ÖSSZEFOGLALÓ KÖZLEMÉNY
NEW VISTAS AND VIEWS IN THE CONCEPT
OF GENERALIZED EPILEPSIES
Péter HALÁSZ1, Anna KELEMEN2
Pázmány Péter Catholic University, Faculty of Information Technology, Budapest
2National Institute of Neurosurgery, Budapest
1
ÚJ NÉZÔPONTOK A GENERALIZÁLT EPILEPSZIÁK
SZEMLÉLETÉBEN
Halász P, MD; Kelemen A, MD
Ideggyogy Sz 2009;62(11–12):366–380.
The aim of this work is to show explicitly why the “idiopathic
generalized epilepsy” concept becomes outfashioned and
untenable. As the concept of “generalized epilepsies” is
from long ago closely related to the thalamo-cortical system, we briefly summarize the functional anatomy, the double working mode of the thalamo-cortical system in different
vigilance states and it's role in development of the spike –
wave pattern. The next part shows weaknesses of this concept from the EEG, seizure semiology, and neuroimaging
point of view. Further experimental and clinical arguments
are accumulated from the reflex epileptic features in IGE,
indicating local/regional cortical hyperexcitability. A separate part is devoted to genetic aspects of the question. Lastly
implications to epilepsy classification are shown and an outlook toward a unified epilepsy concept is provided.
The epileptic disorder of the thalamo-cortical system is
responsible for the development of “generalized", synchronous spike-wave paroxysms as the common neurophysiological background in “primary” – idiopathic and in
“secondary” generalized epilepsies.
This disorder is specifically related to the burstfiring working
mode of the thalamo-cortical system during NREM sleep (is
an epileptic exageration of it).
The “generalized” epilepsy category should be abandoned,
being misleading. Epilepsies are proposed to be classified
according to their network properties and relations to different physiological systems of the brain. The different phenotypes, named earlier idiopathic (primary) generalized, or
symptomatic (secondary) generalized (with encephalopathic
features), should be delineated depending on the following
factors: 1. speed and extent of syncronization within the thalamo-cortical system, 2. the way how the thalamo-cortical
system is involved, 3. which kind of cortical triggers play
role, 4. the degree and level of the disorder (restricted to
the molecular level or extended to the level of structural
alterations – in the cortex or more diffusely, 5. genetic targets and features.
Munkánk célja, hogy megmutassuk, miért vált elavulttá és
tarthatatlanná az „idiopathiás generalizált epilepszia” (IGE)
koncepció. Elôször a koncepció kialakulásának történetét
ismertetjük. Miután a koncepció régóta szorosan összefügg
a thalamocorticalis rendszerrel, röviden összefoglaljuk a
rendszer funkcionális anatómiáját, mûködésének kettôsségét ébren és alvás közben, a rendszer szoros összefüggését az NREM alvással és végül azt, hogy hogyan történhet
a szinkrón bilaterális kiterjedt tüske-hullám minta
kialakulása a rendszer közremûködésével. A következô
részekben megmutatjuk, hogy milyen argumentumok
hozhatók fel a koncepció ellen az EEG-tünetek, a rohamszemiológia és a képalkotó vizsgálatok adatai alapján.
További ellenérveket ismertetünk az IGE-reflex epilepsziás
vonásai és lokális/regionális kérgi hyperexcitabilitás jelenlétére utaló adatok, valamint azoknak az állatkísérletes adatoknak az alapján, amelyek elsôdleges kérgi indító
területekre utalnak és emberi megfigyelésekkel is összeegyeztethetôek. A további részben a genetikai háttérre
vonatkozó kutatások adatait csoportosítjuk. Végül az epilepsziaosztályozás módosításának szükségessége mellett
érvelünk, és egyben egy, a jelenleginél egységesebb epilepsziaklasszifikáció lehetôségét vetjük fel, amelyben fiziológiai
rendszerekhez kötött „rendszer-”, illetve „hálózatepilepsziákban” gondolkodnánk.
A thalamocorticalis rendszer epilepsziás mûködészavara
tehetô felelôssé a „primer", illetve „szekunder” tüske-hullám
szinkronizáció mint közös neurobiológiai szubsztrátum
kialakulásáért és az „idiopathiás generalizált epilepszia” (és
altípusai) tüneteiért. Ez a mûködészavar specifikusan összefügg a thalamocorticalis rendszer burstfiring NREM alvásbeli
munkamódjával és lényegében ennek az epilepsziás
exagerációja.
A „generalizált” epilepszia terminust, mint félrevezetôt, el
kell vetni. A csoporton belüli variációk biológiai kontinuum
részeként kezelhetôk, és a fenotípus-különbségek a
következô faktorok figyelembevételével értelmezhetôk: 1. a
thalamocorticalis rendszeren belüli szinkronizáció sebessége
és kiterjedése, 2. a thalamocorticalis rendszer bevonódásának módja, 3. a kérgi triggerek helye és természete, 4. a
mûködészavar szintje a molekuláris biológiai szinttôl az agyi
strukturális eltérések szintjéig, valamint 5. a genetikai
tényezôk, szerepe szerint.
Keywords: idiopathic generalized epilepsy (IGE),
thalamo-cortical system,
bilateral synchronous spike-wave discharges,
classification of epilepsies, epileptic networks
Kulcsszavak: idiopathiás generalizált epilepszia (IGE),
thalamocorticalis rendszer,
bilaterális szinkrón tüske-hullám kisülések,
epilepsziák osztályozása, epilepsziás hálózatok
366 Halász: New vistas and views in the concept of generalized epilepsies
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Corresponding author: Péter HALÁSZ, Pázmány Péter Catholic University, Faculty of Information Technology,
1364 Budapest 4., Pf. 178. E-mail: halasz35@gmail.com
Érkezett: 2009. április 29.
Elfogadva: 2009. május 15.
www.elitmed.hu
A
fter the discovery of EEG epilepsy became
conceptualized as an electro-clinical constellation. Due to the work of the Montreal school a
functional map of the human cortex has been developed and neurologists dealing with epilepsy
became more and more experienced to read the language of seizure symptoms in terms of cerebral
localization.
