Ovariectomy enhances spike-wave discharges in WAG/Rij rats

Objective

To determine the effect of withdrawal of ovarian hormones on the occurrence of absence seizures in WAG/Rij rats, a well-validated animal model for absence epilepsy.

Methods

Two weeks after electroencephalography (EEG) electrodes were implanted, video-EEG recordings of 16 adult female WAG/Rij rats were made. The rats were then randomly assigned to undergo ovariectomy or sham surgery. One week after surgical procedures, EEG recordings were made for five consecutive days. The EEGs were amplified and filtered between 1 and 100 Hz and digitized at 200 Hz.

Results

In the ovariectomy group, both duration and the number of spike-wave discharges increased.

Conclusion

The present data suggest that ovariectomy enhances the occurrence of spike-wave discharges and absence seizures in WAG/Rij rats.     

Electrophysiological and pharmacological characteristics of two types of spike-wave discharges in WAG/Rij rats

Rats of the WAG/Rij strain are commonly seen as a genetic model for generalised absence epilepsy in man. Interestingly, generalised absence epilepsy shows, in addition to the fully generalised spike-wave discharges, a second type of spike-wave discharge, which lasts for a shorter time, has a lower frequency, and a lower incidence. The originally described distinction between the two types of spike-wave discharges was mainly based on the shape, polarity and duration of the discharges. In the present study other characteristics such as the spatial and temporal distribution of the spike and wave components of the two discharges and frequency spectra were found to differ between the two types. In addition, a reciprocal regulation of the two types of spike-wave discharges by drugs affecting the dopaminergic system (haloperidol and apomorphine) was observed. The results convincingly demonstrate the difference between the two phenomena and warrant the search for neurobiological mechanisms underlying both types of spike-wave discharges.     

Chromosomal mapping of genetic loci controlling absence epilepsy phenotypes in the WAG/Rij rat

PURPOSE: The WAG/Rij rat is among the most appropriate models for the study of spontaneous childhood absence epilepsy, without complex neurologic disorders that are associated with some mouse models for absence epilepsy. Previous studies have allowed the identification of distinct types of spike-wave discharges (SWDs) characterizing seizures in this strain. The purpose of this study was to investigate the genetic basis of electroencephalographic (EEG) properties of SWDs. METHODS: An intercross was derived from WAG/Rij and ACI inbred strains that are known to differ substantially in the number of SWDs. Phenotypic analyses based on 23-h EEG recording in all progenies allowed the quantification of type I and type II SWD phenotypes. A genome-wide scan was performed with 145 microsatellite markers, which were used to test for evidence of genetic linkage to SWD quantitative phenotypes. RESULTS: We were able to map quantitative trait loci independently, controlling type I and type II SWD variables to rat chromosomes 5 and 9. Strongest linkages were obtained for D5Mgh15 and total duration of type II SWD (lod, 3.64) and for D9Rat103 and the average duration of type I SWD (lod, 3.91). These loci were denoted T2swd/wag and T1swd/wag, respectively. CONCLUSIONS: The independent genetic control of type I and type II SWDs underlines the complexity of the molecular mechanisms participating in SWDs. The identification of these genetic loci represents an important step in our fundamental knowledge of the architecture of SWDs and may provide new insights for resolving the genetic heterogeneity of absence epilepsy.     

Some solvents for antiepileptics have proepileptic potencies in the WAG/Rij rat model for absence epilepsy

Some solvents for antiepileptics were tested, for 4 consecutive days, in a rat model (the WAG/Rij inbred strain) for absence epilepsy. Electroencephalogram registrations and behavioral observations suggested that both Tween-80 and a mixture of saline/ethanol/propylene glycol caused an increase in the number of epileptic phenomena. This increase was not significant and restricted to injection day 1 with Tween-80 but was significantly present during all 4 injection days with the saline/ethanol/propylene glycol mixture. Furthermore, with this latter solvent the increase became larger during consecutive days. Because of the proepileptic potencies and the differential time effects of these solvents, their usage should be seriously questioned.     

