic epilepsies
tex which could promote epileptogenesis (Jacobs et
Monogenic epileptic disorders are rare, account-
al., 1999).
ing for no more than 1% of patients. Recent
Tuberous sclerosis is a developmental disorder
advances in the genetics and molecular biology of
with autosomal dominant inheritance in which dis-
these diseases unravelled the underlying patho-
ordered neuronal migration and epilepsy are com-
physiology of some of these epileptic syndromes.
monly found. Periventricular heterotopia is an X-
In 1996, Berkovic et al. described a new epilep-
linked dominant disorder of cerebral cortical devel-
tic syndrome : familial temporal lobe epilepsy.
opment. Fox et al. (1998) showed that mutations in
Simple partial seizures with psychic or autonomic
the filamin 1 gene prevent migration of cerebral
symptoms are frequently occurring seizure types
cortical neurons causing periventricular hetero-
whereas complex partial fits are infrequent.
topia. Affected females present with epilepsy
Pedigree analysis suggested autosomal dominant
whereas affected males die embryonically.
inheritance with age-dependent penetrance
Recently, however, a male patient with bilateral
(Berkovic et al., 1996). Linkage to chromosome
periventricular and subcortical heterotopia was
10q has been reported in one family but the genet-
described which raises the possibility of a novel
ic defect remains to be elucidated (Berkovic and
gene involved in brain formation (Sisodiya et al.,
Scheffer, 1997a).
2000). X-linked lissencephaly and double cortex
Autosomal dominant partial epilepsy with audi-
syndrome is another disorder of neuronal migra-
tory features is characterized by auditory hallucina-
tion. Double cortex or subcortical band heterotopia
tions, although other sensory symptoms have been
often occurs in females whereas more severe
reported as well (Winamer et al., 2000). Clinical
lissencephaly is found in affected males. A causal
semiology points to a lateral temporal localization
mutation in a gene called doublecortin was recent-
which is supported by electroencephalogram
ly identified (Gleeson et al., 1998). It was suggest-
(EEG)-data that revealed inconstant focal abnor-
ed that doublecortin acts as an intracellular signal-
malities over both temporal regions (Michelucci et
ing molecule critical for the migration of develop-
al., 2000). In a single case, brain Magnetic
ing neurons (Allen and Walsh, 1999).
Resonance Imaging (MRI) showed atrophy with an
Although these disorders are relatively rare,
increased T2 signal in the lateral portion of the
studying the underlying pathophysiological mecha-
right temporal lobe (Michelucci et al., 2000). This
nisms may shed light on the pathophysiology of
epileptic syndrome was found to be linked to chro-
more common epileptic syndromes.
mosome 10q22-24 (Winamer et al., 2000).
Gene defects underlying four other monogenic
2.2. GENETICS OF HUMAN EPILEPSY
epilepsies (generalized epilepsy with febrile
seizures, autosomal dominant nocturnal frontal
Epilepsies with complex inheritance
lobe epilepsy, benign familial neonatal convulsions
About 40% of patients suffering from epilepsy and episodic ataxia type 1 with partial seizures)
have a genetic background that contributes to the have recently been identified, shedding new light
aetiology of epilepsy (Gardiner, 2000). Most famil- on the pathophysiology of epilepsy as these dis-
ial epilepsies like juvenile myoclonic epilepsy, eases are caused by ion channel mutations
childhood absence epilepsy, and benign childhood (Steinlein, 1998 ; Zuberi et al., 1999).
epilepsy with centrotemporal spikes have a com- Generalized epilepsy with febrile seizures type I
plex mode of inheritance resulting from the inter- is an autosomal dominant epileptic syndrome that
action of several loci together with environmental is caused by a point mutation in the b1-subunit of a
factors (McNamara, 1999). voltage-gated Na+ channel (Wallace et al., 1998)
In patients with absence seizures (and their first whereas type II is caused by a point mutation in the
degree relatives), biochemical changes (e.g. a1-subunit of a voltage-gated Na+ channel (Escayg
increased plasma glutamate levels) have been iden- et al., 2000). These mutations cause distinct types
tified which can be related to a generalized increase of epilepsy in different members of the same fami-
in cortical excitability (Van Gelder et al., 1980). ly, which may result from inheritance of the mutant
Probably, the genetic predisposition of absence gene in the context of other susceptibility genes or
epilepsy is based on a gene-dependent biochemical environmental factors (McNamara, 1999).
PATHOPHYSIOLOGY OF EPILEPSY 203