According to the work of Jackson, Penfield and
Jasper, epilepsy is considered as a paroxysmal brain
disorder in which excessive synchronous discharges of certain neuron-populations initiate
seizures. The symptomatology of seizures is determined by functional properties of the cortex the
seizure starts from, and by the routes and extension
of seizure propagation.
In 1933 Berger1 described the pattern consisting
of spike (called dart) and wave (called dome) complexes alternating in a strict 3 Hz rhythm. Two
years later Gibbs, Davis and Lennox2, showed that
they are generalized over the whole scalp, and connected this pattern with “petit mal” fits (absence
seizures by our contemporary terminology).
In 1941 Jasper and Kershman3 showed that 86%
of patients showing generalized spike-wave pattern
exhibited generalized tonic-clonic seizures.
These findings outlined a patient group with an
EEG pattern involving at once the whole scalp and
with seizures lacking localizatory symptoms. It was
difficult to fit these features into the general localizatory concept of epilepsy. Looking for a hypothetical focus from where the synchronous bilateral
discharges and the from the start generalized
seizures may origin, led to the centrencephalic
epilepsy concept of Penfield and Jasper4.
Several neurophysiological and clinical electrophysiological findings rendered this concept to be
probable. The discovery of the thalamic non-specific system, producing widespread recruiting cortical
effect to stimulation5 provided the anatomo-functional substrate: a midline structure having a general influence on the cortical mantle. In 1940 Lewy
and Gamon6 evoked cortical spike-wave pattern by
thalamic electrical stimulation. In 1947 Jasper and
Droogleever Fortuyn7 stimulating with 3 Hz in the
thalamic intralaminar nuclei at the vicinity of the
anterior part of the massa intermedia evoked spikewave answer in cats. Again two years later Hunter
and Jasper8 observed clinical response (arrest and
twiching) to stimulation of the nucleus dorsomedialis during evoked cortical spike-wave pattern.
Guerrero et al9 in kittens, with aluminiumoxide
placed to the thalamic intralaminar nuclei and
Pollen et al10 in young cats anaesthetized with barbiturate, stimulating the intralaminar nuclei, were
also able to elicit bilateral spike-wave paroxysms.
Later Bancaud et al11 elicited bilateral spike-wave
activity with electric stimulation of the frontomedial cortex during stereo-electroencephalographic
interventions in an IGE patient who had spontaneous spike-wave discharges.
According to the “centrencephalic ” concept, in
patients with generalized spike-wave EEG pattern
and petit mal and/or GTC seizures, the missing
focus is in the non-specific thalamic system, which
conveys thalamic excitation diffusely to the cortex.
This concept was in a good agreement with another
theoretical construction of Jackson, who assumed,
that the highest organizational level of brain functions is in the centrencephalic system (situated in
the diencephalon and thalamus) where integration
between the two hemisheres occurs. Loss of consciousness in petit mal fits was explained nicely by
functional impairment of this system.
When EEG became a routine diagnostic procedure different morphological variations of the generalized spike-wave pattern and their correlation
with clinical seizures, course and outcome has been
described. The family of generalized epilepsies
without focal structural brain damage became
delineated by the ILAE epilepsy classification12
under the heading of “idiopathic generalized
epilepsies”.
From a syndromatological point of view the following types were delineated: 1. childhood absence
epilepsy (CAE), 2. juvenile absence epilepsy (JAE),
3. myoclonic absence epilepsy (MAE), 4. eyelid
myoclonia with absences (EMA), 5. perioral
myoclonies with absences (PMAE), 6. juvenile
myoclonic epilepsy (JME) with jerks without loss of
consciousness and GTC seizures, and 7. IGE with
awakening GTC seizures (EGMA).
Ideggyogy Sz 2009;62(11–12):366–380.
367
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Pathophysiology of “generalized
epilepsies”
NETWORK PROPERTIES, TRANSMITTER/RECEPTOR TYPES
OF THE THALAMO-CORTICAL CIRCUITRY
The basic connections in the thalamo-cortical and
intrathalamic loops are as follows: neurons of the
sensory thalamic nuclei and the cortical pyramidal
neurons have a reciprocal, mutually glutaminergic
excitatory connection.
Both the thalamo-cortical (TC) and corticothalamic (CT) projections give an excitatory collateral to
the nucleus reticularis thalami and perigeniculate
nuclei (NRT/PGN). The latter structures send
inhibitory GABA-ergic innervation to thalamic
neurons and to other reticular nuclei providing a
strong inhibitory gating influence which determines
the rhythmic activity generated by the thalamic network13. Based on these network properties the
reciprocal connectivity between excitatory (glutaminergic) and inhibitory (GABAergic) neurons
creates an oscillatory circuit. CT cells project with
powerful excitatory influence on the NRT/PGN
neurones promoting their inhibitory action on the
TC cells and also excitatory collaterals to the TC
neurons. TC neurones exhibit a strong postinhibitory rebound response, the synaptic inhibiton
exerted by the NRT/PGN neurones results in a
rebound burst of action potential conveying excita-
tion back to the NRT/PGN neurons leading to a
reactivation of the circuit. The syncronization of the
thalamic network is promoted by gap-junctions
(electric synapses) mediated by axon collaterals of
the NRT/PGN cells (figure 1.).
THE WAKING AND SLEEP WORKING MODE DIFFERS
IN THE THALAMO-CORTICAL SYSTEM
Two kinds of working mode of the system has been
revealed. During wakefullness the system works as
a relay center which faithfully conveys input from
the outher world towards the cortex. This is executed by the so called “tonic activity” of the network
reflected by desyncronized EEG. During NREM
sleep this desyncronized activity and tonic mode is
replaced by synchronized rhythmic activity in the
form of delta, spindle, and other slow waves. This
working mode is called burstfiring, interrupting the
information flow from the outer world toward the
cortex.