Internal desynchronization facilitates seizures

Purpose: The occurrence of spike‐wave discharges (SWDs) in WAG/Rij rats is modulated by the circadian timing system and is shaped by the presence of a light–dark cycle, motor activity, and state of vigilance. Here it is investigated whether the response to a phase shift is different between the SWDs and general motor activity rhythm. The process of reentrainment of both rhythms and its effect on number of absences was compared after a phase shift in the light–dark cycle, a condition known to induce internal desynchronization in the circadian timing system. Methods: Chronic electroencephalographic and motor activity recordings were made in adult WAG/Rij rats, kept in the 12:12 h light–dark cycle. After four baseline days, rats were exposed to an 8‐h phase delay by shifting the light onset. Recordings were continuously made for another 10 consecutive days. Key Findings: An immediate effect of the phase shift on both rhythms was observed: the acrophases were 7.5 h advanced. Next, they gradually returned to the baseline level, however, with a different speed. The more robust motor activity rhythm stabilizes first, whereas the weaker rhythm of SWDs adapted more slowly. The phase shift caused a prolonged aggravation of epileptic activity, observed mostly during the light phase. Significance: Different speed and character of reentrainment suggests that the occurrence of seizures and motor activity are controlled by distinct circadian oscillators. The prolonged increase in absences after the phase shift has immediate practical consequences.     

Comparison of the antiepileptogenic effects of an early long‐term treatment with ethosuximide or levetiracetam in a genetic animal model of absence epilepsy

Purpose: Epilepsy is a heterogeneous syndrome characterized by recurrent, spontaneous seizures; continuous medication is, therefore, necessary, even after the seizures have long been suppressed with antiepileptic drug (AED) treatments. The most disturbing issue is the inability of AEDs to provide a persistent cure, because these compounds generally suppress the occurrence of epileptic seizures without necessarily having antiepileptogenic properties. The aim of our experiments was to determine, in the WAG/Rij model of absence epilepsy, if early long‐term treatment with some established antiabsence drugs might prevent the development of seizures, and whether such an effect could be sustained. Methods: WAG/Rij rats were treated for ～3.5 months (starting at 1.5 months of age, before seizure onset) with either ethosuximide (ETH; drug of choice for absence epilepsy) or levetiracetam (LEV; a broad‐spectrum AED with antiabsence and antiepileptogenic properties). Results: We have demonstrated that both drugs are able to reduce the development of absence seizures, exhibiting antiepileptogenic effects in this specific animal model. Discussion: These findings suggest that absence epilepsy in this strain of rats very likely follows an epileptogenic process during life and that early therapeutic intervention is possible, thereby opening a new area of research for absence epilepsy and AED treatment strategies.     

Metabotropic glutamate receptors in the thalamocortical network: strategic targets for the treatment of absence epilepsy

Metabotropic glutamate (mGlu) receptors are positioned at synapses of the thalamocortical network that underlie the development of spike-and-wave discharges (SWDs) associated with absence epilepsy. The modulatory role of individual mGlu receptor subtypes on excitatory and inhibitory synaptic transmission in the cortico-thalamo-cortical circuitry makes subtype-selective mGlu receptor ligands potential candidates as novel antiabsence drugs. Some of these compounds are under clinical development for the treatment of numerous neurologic and psychiatric disorders, and might be soon available for clinical studies in patients with absence seizures refractory to conventional medications. Herein we review the growing evidence that links mGlu receptors to the pathophysiology of pathologic SWDs moving from the anatomic localization and function of distinct mGlu receptor subtypes in the cortico-thalamo-cortical network to in vivo studies in mouse and rat models of absence epilepsy.     

Unilateral thalamic lesions and generalized or lateralized spike wave discharges

We report four adult patients who had thalamic lesions and lateralized or generalized spike wave discharges (SWDs). The first two patients also had cortical lesions. The role of the cortex and thalamus in the generation of SWDs is discussed. The third patient had a history of idiopathic generalized epilepsy (IGE) with intractable seizures. The last patient had partial seizures and absences. The coexistence of IGE with refractory focal epilepsy and the relation with thalamic lesions are discussed.     