Benign familial neonatal convulsions is a syn- metabolism at the medial thalamic nucleus (Juhász
drome that is inherited in an autosomal dominant et al., 1999). These findings are common and have
pattern. Mutations of two distinct but related volt- strong lateralization value for the seizure focus in
age-gated K+ channel genes have been identified human temporal lobe epilepsy. The decreased ben-
(Biervert et al., 1998). Although both genes zodiazepine receptor binding possibly reflects neu-
(KCNQ2 and KCNQ3) are located on different ronal loss but may also indicate decreased benzodi-
chromosomes (20q and 8q respectively), their co- azepine receptor density in the medial thalamic
expression explains how these 2 different muta- nucleus which remains to be elucidated. This struc-
tions cause an identical disease phenotype. ture may indeed play an important role in temporal
In some families, autosomal dominant nocturnal lobe epilepsy as the nucleus medialis thamali has
frontal lobe epilepsy is caused by a point mutation strong reciprocal connections with other parts of
in a gene on chromosome 20q (CHRNA4), encod- the limbic system (Engelborghs et al., 1998b ;
ing the a4 subunit of the neuronal nicotinic acetyl- Juhász et al., 1999). Interictal PET studies revealed
choline (ACh) receptor (Steinlein et al., 1995). At increased glucose metabolism and FMZ binding in
least some ACh receptors are located presynapti- the lateral thalamus of patients with temporal lobe
cally, thus promoting the release of neurotransmit- epilepsy, possibly reflecting an upregulation of
ters as GABA. The mutant receptor causes a reduc- GABA-mediated inhibitory circuits (Juhász et al.,
tion of ACh-mediated Ca2+ flux, which results in 1999).
a decrease of GABA released from presynaptic A recent study investigated expression and dis-
terminals leading to synaptic disinhibition tribution of GABA(A)-receptors in the hippocam-
(McNamara, 1999). However, the majority of the pus of pilocarpine-treated rats (Fritschy et al.,
families with autosomal dominant nocturnal 1999). A loss of a critical number of interneurons
frontal-lobe epilepsy are not linked to CHRNA4, in the gyrus dentatus was noticed, which might
indicating the presence of genetic heterogeneity play a role in seizure initiation (Fritschy et al.,
(Gardiner, 2000). 1999). Meanwhile, long-lasting upregulation of
Episodic ataxia type 1 is a rare autosomal domi- GABA(A)-receptors in granule cells was found,
nant disorder, characterized by brief episodes of which might represent a compensatory response to
ataxia associated with myokymia (Zuberi et al., seizure activity (Fritschy et al., 1999). Central ben-
1999). The patients suffering from this syndrome zodiazepine receptor density in the CA1 region was
also show partial epileptic fits. The syndrome is shown to be significantly reduced by means of
associated with point mutations in the human volt- autoradiography in post-mortem samples of
age-gated potassium channel gene on chromosome patients with hippocampal sclerosis (Hand et al.,
12p13 (Zuberi et al., 1999). As potassium channels 1997). On the other hand, affinity for FM2 was
determine the excitability of neurons, it is suggest- increased in subiculum and gyrus dentatus (Hand et
ed that this mutation is pathogenic (Zuberi et al., al., 1997). Other publications suggest that en-
1999). hanced sensitivity to glutamate may be an impor-
These recent discoveries illustrate that ion chan- tant element in the pathophysiology of temporal
nel dysfunctions can play a crucial role in the lobe epilepsy as a quantitative autoradiographic
pathophysiology of epilepsy. As several AEDs act analysis of ionotropic glutamate receptor subtypes
on ion channels, these findings are relevant to other revealed an upregulation in the reorganized human
epileptic syndromes in man. epileptogenic hippocampus (Brines et al., 1997).