The cellular substrate of the burstfiring mode is
mainly due to special membrane and receptor characteristics of the participating cells and their
wiring14, 15. The membrane conductance of thalamic
neurons is characterized by the presence of low
threshold T-type Ca2 channels, the bursting properties of which have a role in the amplification of thalamic oscillations. In the wake state, T-current is
inactivated and does not interfere in the transmission of sensory information relayed by the thalamus. Depolarization of the thalamic neurons is
thalamus
provided in the wake state by the
cortex
ascending influence of the brain
stem activating system. When we
go to sleep a cascade of events
starts and the working mode of the
thalamo-cortical system is going
to change. Desinactivation of the
low threshold Ca2 current domiCT
TC
nates the functional properties of
the thalamic neurons when they
are hyperpolarized compared to
their waking resting membrane
NRT/PGN
potentials. This occurs in the period of drowsiness and transition
from wake state to slow wave
Pro-oscillatory-glutaminerg
sleep when ascending arousal
Anti-oscillatory – GABA-erg (a3, b3 and g2)
decreases. Under this condition
the relay neuron will respond to
Pro-oscillatory – GABA-erg (a1, b2 and g2)
the inhibitory feedback from the
NRT with a rebound Ca2 burst.
Figure 1. Basic circuitry in the thalamo-cortical system14. (Modified)
Since the NRT innervates large
CT: cortico-thalamic, TC: thalamo-cortical, NRT/PGN: reticularis thalami/perigeniculate nuclei
thalamic neuron populations, syn-
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chronized GABA-A and -B-ergic inhibitory postsynaptic potentials desinactivate low threshold Ca2
current spikes in an important number of thalamic
neurons what is reflected by spindle waves and at
the same time initiates rebound excitation. This
excitation then reactivates NRT and activates the
cortex. Reactivated NRT initiates an inhibitory
postsynaptic potential in thalamic neurons forming
again a second spindle wave. The hyperpolarization
of thalamic neurons reopens the way for the activation of spike burst based on Ca2 current and the
whole excitatory inhibitory cycle involving the
NRT and thalamic relay cells is set into motion
again. The NRT is the driving force of spindling.
Thalamic structures isolated from NRT do not show
oscillatory behavior, while the NRT produce spindling even after isolation from the rest of the thalamus13.
NREM sleep is induced by inhibitory influences
originating from the basal forebrain on brain stem
arousal centers and therefore releasing the suppressing effect of the arousal system on the thalamo-cortical system16.
FROM “BURSTING-MODE” TO SPIKE-WAVE PATTERN
After exploration of the phasic inhibitory gating
exerted by the NRT on the thalamo-cortical circuit,
it became clear that this mechanism could be the
basis of the spike-wave pattern in absence epilepsy.
Gloor showed that the same thalamic volley eliciting spindles on the cortex in normal sleep evokes
the spike-wave pattern when cortical excitability is
elevated by application of penicillin17. They also
showed that arousal influences were able to block
spike-wave paroxysms by depolarizing the thalamic relay cells; while shifts toward sleep promoted
their appearence. The transition from spindles to
spike-wave was hypothetized to be underlied by the
increase of cortical recurrent inhibition resulting in
a longer lasting slow-wave. In recent years the possible role of the increased function of low threshold
Ca2 current in thalamic (NRT and relay cell) neurons became more and more evident. This would
classify IGEs among “channelopathies”. An other
explanation was given by Bal et al18, 19..
The pharmacological block of GABA-A receptors in ferret geniculate slices results in the transformation of spindle waves into paroxysmal activity such, that both thalamo-cortical and perigeniculate neurons greatly increase the intensity of their
burst discharges and become phase-locked into a 2to 4-Hz rhythm. This observation suggested that
this shift from normal to paroxysmal activity resulted from the disinhibition of perigeniculate neurons
from one another, resulting in an increase in discharge of these cells and a large increase in the
postsynaptic activation of GABA B receptors in
thalamo-cortical neurons20, 21. Thus, the spindle
waves are slowly transformed into a paroxysmal
oscillation that resembles to spike-and-wave pattern.
However, the thalamo-cortical circuit may be
influenced via several ascending and descending
pathways from the brain stem and the cortex.
Therefore, it is not surprising that the same distorsion of functions resulting in epileptic spike-wave
discharges in the system could stem from influences from different key points in the network.
Pharmacological factors in play external to the thalamo-cortical circutry include cholinergic, dopaminergic, noradrenergic and serotoninergic mechanisms. Pathways that utilize these various transmitters project onto the thalamus and/or cortex from
sites distant to those structures and may modulate
the process either from up or down. Perturbation in
one or more of these neuronal networks may led to
abnormal neuronal oscillatory rhythms within thalamo-cortical circuitry, with a resultant generation
of bilaterally synchronous spike-wave discharges
that characterize IGE.
The Montreal school22 emphasized the coexistence of three components which may promote the
development of IGE like epileptic states: increased
excitability of the cortex, weakness of the brainstem tonic arousal influence and phasically inhibited thalamo-cortical stream of impulses, now known
as “bursting mode” of the thalamo-cortical system.
To the role of the last factor we will return in the
chapter dealing with the relationship of IGE and
vigilance level and NREM sleep.
Pharmacology of spike-wave pattern
A number of mechanisms regulate the ability of the
thalamo-cortical network to undergo oscillatory
burstfiring. Circuitry, and the nature of synaptic
transmission within the cortico-thalamic network,
explains the pharmacological responsivity of idiopathic generalized epilepsies.
GLUTAMATE TRANSMISSION BETWEEN CORTICAL PYRAMID
CELLS AND THALAMIC RELAY CELLS
Activation of cortico-thalamic pathways has been
shown to generate excitatory postsynaptic potentials in thalamic relay neurons mediated by NMDA
receptors. Since diffuse cortical hyperexcitability
has been found to be associated with absence-like
Ideggyogy Sz 2009;62(11–12):366–380.