Electroencephalographic characterization of spike-wave discharges in cortex and thalamus in WAG/Rij rats

PURPOSE: The waveform of spontaneous spike-wave discharges (SWD) in the electroencephalogram (EEG) was delineated in the WAG/Rij rat model of absence epilepsy according to the definitions of clinical electroencephalography. We defined four elements in SWD based on the schema of Weir (1965): Spike 1 and 2, Positive Transient (PT), and Wave. The EEG patterns of generalized type I and local type II SWD in cortical and thalamic areas were analyzed. METHODS: EEGs were recorded in freely moving rats epidurally from different cortical regions and with deep electrodes from the specific and reticular thalamic nuclei. Grand average SWD waveforms were computed to assess spatiotemporal patterns of seizures. RESULTS: SWD I in the frontal cortex comprised of a large Spike 2 + Wave, and in the thalamus PT + Wave. Small transient spikes were associated with SWD I in the anterior-middle part of the cortex. SWD II were found in the occipital cortex as a sequence of (occasional) Spike 1 + PT + Wave. CONCLUSIONS: The EEG structure of SWD in WAG/Rij rats was comparable with that of epileptic patients, suggesting face validity of the WAG/Rij model. Fast transients spikes are an integrative part of SWD I. Time-amplitude linkage between cortical and thalamic counterparts of SWD I suggests a complex spatiotemporal organization of SWD I. The thalamus sustained SWD I, but not SWD II.     

The effects of vigabatrin on spike and wave discharges in WAG/Rij rats

The effects of vigabatrin, which increases GABA concentrations by inhibiting GABA transaminase, on spike and wave discharges (SWDs) in the electroencephalogram of WAG/Rij rats were studied. Vigabatrin increased the incidence and duration of the SWDs, suggesting a quantitative GABA(A)ergic involvement in the mechanism(s) underlying the starting and stopping of an ongoing SWD. Also, vigabatrin decreased the SWD peak frequency, suggesting an important role of GABA(B) in the mechanism(s) underlying the peak frequency of the SWDs. Vigabatrin gradually changed the course of the hazard rates of the SWD durations, suggesting a qualitative GABAergic role in the mechanism(s) underlying the stopping of an ongoing SWD.     

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

The WAG/Rij rat model has recently gathered attention as a suitable animal model of absence epileptogenesis. This latter term has a broad definition encompassing any possible cause that determines the development of spontaneous seizures; however, most of, if not all, preclinical knowledge on epileptogenesis is confined to the study of post-brain insult models such as traumatic brain injury or post-status epilepticus models. WAG/Rij rats, but also synapsin 2 knockout, Kv7 current–deficient mice represent the first examples of genetic models where an efficacious antiepileptogenic treatment (ethosuximide) was started before seizure onset. In this review, we have critically reconsidered all articles published regarding WAG/Rij rats, from the perspective that the period before SWD onset is considered as the latent period. In our new theory on seizure development, it is proposed that genes might be considered as the initial ‘insult’ responsible for all plastic changes underpinning the development of spontaneous seizures. According to this idea, in WAG/Rij rats, genetic predisposition would lead to the development of abnormal bilateral cortical epileptic foci, which would then non-genetically stimulate the rest of the brain to rearrange networks in order to phenotypically develop seizures similarly to what happens during electrical kindling.     

Effects of the combination of valproate and ethosuximide on spike wave discharges in WAG/Rij rats

OBJECTIVE: We studied the interaction between valproate (VPA) and ethosuximide (ESM) in diminishing the incidence of absence-like spike-wave discharges (SWDs) in the EEG of WAG/Rij rats. METHODS: VPA, ESM, their combination and saline were evaluated in 16 rats. The doses of VPA ranged from 0 to 280 mg/kg and the doses of ESM ranged from 0 to 40 mg/kg. For the drug combination, a fixed weight ratio of 7/1 VPA/ESM was used. The incidence of SWDs in the EEG was determined for the period of 15-75 min after injection and compared to the incidence of SWDs prior to injection. The sigmoid-E(max) equation was fitted to the data. Isobolic analysis, on 50% effect, was used to assess the character of the drug interaction. RESULTS: The parameters for diminishing the incidence of the SWDs were: VPA: ED(50): 121mg/kg; ESM: ED(50): 21.5mg/kg; VPA/ESM: ED(50): 112/16 mg/kg. Isobolic analysis showed that a higher drug load was needed of the combination than of the individual drugs to achieve a 50% reduction of SWDs: factor 1.67; P = 0.012. CONCLUSION: The interaction between valproate and ethosuximide was shown to be infra-additive in diminishing the incidence of SWDs in WAG/Rij rats.     