2.3. PATHOPHYSIOLOGY OF DISTINCT TYPES OF EPILEPSY Gelastic epilepsy


Gelastic seizures are frequently caused by hypo-
Mesial temporal lobe epilepsy
thalamic hamartomas (Engelborghs et al., 2000). In
Mesial temporal lobe epilepsy is characterized a series of 9 patients with gelastic seizures, 4 had
by recurrent complex partial seizures and hip- hypothalamic hamartoma (Striano et al., 1999).
pocampal sclerosis. Ipsilateral to the epileptogenic Hypothalamic hamartomas are rare congenital mal-
focus, hippocampal neuronal loss results in signifi- formations and often present as a clinical syn-
cantly reduced hippocampal volumes as measured drome, characterized by pubertas praecox, mental
by means of MRI (Jokeit et al., 1999). Besides hip- retardation, and gelastic seizures. Later, refractory
pocampal volumetry, MR proton spectroscopy was epilepsy with multiple seizure types develops.
shown to be a valuable tool to correctly lateralize Patients with hypothalamic hamartoma may as well
patients with mesial temporal lobe epilepsy have focal epileptiform discharges in the anterior
(Kuzniecky et al., 1998). In patients with temporal or frontal lobe on ictal electrocortico-
intractable temporal lobe epilepsy, interictal graphic recordings but focal cortical resection was
Positron Emission Tomography (PET) studies shown not to affect seizure frequency (Cascino et
found decreased [11C]flumazenil (FMZ) binding al., 1993). According to depth electrode data show-
(benzodiazepine receptor binding) and glucose ing ictal onset from the lesion, seizures seem to
204 S. ENGELBORGHS ET AL.

begin in the intrinsically epileptogenic hamartoma model for complex partial seizures (Fisher, 1989).
(Munari et al., 1995 ; Kuzniecky et al., 1997). Ictal Although kindling has been shown to be phenome-
single-photon emission computed tomography per- nologically different from other types of plastic
formed during typical gelastic seizures demonstrat- changes in the central nervous system (Sutula,
ed hyperperfusion in the hamartoma and the hypo- 1991), there are many points of similarity between
thalamic region (Kuzniecky et al., 1997). More- kindling and the process of long-term potentiation.
over, complete surgical extirpation or a gamma Kindling has been shown to depend upon function-
knife radiosurgical treatment of the hypothalamic al as well as structural changes in glutamatergic
hamartoma results in seizure remission (Kuzniecky synapses. The anticonvulsant effects of glutamate
et al., 1997 ; Georgakoulias et al., 1998 ; Unger et receptor blocking agents like NMDA antagonists
al., 2000). It therefore seems probable that epilep- seem to be at least partly due to their inhibitory
tic discharges arise in the hypothalamus and spread effects on in vitro kindling.
via hypothalamic-amygdala connections to pro-
duce focal temporal lobe ictal discharges (Saper, 4. Ictogenesis
1990 ; Berkovic et al., 1997b).
Excitability is a key feature of ictogenesis that
Rasmussen encephalitis may originate from individual neurons, neuronal
Rasmussen encephalitis is a rare, progressive, environment or a population of neurons (Traub et
neurodegenerative illness of unknown cause that al., 1996). Excitability arising from single neurons
typically affects children in the first decade of life may be caused by alterations in membrane or meta-
(Rasmussen et al., 1958). Severe seizures that are bolic properties of individual neurons. When regu-
refractory to anti-epileptic medication, hemispher- lation of environmental, extracellular concentra-
ic atrophy, and dementia are cardinal features of tions of ions or neurotransmitters is suboptimal, the
this disease. Rabbits immunized with glutamate resulting imbalance might enhance neuronal exci-
receptor subunit 3 (GluR3) protein developed tation. Collective anatomic or physiologic neuronal
epilepsy and cerebral histopathological changes alterations may convert neurons into a hyperex-
characteristic of Rasmussen encephalitis (Rogers et citable neuronal population. In reality, these three
al., 1994). This led to the discovery of anti-GluR3 theoretical mechanisms are thought to interact dur-
antibodies in serum of patients with Rasmussen ing specific ictal episodes. Each epileptic focus is
encephalitis (Rogers et al., 1994). Effectiveness of unique as the differential contribution of these three
plasma exchanges or intravenous immunoglobin concepts leading to ictal events is thought to differ
therapy as treatment of Rasmussen encephalitis from focus to focus.
was demonstrated in a series of patients (Andrews
et al., 1996 ; Topcu et al., 1999), which further 4.1. EXCITABILITY ARISING FROM INDIVIDUAL NEURONS
proves the auto-immune pathogenesis of Ras- Functional and perhaps structural changes occur
mussen encephalitis. in the postsynaptic membrane, thus altering the
Insights gained from the study of Rasmussen character of receptor protein - conductance chan-
encephalitis may help to increase our knowledge nels, thereby favoring development of paroxysmal
about more common forms of epilepsy. Some depolarizing shift (PDS) and enhanced excitability.
patients undergoing temporal lobectomy for refrac- Epileptic neurons appear to have increased Ca2+
tory epilepsy show localized inflammatory histo- conductance. It may be that latent Ca2+ channels are
pathological changes and increased auto-antibodies used, that the efficacy of Ca2+ channels is increased
in serum (Dambinova et al., 1997 ; Peltola et al., or that the number of Ca2+ channels is chronically
2000) ; whether or not this is caused by an auto- elevated. However, development of burst activity
immune pathogenesis remains to be elucidated depends on the net inward current and not on the
(McNamara, 1999). absolute magnitude of the inward current. When
extracellular K+ concentrations are increased (as
3. Kindling and epileptogenesis during seizure activity), the K+ equilibrium across
the neuronal membrane is reduced, resulting in
Goddard (1967) was the first to describe that reduced outward K+ currents. The net current will
periodic stimulation of neural pathways progres- become inward, depolarizing the neuron to the
sively leads to recurrent behavioral and electro- extent that Ca2+ currents will be triggered. This
graphic seizures. Kindling procedures have provid- results in a PDS and a burst of spikes (Fig. 1)
ed a substrate for the study of the role of enhanced (Dichter, 1997).
synaptic efficacy in seizure disorders. It is now
considered to be a first choice experimental proce- 4.2. EXCITABILITY ARISING FROM NEURONAL MICRO-
dure in the study of the potential mechanisms of ENVIRONMENT
epileptogenesis. The phenomenon can be evoked in
various brain regions, but amygdala kindling is Both functional and structural alterations occur
most frequently used in epilepsy research as a in epileptic foci. The functional changes involve
PATHOPHYSIOLOGY OF EPILEPSY 205