369
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seizures in the feline penicillin model22, it is possible that there is an increased excitatory synaptic
input to the thalamus from the cortex during the
development of spike-wave discharges. However,
the role of thalamic NMDA receptors in spike-wave
paroxysms was not supported in the GHB (gabahydroxy-butirate) model23.
tic drugs. Extrinsic mechanisms that increase or
decrease the propensity of oscillatory working
mode may also influence the propensity of spikewave paroxysms and absence seizures. Increase of
the cholinergic and dopaminergic input attenuates
the appearence of absences and spike-wave discharges, decrease of their influence has the opposite
effect.
GABA-ERGIC (A AND B) NEUROTRANSMISSION BETWEEN NRT
AND THE TC RELAY CELLS
GABA mimetic agents, either direct or indirect
GABA agonists such as muscimol and THIP
(4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol)
exacerbate absence seizures and increase the
propensity and synchrony of spike-wave paroxysms
in experimental animals, although GABA-A antagonists do not protect against seizures24. Clinical
experience with antiepileptics acting on the GABA
mechanism seems to support this. Vigabatrin elevating the level of GABA by irreversible inhibition
of the GABA transaminase enzymes, increases
seizure propensity in idiopathic generalized epilepsies and also in the GAERS (Genetic Absence
Epileptic Rats of Strassbourg)25. The same is true
for the GABA reuptake inhibitor drug (tiagabin).
Benzodiazepines are exceptions, probably because
their selective effect on the GABA-ergic transmission in the cortex and less in the thalamus. GABAB receptors are not coupled to the Cl channels but
gate Ca2 and/or K channels. The neuronal response
to GABA-B agonist compounds is slow hyperpolarization compared to the faster GABA-A action.
GABA-B mediated inhibition seems to be essential
for absence seizures generation. GABA-B receptor
activation by Baclofen promotes burstfiring and
consequently absence seizures, while GABA-B
antagonists dose-dependently decrease the frequency of absences in the lh/lh mice, GAERS rats, and
in GBH and pentylentetracor pharmacological
models. Pertussis toxin (PTx) treatment reduces
GABA B receptor mediated events. In the GAERS
spike-wave discharges were reduced by 70-80% in
thalamic nuclei after PTx treatment26, 27.
INTRINSIC MECHANISMS WHICH ARE RESPONSIBLE FOR
DE-ACTIVATING T-TYPE CA2 CHANNELS IN THE CT AND NRT
CELLS AND INFLUENCE THE ENGAGEMENT OF THE SYSTEM
INTO BURST-FIRING
It has long been known that absences could be specifically well controlled by succinimides T-type
Ca2 current blockers28, 29.
Each of these mechanisms represents a potential
target for existing and newly developing antiepilep-
Relationship between NREM sleep
and IGE symptoms
There is a close relationship between vigilance
level and expression of spike-wave paroxysms.
Spontaneous paroxysms are promoted by transitory
decreases of vigilance level of awake state30–32, after
awakening, after lunch, in evening sleepiness, during boring tasks or situations, experimental depression of reticular arousal functions33, and after sleep
deprivation. Spontaneous paroxysms are inhibited
by a sudden increase in vigilance33–35, arousals
(calling by name), and experimental stimulation of
the reticular arousal system36. This relationship
stems from the common “burstfiring” working
mode of the thalamo-cortical system sharing by a
mechanism that sets into motion both in shifts
toward slow wave sleep and in spike-wave pattern.
However, the fact that spike-wave activation in the
form of absence-like 3 Hz paroxysms occurs selectively in transitional periods (between slow wave
sleep and wakefulness, and between slow wave and
REM sleep), and that spike-wave pattern is absent
in REM sleep both in humans37–41, and animals42, 43
and is present only in distorted groups during deep
slow wave sleep, needs explanation.
Studies analyzing this relationship have shown
that not only the level of vigilance differs but activation in these transitional periods is closely connected with sudden oscillations of vigilance
attached to the so called phasic events of sleep.
Spontaneous paroxysms (with or without clinical
manifestations) have been associated with arousaldependent phasic events preceded by K-complexes
and/or slow waves44, 45. With sensory stimulation
these dynamic changes could have been experimentally elicited and studied45. Association of generalized spike-wave pattern in IGE with arousal instability in NREM sleep can be measured by the cyclic
alternating pattern (CAP) phenomenon, the frequency of which is proportional with arousal instability. Sleep EEG analysis of 10 primary generalized patients46 showed significant prevalence of
spike-wave paroxysms during CAP as compared to
NCAP periods (68% vs. 32%), 93% of all the spike-
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wave pattern occured in CAP were found in the
reactive phase A. In sleep EEG analysis of 10 JME
patients47 spiking rate was significantly higher in
CAP A phase compared to NCAP, and showed
strong inhibition in CAP B phase.
The link between EEG arousal phenomena and
spike-wave paroxysms is in apparent contradiction
to the association of spike-wave pattern and sleeplike bursting mode of the thalamo-cortical system.
To solve this contradiction we should take into consideration that most of the evoked phasic events
during the dominance of the bursting mode show
the features of sleep response. They contain clear
cut slow wave sleep elements (single or serial Kcomplexes, slow wave groups) occurring in the
same form as in the spontaneously appearing counterparts. Each arousal during slow wave sleep
seems to evoke a regulatory rebound shift toward
sleep, which seems to be the best activator of the
oscillatory mode of thalamo-cortical network and
the spike-wave mechanisms as well41, 45.
DECREASE OF CORTICAL ACTIVITY DURING ABSENCE
SEIZURES
Three Hz synchronized spike-wave oscillation in
the thalamo-cortical network associated with
absences are composed by two distinct components. The underlying events during the “spike”
component proved to be unequivocally a pronounced glutamatergic burst discharge both in cortical and thalamic relay cells. The “wave” component was previously viewed as summated inhibitory postsynaptic potentials attributed to GABA-ergic
inhibitory process in pyramidal cortical neurons.
