Trends in Pharmacological Sciences
Pharmacology of absence epilepsy
Section snippets
Animal models of absence epilepsy
Validation of animal models of absence epilepsy requires certain criteria to be met for them to be representative of the human condition [4]. These should include close correlation of electroencephalographic characteristics and associated behaviours, appropriate ontogeny, a pharmacological profile of SWD attenuation or exacerbation that mirrors the childhood disease, and demonstration of SWD activity in the cortex and thalamus, but not in the hippocampus. These animal models can be subdivided
Pathogenesis of absence epilepsy
The involvement of a thalamocortical circuit, particularly the contribution of the ventrobasal thalamus (VB) and reticular thalamic nucleus (RTN), in the propagation of absence seizures has been established for several years 10, 11, 12, 13 (Figure 1b). Aberrant corticothalamic rhythms are believed to be the substrate of SWD. Thalamic neurons have the ability to shift between an oscillatory and burst firing mode [14], and this regulates the impact of external stimuli. Oscillatory neuronal
Pharmacological modification of absence seizures
The mainstays of the therapeutic treatment of absence epilepsy, over at least the past three decades, have been sodium valproate and ethosuximide. However, there are other compounds that, although not used clinically, can suppress SWD activity in animal models and either have been shown to exert the same effect in humans or might be predicted to do so. Substances that have the opposite effect and exacerbate seizure activity, both in animal models and clinically, also exist. Table 2 summarizes
Treatment strategies for absence epilepsy
If typical absence seizures are the only type of seizure present, then monotherapy with ethosuximide, sodium valproate or lamotrigine is usually indicated, with symptom-led titration up to the maximum tolerated dose. If this fails, or if there are unacceptable adverse reactions, then an alternative monotherapy is usually sought. Only in a small percentage of cases of typical absence epilepsy is polytherapy required, with a combination of sodium valproate and lamotrigine being the most common.
Future directions
Although it has long been known that interplay between the thalamus and the cortex is crucial for the generation of generalized absence seizures, it has only recently become apparent that these seizures might be initiated at a specific cortical site (S1po) and that they then generalize from this focus [24]. Furthermore, the demonstration that ethosuximide, a core therapy for absence epilepsy during several decades, might exert its inhibitory effects on absence seizures at this focus [40] raises
Note added in proof
Recently, a novel spontaneous rat model of absence epilepsy, the Fischer-344 rat, has been described [62]. Unlike the GAERS and WAG/Rij strains, these rats have never been genetically pre-selected. However, in common with the chemically induced THIP {4,5,6,7-tetrahydroisoxazolo[4,5,-c]pyridine-3-ol} model (Table 1), the absence seizures are exacerbated rather than attenuated by sodium valproate, the traditional drug used to treat absence epilepsy.
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2018, Clinical NeurophysiologyCitation Excerpt :Sleep spindles require reticular thalamic cells for their generation and occur in the thalamus of decorticated cats although they seem to be modulated by cortical feedback and hence cortex and thalamus constitute a unified oscillatory structure (Steriade et al., 1985; Timofeev and Steriade, 1996). Zero-lag estimates in sleep spindles shown before, accompanied by very high levels of interhemispheric synchronisation, are consistent with our current findings and may occur through the nucleus reticularis thalami (RT) and corticothalamic (CT) relay cell involvement (Timofeev and Steriade, 1996; Manning et al., 2003; Hughes, 2009; Chen et al., 2014; Depaulis et al., 2016). These lines of evidence suggest that the thalamus relays distant cortical neuronal networks into a tight zero lag synchronicity during typical absences.
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