MFS was demonstrated in patients with refracto-


ry temporal lobe epilepsy with hippocampal sclero-
sis 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 fre-
quency.

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).

FIG. 2. — Many central neurons burst, but rarely in a pro-


concentrations of cations and anions, metabolic longed manner (panel A). In an epileptic focus, neurons burst
alterations, and changes in neurotransmitter levels. spontaneously and for prolonged periods (note the paroxysmal
The structural changes involve both neurons and depolarization shift) (panel B).
glia. Excessive extracellular K+ depolarizes neu-
rons and leads to spike discharge. During seizures,
changes in extracellular Ca2+ (a decrease of 85%)
precede those of K+ by milliseconds and Ca2+ levels
5. Mechanisms of interictal-ictal transition
return to normal more quickly than K+.
Glia are able to clear neurotransmitters from the
Mechanisms producing signal amplification,
extracellular space and to buffer K+ thus correcting
synchronicity, and spread of activity are likely to be
the increased extracellular K+ concentrations that
involved in interictal-ictal transitions. Different
occur during seizures. Epileptic foci may show pro-
theoretical mechanisms of interictal-ictal transition
liferation of glia that differ however in morpholog-
are summarized in table 1 and discussed in the fol-
ical and physiological properties (Bordey and
lowing section. In vivo, interictal-ictal transition
Sontheimer, 1998). Gliosis will affect glial K+
can seldom be attributed to one theoretical mecha-
buffering capacity and hence may contribute to
nism, but often results from the interaction of dif-
seizure generation (Grisar et al., 1999).
ferent mechanisms.
4.3. THE EPILEPTIC CELL POPULATION
5.1. NONSYNAPTIC MECHANISMS
Collective anatomic or physiologic neuronal
Alterations in ionic microenvironment
alterations might produce progressive, network-
dependent facilitation of excitability, perhaps cou- Repetitive ictal and interictal activity causes
pled with a decrease of inhibitory influences, e.g. increases in extracellular K+ leading to increased
due to selective loss of inhibitory neurons. Mossy neuronal excitability (Moody et al., 1974). Some
fiber sprouting (MFS) is an example of neuronal neurons are very sensitive to changes in membrane
alterations leading to increased excitability K+ currents, e.g. pyramidal cells in the CA1 region
(Cavazos et al., 1991). of the hippocampus (Rutecki et al., 1985).
206 S. ENGELBORGHS ET AL.