Later Steriade et al48 showed that instead of inhibition a “disfacilitation” is present during the “wave”
component.
Transcranial Doppler (TCD) and Single Photon
Cranial Tomography (SPECT) studies in experimental animals49, 50 and in humans51 showed cortical
decrease and thalamic increase of blood flow during absences. On functional Magnetic Resonance
Imaging (fMRI) studies thalamic structures showed
positive Blood Oxygen Level Dependent (BOLD)
activation while over wide cortical fields patchy
negative BOLD activation has been observed52.
DECREASE OF CORTICAL ACTIVITY DURING NREM SLEEP
Steriade et al53 discovered that beside delta activity
of slow wave sleep a slower oscillation (<1 Hz,
generally 0.5-1.0 Hz) exists and this slow oscillation plays role in grouping of delta waves and spindles during deep NREM sleep. This slow oscilla-
tion is essentially cortical in origin, surviving thalamotomy. The slow oscillation consists of a prolonged depolarizing phase (up-state), followed by
long-lasting hyperpolarization (down-state). The
up-state consists dense excitatory and inhibitory
synaptic activity, while the down-state is characterized by cessation of synaptic barrages (disfacilitation). The Steriade group provided ample evidences
that slow oscillation involves the cortex widely,
opposed to faster oscillations originating in more
restricted circuits. Other rhytms appear in coalescence with the slow oscillation.
The production of deltas are under a homeostatic process; the amount of deltas depend on the preceding time spent awake54. Even any local wake utilization increases the amount of deltas over the corresponding cortical field55. Sleep deprivation increases the delta power and also the strength of
reactive delta bouts56.
Regional blood flow studies57 during NREM
sleep showed decrease in the brain stem structures,
thalamus’ sensory relay nuclei, centrum medianum
and less robust decrease in the nucley related to the
prefrontal motor cortex and heteromodal cortical
fields (prefrontal association areas, inferior parietal
lobule and supramarginal and angular regions). We
can assume, that disfacilitation during deep NREM
sleep in the down-state involving large cortical
fields (association areas) contributes to the decrease
in regional blod flow, mainly of the frontal lobes.
NREM AND IGE ABSENCES SHARE COMMON
PHYSIOLOGICAL BACKGROUND
Both in deep NREM sleep and in absences the cortical activity is reduced in certain (mainly frontal)
areas. This seems to be paradoxical concerning an
epileptic activity, but provides explanations for the
cognitive deficit during absence seizures and in a
certain extent also for interictal cognitive deficits
associated with prolonged spike-wave activity in
sleep as it was detailed before. In absence the loss
of contact with the outer world may have a twofold
reason, becouse: 1. the bursting mode interrupts the
continuous flow of information from our surrounding to the cortex and 2. the disfacilitation during the
“wave” component involving the cortical association areas decreases the possibilities of cortical
elaboration.
The sensory information flow is interrupted in
both conditions. Sensory stimuli have an awakening effect in sleep and a disruptive effect in absence
seizures too. Sleep induction promotes absences
and awakening inhibits both sleep and absences.
The neuroimaging counterparts of NREM sleep and
Ideggyogy Sz 2009;62(11–12):366–380.
371
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absences are strikingly similar. The same is true for
the neurophysiological picture of absences and
NREM sleep oscillations as it was detailed above.
So the functional neuroimaging, neurophysiological and clinical data became recently highly congruent, pointing to the thalamo-cortical network as
a common substrate of NREM sleep and IGE.
Therefore the slogan of Steriade: “sleep and epilepsy are bedfellows” is really very witty here.
Spike-wave discharges of IGE represent the
epileptic exageration of the bursting mode of the
thalamo-cortical system. Therefore the inducement
or shift toward NREM sleep promotes the manifestations of IGE. The wellknown activating effect of
sleep deprivation and sleep per se is probably related to the same mechanism58.
Leaks in the generalized epilepsy
concept – The concept of focal (cortical)
origin
From the beginning of electro-clinical observations
there were experiences in favour of “focal” features
from both, the clinical and the EEG side, not fitting
into the original “primary generalized” concept.
EEG OBSERVATIONS
In many patients the “generalized” spike-wave pattern is not quite symmetric over the two hemispheres, the pattern shows localized onset and focal
discharges were observed in addition to the generalized pattern59–65. Already Gibbs and Gibbs suggested that spike-wave discharges originate in the
cortex, because Bennett66 have shown that pentylentetrazol injected to the carotis system reaching
essentially the cortex evoked bilateral spike-wave
discharges while injected into the vertebral system,
targeting the midline diencephalic structures, failed
to evoke them. Gloor and Tesla67 showed the same
with Amytal injections.
Focal finding were reported recently by Leutmezer et al68 beside generalized spike-wave discharges in IGE patients. Unterberger et al.69 in
JME, Usui et al and Yoshinaga et al70, 71., Holmes et
al72 were able to detect focal cortical onset in
absence epilepsy with source localisation method.
Regional, bilateral frontal origin or at least participation was suggested by mapping studies73 in
human absence spike-wave and directional spread
over the scalp with a speed of 2-15 m/sec by toposcopy74.
Several case studies described focal frontal spiking and frontal seizure onset in absence epilepsy
and in nonconvulsive status epilepticus75–78 showing
bifrontal asymmetric electrical fields both for the
spike and the wave component behind the seemingly more widespread EEG appearence.
However all these data about “focality” were
held for long time as exceptions “proving the rule”,
although some authors suggested cortical origin
with maximal frontal lobe involvement very
early79, 80.
Almost parallely with the description of the 3 Hz
generalized spike-wave pattern a slower variation
with a frequency range around 2 Hz has also been
delineated. Asymmetries and focal features were
described with this variation even more frequently
and focal seizure symptomes and cerebral structural
pathologies, furthermore cognitive deficits were
associated.