Rhythmic neuronal activity in S2 somatosensory and insular cortices contribute to the initiation of absence‐related spike‐and‐wave discharges

Purpose: The origin of bilateral synchronous spike‐and‐wave discharges (SWDs) that underlie absence seizures has been widely debated. Studies in genetic rodent models suggest that SWDs originate from a restricted region in the somatosensory cortex. The properties of this initiation site remain unknown. Our goal was to characterize the interictal, preictal and ictal neuronal activity in the primary and secondary cortical regions (S1, S2) and in the adjacent insular cortex (IC) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Methods: We performed electroencephalography (EEG) recordings in combination with multisite local field potential (LFP) and single cell juxtacellular recordings, and cortical electrical stimulations, in freely moving rats and those under neurolept‐anesthesia. Key Findings: The onset of the SWDs was preceded by 5–9 Hz field potential oscillations, which were detected earlier in S2 and IC than in S1. Sustained SWDs could be triggered by a 2‐s train of 7‐Hz electrical stimuli at a lower current intensity in S2 than in S1. In S2 and IC, subsets of neurons displayed rhythmic firing (5–9 Hz) in between seizures. S2 and IC layers V and VI neurons fired during the same time window, whereas in S1 layer VI, neurons fired before layer V neurons. Just before the spike component of each SW complex, short‐lasting high‐frequency oscillations consistently occurred in IC ～20 msec before S1. Significance: Our findings demonstrate that the S2/IC cortical areas are a critical component of the macro‐network that is responsible for the generation of absence‐related SWDs.     

Onset and propagation of spike and slow wave discharges in human absence epilepsy: A MEG study

Purpose: A nonlinear association and a source localization technique were used to describe the onset and propagation of spike‐and‐slow‐wave discharges (SWDs) in children with absence seizures. Previous studies have emphasized a leading cortical role in the generation of absence seizures in genetic epileptic rats. Methods: Synchronization between all magnetoencephalography (MEG) sensor‐couples before and during SWDs in five patients was investigated over time. A source localization [beamformer, SAM(g₂)] technique was used to find brain regions associated with the origin of the spikes of the SWDs. Results: The onset of SWDs was characterized by high associations at left and right frontal regions. An alternating pattern of high synchronization was found during trains of SWDs: generalized during the wave and localized during the spike; the origin of the spike was different from the onset of SWDs, more frontal lateral and medial parietal. The localization of this latter region was confirmed with SAM(g₂). Discussion: The outcome of the nonlinear association techniques demonstrated that SWDs have a local cortical onset, whereas the association and beamformer technique support a local or even a focal cortical involvement in the occurrence of the spike in a train of SWDs. In all, the cortex contains local frontal and parietal sites relevant before the onset of the generalized pattern of SWDs and other ones that might contain the driving force behind the spike in trains of 3–4 Hz SWDs.     

Auditory evoked potentials from auditory cortex, medial geniculate nucleus, and inferior colliculus during sleep–wake states and spike-wave discharges in the WAG/Rij rat

Objective: Click auditory evoked potentials (AEP) were simultaneously recorded from the auditory cortex (ACx), the medial geniculate nucleus (MGN), and the inferior colliculus (IC) in the freely moving WAG/Rij rat, to investigate state-dependent changes of the AEP in different anatomical locations along the auditory pathway. Methods: AEPs obtained during active (AW) and passive wakefulness (PW), slow wave sleep (SWS), rapid-eye-movement sleep (REM) and generalized spike-wave discharges (SWD; a specific trait of the WAG/Rij rat, a genetic model for absence epilepsy), were compared. Results: The early components in ACx, MGN and IC were stable throughout the sleep–wake cycle and SWD, apart from a slight increase in the IC during SWD. At all three locations a prominent enlargement of a later component (i.e., N32 in IC, N33 in MGN, and N44 in ACx) was found during SWS and SWD. Conclusions: The early AEP components are not modulated by the normal sleep–wake states, and are not impaired during SWD. A strong state-dependent modulation of a later AEP component occurs at all three anatomical locations investigated. This suggests that apart from the thalamic burst firing mode, additional mechanisms must exist for the enlargement of the AEP during EEG-synchronized states at the prethalamic and cortical level.     