Table 1 5.2. SYNAPTIC MECHANISMS


Summary of mechanisms of interictal-ictal transition
Two theoretical mechanisms can occur :
Nonsynaptic mechanisms decreased effectiveness of inhibitory synaptic
1. Alterations in ionic microenvironment ; e.g. increased mechanisms or facilitation of excitatory synaptic
extracellular K+, decreased extracellular Ca++ events. Both mechanisms will be discussed in the
2. Decreases in size of extracellular space following section.
3. Failure of ion transport : Na+-K+ pump or Cl--K+ co-trans-
port
4. Presynaptic terminal bursting 6. Neurochemical mechanisms underlying
5. Ephaptic interactions epilepsy
Synaptic mechanisms 6.1. GABA
1. Depression of GABA-ergic inhibition
2. NMDA receptor activation ; voltage-dependent EPSPs The GABA hypothesis of epilepsy implies that a
3. Frequency potentiation of EPSPs reduction of GABA-ergic inhibition results in
4. Actions of modulators
epilepsy whereas an enhancement of GABA-ergic
inhibition results in an anti-epileptic effect (De
Deyn et al., 1990). Inhibitory postsynaptic poten-
tials (IPSPs) gradually decrease in amplitude dur-
ing repetitive activation of cortical circuits. This
phenomenon might be caused by decreases in
Active ion transport
GABA release from terminals, desensitization of
Activation of the Na+-K+ pump is important for GABA receptors that are coupled to increases in Cl-
regulation of neuronal excitability during excessive conductance or alterations in the ionic gradient
neuronal discharges (Ayala et al., 1970). Sub- because of intracellular accumulation of Cl- (Wong
stances like ouabain that block the Na+-K+ pump and Watkins, 1982). In case of intracellular accu-
can induce epileptogenesis in animal models. mulation of Cl-, passive redistribution is ineffective.
Hypoxia or ischemia can result in Na+-K+ pump Moreover, Cl--K+ co-transport becomes less effec-
failure thus promoting interictal-ictal transition. tive during seizures as it depends on the K+ gradi-
A Cl--K+ co-transport mechanism controls the ent. As Cl--K+ co-transport depends on metabolic
intracellular Cl- concentration and the Cl- gradient processes, its effectiveness may be affected by
across the cell membrane which regulates effec- hypoxia or ischemia as well. These mechanisms
tiveness of GABA-activated inhibitory Cl- currents. may play a critical role in ictogenesis and interic-
Interference with this process could cause a pro- tal-ictal transition.
gressive decrease in the effectiveness of GABA- Several studies have shown that GABA is
ergic inhibition leading to increased excitability involved in pathophysiology of epilepsy in both
(Prince, 1988). animal models and patients suffering from epilep-
sy. GABA levels and glutamic acid decarboxylase
Presynaptic terminal bursting (GAD) activity were shown to be reduced in
epileptic foci surgically excised from patients with
The amount of transmitter released is related to
intractable epilepsy and in CSF of patients with
depolarization of presynaptic terminals. Changes in
certain types of epilepsy (De Deyn et al., 1990). In
axon terminal excitability will have effects on
stiff-man syndrome, a disease associated with
synaptic excitation (Prince, 1988).
epilepsy and diabetes mellitus, auto-antibodies to
Abnormal bursts of action potentials occur in the
GAD were demonstrated (Solimena et al., 1988). A
axonal arborizations of thalamocortical relay cells
reduction of 3H-GABA binding has been reported
during epileptogenesis. Since one thalamocortical
in human brain tissue from epileptic patients
relay cell ends on a large number of cortical neu-
whereas PET studies demonstrated reduced benzo-
rons, synchronization can occur which might play
diazepine receptor binding in human epileptic foci
an important role in interictal-ictal transition
(Savic et al., 1996). The degree of benzodiazepine
(Engelborghs et al., 1998b).
receptor reduction showed a positive correlation
with seizure frequency.
Ephaptic interaction
The GABA receptor complex is involved in var-
Ephaptic interactions are produced when cur- ious animal models of epilepsy as well. Low CSF
rents from activated neurons excite adjacent neu- levels of GABA were revealed in dogs with epi-
rons in the absence of synaptic connections. lepsy (Löscher and Swartz-Porsche, 1986). Redu-
Ephaptic effects are strongly dependent on the size ced GAD levels were revealed in the substantia
of the extracellular space. When extracellular space nigra of amygdala-kindled rats (Löscher and
is small, ephaptic interactions are promoted (Traub Schwark, 1985). Significant alterations in GABA
et al., 1985). and benzodiazepine binding have been shown in
PATHOPHYSIOLOGY OF EPILEPSY 207