To harmonize these findings with the centrencephalic hypothesis Jasper and co-workers developed the concept of “secondary bilateral synchrony”81, 82. This concept was firstly based on the
observation of Tükel and Jasper83 who described 31
patients who had surgically proven epileptogenic
focal cortical lesions localized to the supracallosal
frontal medial surface. Twenty one of them had
generalized spike-wave pattern with a frequency
range 2-3.5 Hz and the majority had 2-2.5 Hz pattern, but also had focal features and independent
focal discharges pointing to the parasagittal region.
The EEG abnormalities vanished after surgery.
According to the original concept of Jasper the
focal cortical epileptic discharges may transform to
bilateral spike-wave pattern with (secondary)
involvement of the thalamic non-specific system.
Later japanese authors84 have shown that the phenomenon of “secondary bilateral synchrony” can be
explained by fast cortico-cortical spread, without
involvement of the thalamic system.
FOCAL FEATURES IN SEIZURE SEMIOLOGY, COGNITION,
NEUROIMAGING AND HISTOLOGY
It is a common experience to see localized motor
symptoms as adversion, unilateral facial convulsion, asymmetric involvement of limbs in “generalized” tonic-clonic seizures of patients otherwise
fullfilling the criteria of IGE. Even in typical
absence seizures Stefan85 clearly recognized focal
features in the form of a somatotopic cranio-caudal
march. The study of cognitive impairments during
absences also supports more a patchy than diffuse
involvement of the cortex86. The jerks of JME can
be unilateral or with unilateral predominance and
even if it is bilateral symmetric reflects only motor
(that means local or regional) cortical involvement,
372 Halász: New vistas and views in the concept of generalized epilepsies
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since in this form loss of consciousness is not present.
An other line of evidences come from those
cases where local cortical lesions were found behind seemingly “generalized” EEG and clinical features87. Quantitative MRI and magnetic resonance
spectroscopy studies recently showed focal structural alterations88 in the frontal lobe89. Savic90 found
decreased NAA values in JME patients91. Neuropsychological studies confirmed the early statement of Janz92, that JME patient’s personality traits
are similar to those seen in frontal lobe damaged
patients93. One study has shown microdysgenezis in
CAE és JME patients94 in the frontal lobe.
REFLEX EPILEPTIC FEATURES IN IGE INDICATING
LOCAL/REGIONAL CORTICAL HYPEREXCITABILITY
It is well known, that activation of specific cortical
areas by sensory, non verbal or verbal cognitive
stimuli may induce generalized seizures. The electroclinical characteristics, pharmacological responsiveness of the patients having reflex seizures are
identical with different forms of IGE especially
JME95.
Photosensitivity is most frequently associated
with JME (in 40-90%)96, 97. Pattern sensitivity,
elicited by escalator steps, stripped wallpaper or
clothings98 television and video games can elicit
generalized seizures in IGE patients99, 100. When the
appropriate visual stimuli activates a critical
amount of cortical tissue in the striate and parastriate cortex, synchronized neuronal activity producing local epileptic discharge is induced and latter,
by propagation from parieto-occipital areas to cortico-thalamic and cortico-cortical pathways generalized epileptic discharges and consequently generalized seizure symptoms develop.
Seizures may be induced by thinking101 (calculation, decision making, playing chess, scrabble
or card games). The EEG in majority of these
patients shows generalized epileptic discharges,
while neuropsychological evaluation reveals regional deficits mainly of parietal lobe functions. Inoue
et al102 emphasized the role of motor components in
seizure induction, and proposed the term “praxisinduced epilepsy”. Arithmetic and spacial task
solving probably activate dominant parietal areas
and involvement (induction) of praxis helps to
reach “critical mass” activation, consequently triggering seizures.
Reading epilepsy is one of the most interesting
epilepsy type in which different variation of reading
activity evokes generalized seizures. The only common factor is the transformation of the linguistic
material from graphemas to language103. Patients
show more or less IGE features. The proper place in
classification of this kind of epilepsy is pending
between the partial and the generalized group104. A
spike triggered fMR study showed activation over
the same posterior dorsolateral prefrontal cortex
area normally activated by reading105. The cortical
hyperexcitability could be determined by genetic
predisposition106, or can develop after aquired lesions107, 108.
These reflex epilepsies clearly shows us that
activation of certain cortical areas by sensory stimuli or verbal and non verbal mental task may trigger
the seizures in certain IGE like patients having
genetically determined or acquired predisposition
to local/regional hyperexcitability.
EXPERIMENTAL AND CLINICAL EVIDENCES FOR CORTICAL
ORIGIN
Several data point to the role of frontal lobe and
other associative cortical areas in the pathogenezis
and probably in seizure initiating in IGE. This was
recently supported by the data of the Luijtilaar
group of Nijmegen and seems to be recognized by
the international epilepsy community. WAG/Rij rat
model is one of the most relevant model of absence
epilepsy and within the IGE group absence is
attributed most likely to the thalamocortical pathogenesis. However the analysis of spontaneous
bilaterally generalized syncronous spike-wave discharges in freely moving WAG/Rij rats revealed a
consistent cortical focus109. This analysis furthermore evidenced that the cortical focus is the main
driving factor in initiating paroxysmal oscillations
in the thalamo-cortical loop via intracortical and
corticothalamic pathways entraining the thalamocortical oscillations in a stepwise way. The cortical
focus location was found in the somatosensory
cortical area of the nose and upper lip showing
rhytmical tremor during the discharges. Alterations
of this particular area have been started to evaluate
in dendrite arborisation properties110, ion channel
alterations111, 112 and antiepileptic drugs injected to
this area proved to deactivate the cortical pacemaker113, 114.
These findings may shed more light to the pathophysiology of human IGE as well, since several
data not fitting in the earlier thalamocortical
hypothesis may gain new meaning. The cortical
focus theory may explain the findings of localised
start and asymmetries of the generalized spikewave pattern, the focal start of clinical seizures and
in general the coexistence of focal and generalized
EEG features. It may explain why seemingly not
Ideggyogy Sz 2009;62(11–12):366–380.
