Evolving concepts on the pathophysiology of generalised absence seizures: the cortical focus theory

Abstract

Three major theories concerning the pathophysiology of generalised absence seizures have been proposed. Penfield and Jasper (1947) put forward the 'centrencephalic' theory, suggesting that the discharges originate from a deep-seated central subcortical pacemaker in the midline thalamus, which diffusely projects to the cortex. This concept was refined by Buzsáki (1991) who proposed that the reticular thalamic nucleus contains the pacemaker cells for the thalamic clock, which imposes its rhythm to the cortex. According to proponents of the cortical theory (Gibbs and Gibbs, 1952; Bancaud, 1969; Lüders et al., 1984; Niedermeyer, 1969), however, the cortex plays a leading role. They found evidence that generalised spike-wave discharges have a focal onset in the frontal cortex. They suggested that seizures became secondarily generalised through a rapid propagation over the cortex. The cortico-reticular theory, postulated by Gloor (1968), formed a reconciliation between the thalamic and cortical theory. Work on the 'feline penicillin generalised epilepsy' model showed that the mechanisms responsible for the spike-wave discharges were linked to the thalamocortical mechanisms that generate spindles. Gloor (1968) demonstrated that rhythmic spindle oscillations generated in the thalamus could be transformed into spike-wave discharges when the cortex was made hyperexcitable. In that case the cortex initiates abnormal hypersynchronous oscillations in the thalamocortical network. Experiments performed in genetically epileptic rats by Meeren et al. (2002) confirmed that a functionally intact thalamocortical network is required for the generation of generalised spike-wave discharges. They investigated the cortico-cortical, intrathalamic and cortico-thalamic interrelationships during spontaneous absence seizures using the advanced signal analysis method of nonlinear association analysis. The analyses revealed a consistent cortical 'focus' within the peri-oral region of the somatosensory cortex. From here, seizure activity spreads rapidly over the cortex, which gives the discharges their generalized appearance. During the first few cycles of the seizure the cortex drives the thalamus, which subsequently becomes entrained into the oscillation. Thereafter cortex and thalamus form a unified network in which both structures drive each other, thus amplifying and maintaining the rhythmic paroxysmal discharges. In this way Meeren's et al. (2002) cortical focus theory for generalised absence epilepsy forms a synthesis between the cortical and the cortico-reticular theory.