Amygdala kindling in the WAG/Rij rat model of absence epilepsy

PURPOSE: The kindling model in rats with genetic absence epilepsy is suitable for studying mechanisms involved in the propagation and generalization of seizure activity in the convulsive and nonconvulsive components of epilepsy. In the present study, we compared the amygdala kindling rate and afterdischarge characteristics of the nonepileptic Wistar control rat with a well-validated model of absence epilepsy, the WAG/Rij rat, and demonstrated the effect of amygdala kindling on spike-and-wave discharges (SWDs) in the WAG/Rij group. METHODS: Electrodes were stereotaxically implanted into the basolateral amygdala of rats for stimulation and recording and into the cortex for recording. After a recovery period, the animals were stimulated at their afterdischarge thresholds. EEG was recorded to analyze SWDs and afterdischarge durations. The seizure severity was evaluated by using Racine's 5-stage scale. RESULTS: All nonepileptic control and four of seven WAG/Rij animals reached a stage 5 seizure state, whereas three animals failed to reach stage 3, 4, or 5 and stayed at stage 2 after application of 30 stimulations. Interestingly, WAG/Rij rats, resistant to kindling, demonstrated a significantly longer duration of SWDs on the first day of the experiment before kindling stimulation than did the kindled WAG/Rij animals. Additionally, the cumulative total duration and the number of SWDs after the kindling stimulation were statistically increased compared with SWDs before kindling stimulation. CONCLUSIONS: The results of our study demonstrate that the progress of amygdala kindling is changed in rats with genetic absence epilepsy, perhaps as a consequence of the hundreds of daily SWDs.     

Effects of age and cortical infarction on EEG dynamic changes associated with spike wave discharges in F344 rats

Rodent models of absence seizures are used to investigate the network properties and regulatory mechanisms of the seizure's generalized spike and wave discharge (SWD). As rats age, SWDs occur more frequently, suggesting aging-related changes in the regulation of the corticothalamic mechanisms generating the SWD. We hypothesized that brain resetting mechanisms – how the brain “resets” itself to a more normal functional state following a transient period of abnormal function, e.g., a SWD – are impaired in aged animals and that brain infarction would further affect these resetting mechanisms. The main objective of this study was to determine the effects of aging, infarction, and their potential interaction on the resetting of EEG dynamics assessed by quantitative EEG (qEEG) measures of linear (signal energy measured by amplitude variation; signal frequency measured by mean zero-crossings) and nonlinear (signal complexity measured by the pattern match regularity statistic and the short-term maximum Lyapunov exponent) brain EEG dynamics in 4- and 20-month-old F344 rats with and without brain infarction. The main findings of the study were: 1) dynamic resetting of both linear and nonlinear EEG characteristics occurred following SWDs; 2) animal age significantly affected the degree of dynamic resetting in all four qEEG measures: SWDs in older rats exhibited a lower degree of dynamic resetting; 3) infarction significantly affected the degree of dynamic resetting only in terms of EEG signal complexity: SWDs in infarcted rats exhibited a lower degree of dynamic resetting; and 4) in all four qEEG measures, there was no significant interaction effect between age and infarction on dynamic resetting. We conclude that recovery of the brain to its interictal state following SWDs was better in young adult animals compared with aged animals, and to a lesser degree, in age-matched controls compared with infarction-injured animal groups, suggesting possible effects of brain resetting mechanisms and/or the disruption of the epileptogenic network that triggers SWDs.     

Effects of ethanol on the development of genetically determined epilepsies in rats

In the present study, we provide evidences for a differential effect of perinatal alcohol exposure with a direct correlation to the genetic background on the development of seizures. Ethanol (EtOH) is a widely used psychoactive substance that exerts its action by affecting multiple targets in the central nervous system. EtOH is known to interact with almost all identified neurotransmitters although its effects on excitatory and inhibitory amino acid neurotransmissions are considered to be particularly important in the mediation of its behavioural effects. Prenatal exposure to alcohol is associated with a wide variety of offspring's abnormalities which lead to the so called foetal alcohol syndrome (FAS), which is also related to a higher susceptibility to convulsions. In our study, a rat strain of convulsive epilepsy, the GEPRs rats, displayed an increase of seizure susceptibility after foetal exposure to this teratogenic drug, while a non-convulsive rat strain of absence epilepsy, the WAG/Rij rat, did not fully develop its characteristic features. However, when all groups of rat where tested for pentyletetrazole-induced convulsion, animals perinatally treated with ethanol were less responsive in comparison to their respective controls. These results are in agreement with previous reports showing how the genetic background can directly influence the teratogenic effects of alcohol, and this can be strictly related to the variability in the observation of offspring anomalies in humans which has lead to a 5-category classification system for individuals exposed to alcohol in uterus.     