373
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related syndromes (as reading epilepsy with JME
and pattern sensitive reflex epilepsies with JME)
show overlaps. Also we may get explanation for the
focal origin and treatability with local interventions
of some childhood syndromes, previously held to
be generalized.
Chloride channel encoding CLCN2
Gene mutations, with hyperpolarizing effect, where
shown to be associated with CAE, JAE and JME
and grand mal in awakening120.
GABA receptors
Lessons learned by human genetic
research
ARE THERE SINGLE GENE DISORDERS UNDERLYING
IGE PHENOTYPES?
Despite the enormous work done in the field of
epilepsy genetics in the past 10 years, the genetical
background of the most common idiophatic epilepsies is not yet resolved. Although, that the genetic
component is the most important etiology is undoubtful, the hope to find channel disfunction
behind common IGEs, is disappointing. Different
channels, receptors and receptor proteins were suspected to be the underlying genetic substrate.
All mutations relevant for epilepsy were related to
GABA-A receptors, a transmitter gated channel
with the central Cl permanent pore, formed by α, β,
γ, δ, ε and θ subunits. Genes having role in IGE are
GABRG2, GABRA1 and GABRD encoding the γ,
α and δ receptors. GABRG2 mutations were shown
in GEFS+, SMEI and FC families and in CAE121.
GABRA1 mutations encoding the alpha 1 subunit
of the GABA-A receptor were found in JME families and in sporadic CAE patients122.
Delta subunits are extrasynaptic and respond to
ambient GABA contributing to tonic inhibition.
Their mutation was found in GEFS+ and JME123.
MULTIPLE GENETIC INFLUENCE?
Low-voltage-activated, or T-type,
calcium channels
The genetic defects of Ca channels are rare in
humans. CACNA1 A (P/Q type of Ca channel) and
CACNAB4 mutations were found in patients with
GTCS, in absence epilepsy and in one patient with
JME, all were loss of function mutations115, 116.
CACNA1H, which mediates low treshold action
potentials to support burstfiring in thalamo-cortical
circuity might have greater importance. This protein
was found in the V cortical layer and in the reticular
thalamic nuclei117. It is believed to play a role in generation of absences. Three types of low voltage Ca
channels exist, giving rise to alternative spliced transcripts. Also single nucleotide polimorfism alter
channel activity, giving rise to different types of
spike-wave patterns118. Over 30 mutations were
found in IGE cases, 12 mutations in CAE and JAE in
Chinese population119 suggesting, that this gene may
be a major susceptibilty gene involved in absence
epilepsy. Unfortunatelly this was not confirmed in
the white European population. It is well known, that
low treshold T-type Ca2 currents regulate the thalamo-cortical bursting mode. The well known antiabsence drug, ethosuccinimide is a T-type current
blocker. In this setting the gain in function of the Ttype channel mutation increases the thalamo-cortical
excitability. Functional voltage-clamp studies of different CACNA1H mutations led unfortunatelly to
contradictory findings, alhough most of them supported the above mentioned theory.
There is evidence of complex inheritance due to
multiple susceptibility genes in most idiopathic epilepsies with or without an environmental component. There are several factors which further complicate genetical research. Incomplete penetrance
which may bias linkage studies, variable expression, genetic anticipation, locus and allelic heterogenity are further modifying factors which make
genetical research in IGE more difficult. Changes
on molecular level therefore may manifest differently on clinical level.
From this orchestra of genes each per se may
have some influence on cellular excitability, and
their inherited set, their fine tuning influences the
particular phenotypic aspect of the inherited IGE,
leading to considerable phenotypic variation within
the family. It becomes clear, that this significant
genetic bacground contributes to clinical heterogenity. This multiple genetic influence has been modelled in mice using strains with known seizure susceptibility differences measuring, and confirming
certain neurophysiological features (for example:
increased GABA-ergic thalamic input in one genetic strain, or different sleep EEG frequency in other).
Also double mutant, or combined mutant rodents
can be studied for exacerbating or silencing features
of certain genes in combination124.
To reveal genetic background in complex, probably multigenetic diseases (as schizophrenia or
autism and also complex epilepsies), the endophenotype concept can be a helpful approach. Endo-
374 Halász: New vistas and views in the concept of generalized epilepsies
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phenotypes are genetically based smaller moduls
of the complex diseases, reflecting usually a certain feature (a piece of mosaic) of the functional
disorder. Accross different forms of IGE we have
several endophenotypic biological markers like the
characteristic EEG trait of bilateral synchronous
spike-wave discharge variants, photosensitivity,
age dependency of symptomes, or even the seizure
types. These markers overlap among accepted IGE
syndromes. Endophenotypic traits, as genically
determined biological features can help to establish
associated features and develop syndromic relationships in better harmony with the genetic background.
Although polygenic inheritance is probable,
recognition of three main generalized phenotypes
(GEFS+, CJAE, JME) suggests, that they are determined by few major susceptibility genes. The mentioned syndromes segregate distinctly in epidemiological studies. They are rather oligogenic, than
polygenic. The genes with major effects are probably ion channel genes, determining the main trait –
for example the EEG 3 Hz spike-wave pattern-acting together with a number of modifying genes
affecting other clinical characteristics of the phenotype. Or vice versa, the main genes such are
CACNA1H or GABRA1 or GABRG2 genes or
other susceptibility genes can act as modifier loci
affecting penetrance or expressivity of the mutations of those monogenic epilepsies that segregate
through large families.
common in Japan, so they proposed to change the
name of the syndrome to “autosomal dominant
epilepsy with febrile seizures” (leaving the term
“generalized” out)126.
Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+) can both arise due to
mutations of SCN1A, the gene encoding the alpha
1 pore-forming subunit of the sodium channel. The
GEFS+ spectrum comprises a range of mild to
severe phenotypes varying from classical febrile
seizures to Dravet syndrome. Dravet syndrome is a
severe infantile onset epilepsy syndrome with multiple seizure types, asymmetric, mostly unilateral
prolonged febrile seizures and statuses. Later in the
course of the disease beside generalized seizures
various focal seizures and focal neurological signs
may appear, with developmental slowing and poor
outcome. More than 70% of patients with Dravet
syndrome have mutations of SCN1A; these include
both truncation and missense mutations. In contrast,
only 10% of GEFS+ families have SCN1A mutations and these comprise missense mutations.