the substantia nigra of genetically seizure-prone mechanism, we have demonstrated the accumula-
gerbils (Olsen et al., 1985). Mice with a genetic tion of a series of uremic guanidino compounds
susceptibility to audiogenic seizures have a lower which were shown to inhibit GABA-ergic neuro-
number of GABA receptors than animals of the transmission (De Deyn and Macdonald, 1990). One
same strain that are not seizure prone (Horton et of these endogenous agents was in addition shown
al., 1982). to be an agonist at the excitatory NMDA receptor
Several endogenous (guanidino compounds) and (D’Hooge et al., 1996 ; De Deyn et al., in press
exogenous (e.g. bicuculline, picrotoxin, penicillin, (a)).
pilocarpine, pentylenetetrazol) convulsants inhibit In patients with absence seizures, plasma gluta-
GABAergic transmission through inhibition of mate levels were found to be significantly
GABA synthesis or through interaction with dis- increased (Van Gelder et al., 1980). Neuronal
tinct sites at the postsynaptic GABA(A) receptor membranes are exposed to increased amounts of
(De Deyn and Macdonald, 1990 ; De Deyn et al., extracellular glutamate thus increasing neuronal
1992 ; D’Hooge et al. 1999). Convulsant agents excitability. A recent study on a genetic rat model
that block synaptic GABA-mediated inhibition, of epilepsy (WAG/RIJ rats ; spontaneous spike-
amplify the dendritic spike-generating mechanism wave (SW) discharges accompanied by behavioral
that involves Ca2+ (Dichter and Ayala, 1987 ; abnormalities) provides evidence for an interaction
Fisher, 1989). Synaptic inputs are thought to trig- of glutamatergic and serotonergic mechanisms in
ger and synchronize this process throughout a pop- the triggering and maintenance of epilepsy
ulation of cells which then might result in an (Filakovszky et al., 1999). Intracerebroventricular
epileptic fit. injection of 8-hydroxy-2-(di-n-propylamino)-
Several AEDs are GABA analogues, block tetralin (8-OH-DPAT), a 5HT1A receptor agonist,
GABA metabolism (e.g. vigabatrin, tiagabine, caused marked increase of the cumulative duration
valproate) or facilitate postsynaptic effects of and number of SW discharges whereas dizocilpine
GABA. However, a study evaluating dose-depen- (MK-801), a NMDA receptor antagonist, decreases
dent behavioral effects of single doses of vigabatrin SW discharges (Gerber et al., 1998). Both sub-
in audiogenic sensitive rats, suggests that the anti- stances opposed each other’s effects in this rat
epileptic properties of vigabatrin not only depend model of epilepsy.
on GABA-ergic neurotransmission but might also
be explained by decreased central nervous 6.3. CATECHOLAMINES
system levels of excitatory amino acids or
increased glycine concentrations (Engelborghs et Abnormalities of CNS catecholamines have
al., 1998a). been reported in several genetic models of epilep-
sy. In spontaneous epileptic rat, dopamine was
6.2. GLUTAMATE decreased in the nucleus caudatus whereas nora-
drenaline was increased in midbrain and brainstem
Glutamatergic synapses play a critical role in all (Hara et al., 1993). Decreased levels of dopamine
epileptic phenomena. Activation of both ionotropic have been found in epileptic foci of epilepsy
and metabotropic postsynaptic glutamate receptors patients (Mori et al., 1987). In animal models of
is proconvulsant. Antagonists of N-methyl-D- absence epilepsy, seizures are exacerbated by
aspartate (NMDA) receptors are powerful anti-con- dopamine antagonists while fits are alleviated by
vulsants in many animal models of epilepsy. dopamine agonists (Snead, 1995). These results
Several genetic alterations have been shown to be suggest that decreased dopamine facilitates appear-
epileptogenic in animal models but no specific ance of seizures by lowering the threshold trigger-
mutation relating to glutamatergic function has yet ing such seizures.
been linked to a human epilepsy syndrome. Tottering mice have an absence-like syndrome
Nevertheless, there is evidence for altered NMDA that is characterized by episodes of behavioral
receptor function in acquired epilepsy in animal arrest associated with 6 to 7 Hz cortical SW EEG