Early molecular and behavioral response to lipopolysaccharide in the WAG/Rij rat model of absence epilepsy and depressive-like behavior,involves interplay between AMPK,AKT/mTOR pathways and neuroinflammatory cytokine release

The mammalian target of rapamycin (mTOR) pathway has been recently indicated as a suitable drug target for the prevention of epileptogenesis. The mTOR pathway is known for its involvement in the control of the immune system. Since neuroinflammation is recognized as a major contributor to epileptogenesis, we wished to examine whether the neuroprotective effects of mTOR modulation could involve a suppression of the neuroinflammatory process in epileptic brain. We have investigated the early molecular mechanisms involved in the effects of intracerebral administration of the lipopolysaccharide (LPS) in the WAG/Rij rat model of absence epilepsy, in relation to seizure generation and depressive-like behavior; we also tested whether the effects of LPS could be modulated by treatment with rapamycin (RAP), a specific mTOR inhibitor. We determined, in specific rat brain areas, levels of p-mTOR/p-p70S6K and also p-AKT/p-AMPK as downstream or upstream indicators of mTOR activity and tested the effects of LPS and RAP co-administration. Changes in the brain levels of pro-inflammatory cytokines IL-1β and TNF-α and their relative mRNA expression levels were measured, and the involvement of nuclear factor-κB (NF-κB) was also examined in vitro. We confirmed that RAP inhibits the aggravation of absence seizures and depressive-like/sickness behavior induced by LPS in the WAG/Rij rats through the activation of mTOR and show that this effect is correlated with the ability of RAP to dampen and delay LPS increases in neuroinflammatory cytokines IL-1β and TNF-α, most likely through inhibition of the activation of NF-κB. Our results suggest that such a mechanism could contribute to the antiseizure, antiepileptogenic and behavioral effects of RAP and further highlight the potential therapeutic usefulness of mTOR inhibition in the management of human epilepsy and other neurological disorders. Furthermore, we show that LPS-dependent neuroinflammatory effects are also mediated by a complex interplay between AKT, AMPK and mTOR with specificity to selective brain areas. In conclusion, neuroinflammation appears to be a highly coordinated phenomenon, where timing of intervention may be carefully evaluated in order to identify the best suitable target.     

Audiogenic kindling in Wistar and WAG/Rij rats: kindling-prone and kindling-resistant subpopulations

Purpose: Audiogenic kindling (AK) is a model of naturally occurring epileptogenesis triggered by repeated sound stimulation of rats genetically prone to audiogenic seizures. It is accepted that limbic seizure networks underlie progressive changes in behavioral seizure pattern during AK. The present study investigated AK progression in rats susceptible and unsusceptible to absence seizures. Methods: Progression of AK as indicated by an appearance and intensification of limbic clonus was examined in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats with genetic absence epilepsy and in Wistar rats. Results: Subpopulations of kindling‐prone and kindling‐resistant rats were found in both Wistar and WAG/Rij strains. Despite identical seizure responses to the first sound stimulation, AK progression dramatically differed between the two subpopulations. AK‐prone rats exhibited rapid kindling development up to maximal stage‐5 severity. In AK‐resistant rats, limbic clonus did not appear after 30 stimulations or if it appeared, it did not progress beyond stage 2. The proportions of AK‐prone and AK‐resistant animals within Wistar and WAG/Rij strains were similar. Comparison of Wistar and WAG/Rij rats within the kindling‐prone and kindling‐resistant groups did not reveal a significant strain effect on AK progression. However, within the WAG/Rij strain, a significantly higher incidence of absence seizures was found in AK‐resistant rats compared to AK‐prone rats. Conclusions: The present study demonstrates that sensitivity to sound‐induced epileptogenesis differs dramatically within Wistar and WAG/Rij strains, whereas genetic susceptibility to absence seizures does not change AK progression significantly. It is supposed that an increased incidence of nonconvulsive seizures and resistance to kindling result from a common seizure modulating mechanism.