GEFS+ has also been associated with mutations of
genes encoding the sodium channel beta 1 subunit,
SCN1B, and the GABA-A receptor gamma 2 subunit, GABRG2. The phenotypic heterogeneity that
is characteristic of GEFS+ families is likely to be
due to modifier genes127. Border line cases falling
between GEFS+ and SMEI were desribed where
focal seizures were not rare128. Also focal seizures
evolving from generalized EEG disharge were
desribed129.
Delineation of generalized epilepsy
with febrile seizures plus (GEFS+)
shaped further the landscape
SOME CLUES?
The discovery of GEFS+ syndrome as a genetically
unique disorder with heterogeneous phenotypes and
later, the discovery of SMEI (Severe Myoclinic
Epilepsy in Infancy) as a spectrum disorder belonging to the most severe end, was a breakthrough
which bridged the dichotomy of focal/generalized
based on genetical clues and was again a nail into
the coffin of the generalized epilepsy concept.
GEFS+ syndrome was described examining
2000 individuals belonging to a large family and
individual phenotypes belonging to a core family.
Different phenotypes from the generalized group
were described, typical febrile seizures (FS), typical
FS but peristing above 6 years of age, FS with
absences, FS with myoclonic seizures, FS with
atonic seizures, and myoclonic astatic epilepsy125.
Later partial seizures were described as a possible
seizure type in GEFS+. Partial seizures were more
Genetic analysis of sets of families suggests that
CAE and JAE share a close genetic relation, whereas JME is a distinct entity. FS and GTCS were frequent in both groups representing a non-specific
susceptibility to seizures. Classic FS were common
in all IGE groups, but FS+ was uncommon in relatives of IGE probands, suggesting that IGE and
GEFS+ are caused by different sets of genes.
What is common and different among
the electro-clinical phenotypes of IGE?
According to the present state of art four types of
IGE has been recognized by the ILAE current classification: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic
epilepsy (JME) with jerks without loss of consciousness and GTC seizures, and IGE with awakening GTC seizures (EGMA). Three additional
Ideggyogy Sz 2009;62(11–12):366–380.
375
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types are proposed: myoclonic absence epilepsy
(MAE), eyelid myoclonia with absences (EMA)
and perioral myoclonia with absences (PMAE)130.
The officially recognized types differ according
to the predominance of absence types, the myoclonic and generalized tonic clonic seizures. JME
and EGMA are characterized by multiple spikes
(JME) and tonic spiking (EGMA) ictally and by
the predominance of motor symptoms starting in
adolescence/young adulthood, compared to CAE
and JAE. They do not have prominent motor symptoms they show overwhelming inhibitory phenomena and occur in a younger age group. The genetical relationship is presently not thoroughly cleared
up, but we know several endophenotypes overlaping between these types. However there are strong
evidences in favor of syndromatic independency130
however, thinking about IGE as a biological continuum131, at least from the conceptual point of
view, is also very convincing. Although there is
some kind of biological unity of the IGE group,
this not justifies to separate them under the arteficial and misleading heading of “generalized epilepsy”. From the physiopathogenetic aspect the
differences regarding the presence or absence of
motor symptoms and their myoclonic or tonic character, may relate to the extent and regionality of
cortical excitation, to the relationship of local
frontal regional initiatory mechanism with the thalamocortical syncronization machine and also to
the role of GABA-ergic (A and B) recurrent inhibition or other receptor abnormalities in the pathological oscillation, promoting hypersynchron epileptic oscillation within the thalamocortical system. All of the aformentioned parts of the system
are obviously underlied by different genetic regulation and further genetic studies may modify the
relationship among different phenotypic (EEG and
clinical) features.
Implications to classification –
toward an unified epilepsy concept
The epileptic disorder of the thalamo-cortical system is responsible for the development of “primary
generalized”, synchronous spike-wave paroxysms,
which were the essential common neurophysiological determinator of IGEs.
This disorder is specifically related to the burstfiring working mode of the thalamo-cortical system
during NREM sleep (is an epileptic exageration of
it).
The epileptic disorder of the thalamo-cortical
system may develop from several reasons, due to
alterations within the system and due to changes of
connected influencing ascending and descending
systems. Epileptic hyperexcitation and seizures
develop stepwise in the system and may have a
localized onset in different cortical areas.
In the WAG/Rij rat model the pacemaker is in
the perioral somato-sensory cortex. In the humans
the frontal cortex has probably a great role too. The
epilepsy type earlier named as IGE is a focal/regional epilepsy which involves a bilateral network
associated with widespread sensory and cognitive
functions of both hemispheres.
The “generalized” epilepsy category should be
abandoned, being misleading. The categorisation of
epilepsies would be best to conceptualize in a multiaxial system, the physiopathogenesis of which
would be determined in terms of network functions,
related to physiological working systems.
The epileptic network of the thalamocortical system, according to our present knowledge, is denominating in the following epilepsies:
– The different subtypes of IGE (CEA, JAE,
JME, GMA etc.).
– The hitherto not classified cases at the borderline of focal epilepsy and IGE.
– LGS.
– LKS-ESES.
The different phenotypes, earlier named idiopathic (primary) generalized, or symptomatic (secondary) generalized (with encephalopathic features), should be delineated depending on the following factors: 1. speed and extent of syncronization within the thalamo-cortical system, 2. the way
how the thalamo-cortical system is involved, 3.
which kind of cortical triggers play role, 4. the
degree and level of the disorder (restricted to the
molecular level or extended to the level of structural alterations – in the cortex or more diffusely, 5.
genetic targets and features.
376 Halász: New vistas and views in the concept of generalized epilepsies
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