models and in men. An increased sensitivity to the discharges. Selective destruction of the ascending
action of glutamate at NMDA receptors is seen in noradrenergic system at birth prevents the onset of
hippocampal slices from kindled rats and in corti- the syndrome. Therefore, it has been suggested that
cal slices from cortical foci in human epilepsy the syndrome is caused by a noradrenergic hyper-
(Hwa and Avoli, 1992). This results in an enhanced innervation of the forebrain (Meldrum, 1994).
entry of Ca2+ into neurons during synaptic activity Recent data indicate that the serotonergic system
(Louvel and Pumain, 1992). Changes in regulates epileptiform activity in a genetic rat
metabotropic glutamate receptor function may also model of absence epilepsy as intraperitoneal or
play a key role in epileptogenesis (Chapman, intracerebroventricular administration of 8-OH-
1998). DPAT caused marked and dose-dependent increas-
Epileptic seizures and epilepsy form frequent es in number and duration of SW discharges
complications of uremia. As a possible underlying (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 neu-
In experimental studies, opioids and opioid pep- rotransmitter receptor complexes. AEDs that
tides had both convulsant and anticonvulsant prop- decrease membrane excitability through interaction
erties (Meldrum, 1994). Kappa agonists suppress with ion channels act on sodium and calcium chan-
SW discharges in an animal model of abscence nels. Most AEDs that interact with neurotransmit-
epilepsy (Przewlocka et al., 1995). Peptides with a ter complexes promote inhibitory GABA-ergic
m agonist action induce hippocampal or limbic neurotransmission although some more recently
seizures when administered intraventricularly pos- developed drugs act through inhibition of excitato-
sibly due to inhibition of inhibiting interneurons. In ry neurotransmission as well. The most frequently
patients with complex partial seizures, PET studies used AEDs and their (presumed) mechanisms of
pointed out that m receptor density is increased in action are summarized in table 3.
the temporal cortex (Mayberg et al., 1991). Numerous AEDs interfere with ion channel
functioning. Both ethosuximide and valproate
7. Pathophysiology of epilepsy and mecha- block voltage-dependent Ca++ channels of the T-
nisms of action of AEDs type which explains their anti-epileptic efficacy in
(Levy et al., 1995 ; Macdonald and Kelly, 1995 ; generalized absence epilepsy (Stefani et al., 1997).
Thomas, 1999) Carbamazepine, felbamate, lamotrigine, oxcar-
bazepine, phenytoin, topiramate, valproate and
Most of the presently used AEDs were discov- zonisamide are known to reduce voltage-dependent
ered by screening without a rationale as to the Na+ currents.
mechanism of action. As knowledge on the patho- Several established AEDs promote inhibitory
physiology of epilepsy increases and the mecha- neurotransmission. Vigabatrin is an enzyme-
nisms of action of most AEDs are at least partially activated irreversible inhibitor of GABA-transami-
unravelled, it becomes clear that most AEDs exert nase and has a weaker GABA uptake inhibitory
their anti-epileptic properties through only a few effect whereas tiagabine is a pure GABA uptake
neurochemical mechanisms that are meanwhile inhibitor. Both AEDs thus increase the functional
basic pathophysiological mechanisms thought to pool of GABA. Benzodiazepines enhance GABA-
cause epileptic fits (table 2). Thanks to increased ergic inhibition through interaction with the GABA
use of animal models of epilepsy, a better insight in (A) receptor. Till present, progabide is the only
the pathophysiology of epilepsy and improved AED exerting GABA agonistic effects at both type
knowledge on mechanisms of action of AEDs, sev- A and B sites. Several other AEDs have (weaker)
eral new more rationally designed AEDs were GABA-ergic properties but act on other mecha-
developed and marketed during the past decade (De nisms as well. The main mechanism underlying
Deyn et al., in press (b)). phenobarbital’s anti-epileptic effects is attributed to

