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Pathophysiology of epilepsy
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Review article
Pathophysiology of epilepsy
————
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).
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
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.
Table 2
Correlation between mechanisms of epileptogenesis and mechanisms of action of AEDs
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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