Table 2
Correlation between mechanisms of epileptogenesis and mechanisms of action of AEDs

Mechanisms of epileptogenesis Mechanisms of actions of AEDs


GABA ● Reduced GABA in microgyric cortex ● Increased functional pool of GABA (vigabatrin, tiagabine)
● Reduced benzodiazepine receptor binding in medial ● Enhanced GABA-ergic inhibition (benzodiazepines)
thalamic nucleus (mesial temporal lobe epilepsy) ● GABA agonistic effects (progabide)
● Reduced benzodiazepine receptor density in CA1 region ● (Weaker) GABA-ergic properties (phenobarbital,
(hippocampal sclerosis) gabapentin, topiramate, valproate, zonisamide)
● Reduced GABA levels and GAD activity (epileptic foci)
● Auto-antibodies to GAD (Stiff-man syndrome)
Glu ● Upregulation of hippocampal ionotropic glutamate ● Inhibition of glutamate release (lamotrigine)
receptors (temporal lobe epilepsy) ● Block of glycine site at NMDA receptor (felbamate)
● Anti-gluR3 antibodies (Rasmussen encephalitis)
● Increased plasma glutamate levels (absence seizures)
Na + ● Mutation voltage-gated Na+ channel (generalized ● Reduction of voltage-gated Na+ currents (carbamazepine,
epilepsy with febrile seizures) felbamate, lamotrigine, oxcarbazepine, phenytoin,
topiramate, valproate, zonisamide)
K+ ● Mutation voltage-gated K+ channel
(benign familial neonatal convulsions)
Ca++ ● Reduced ACh-mediated Ca flux ● Reduction of T-type Ca++ currents (ethosuximide, valproate)
(nocturnal frontal lobe epilepsy)
→ Increased membrane excitability → 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
Carbamazepine Blocks voltage-dependent Na+ channels
Limitation of sustained repetitive firing
Ethosuximide Reducing T-type Ca++ currents
Blocking synchronized thalamic firing
Felbamate 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
Gabapentin 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
Lamotrigine Reduces glutamate release
Inhibits voltage-activated Ca++ currents, blocks voltage-dependent Na+ channels
Levetiracetam Unknown mechanism of action
Increases seizure threshold and inhibits seizure spread in kindled rats
Oxcarbazepine Inhibition of voltage-dependent Na+ channels
Inhibition of voltage-activated Ca++ currents
Phenobarbital Enhances GABA action
Reduces sustained repetitive firing
Reduces voltage-dependent Ca++ currents
Phenytoin Blocks voltage-gated Na+ channels
Reduces Ca++ currents
Primidone Reduces sustained repetitive firing - blocks voltage-dependent Na+ currents
Progabide GABA agonist at A and B sites
Remacemide NMDA receptor antagonist
Inactivation of Na+ channels
Tiagabine Neuronal and glial GABA-uptake inhibitor
Topiramate 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
Valproate Increases CNS GABA levels by increased synthesis and reduced catabolism
Blocks T-type Ca++ currents
Enhances Na+ channel inactivation
Vigabatrin GABA-Transaminase inhibitor
Inhibits GABA uptake
Zonisamide Blocks Na+ channels
Blocks T-type Ca++ channels
Enhances GABA action
Inhibition of carbonic anhydrase

the reduction of voltage-dependent Ca++ currents channel inhibition and potentiation of GABA-ergic
although this drug enhances GABA-ergic neuro- neurotransmission, topiramate interferes with exci-
transmission as well. Gabapentin, topiramate, val- tatory neurotransmission as it weakly blocks
proate and zonisamide are other examples of drugs amino-3-hydroxy-5-methyl-4-isoxazole propionic
that have amongst others GABA-ergic properties. acid (AMPA) receptors.
Lamotrigine is currently the best example of a A link between from one side the preclinical
drug acting through excitatory neurotransmission profile and mechanisms of action of AEDs and
as it inhibits the release excitatory amino acids, from the other side clinical profile can be made. In
especially glutamate. Although lamotrigine also general, AEDs exerting anti-epileptic properties
blocks ion channels, its effect on glutamate release through interaction with one single mechanism of
is thought to be primarily responsible for anti- action, have a narrow clinical profile (e.g. ethosuxi-
epileptic properties. Felbamate blocks the glycine mide). However, most AEDs interfere with a com-
site at the NMDA receptor which is at least partial- bination of basic mechanisms of anti-epileptic
ly related to its anti-epileptic effects. Besides ion action such as inhibitory neurotransmission and Na
210 S. ENGELBORGHS ET AL.

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