Interictal spikes in focal epileptogenesis

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Abstract

Interictal electroencephalography (EEG) potentials in focal epilepsies are sustained by synchronous paroxysmal membrane depolarization generated by assemblies of hyperexcitable neurons. It is currently believed that interictal spiking sets a condition that preludes to the onset of an ictal discharge. Such an assumption is based on little experimental evidence. Human pre-surgical studies and recordings in chronic and acute models of focal epilepsy showed that: (i) interictal spikes (IS) and ictal discharges are generated by different populations of neuron through different cellular and network mechanisms; (ii) the cortical region that generates IS (irritative area) does not coincide with the ictal-onset area; (iii) IS frequency does not increase before a seizure and is enhanced just after an ictal event; (iv) spike suppression is found to herald ictal discharges; and (v) enhancement of interictal spiking suppresses ictal events. Several experimental evidences indicate that the highly synchronous cellular discharge associated with an IS is generated by a multitude of mechanisms involving synaptic and non-synaptic communication between neurons. The synchronized neuronal discharge associated with a single IS induces and is followed by a profound and prolonged refractory period sustained by inhibitory potentials and by activity-dependent changes in the ionic composition of the extracellular space. Post-spike depression may be responsible for pacing interictal spiking periodicity commonly observed in both animal models and human focal epilepsies. It is proposed that the strong after-inhibition produced by IS protects against the occurrence of ictal discharges by maintaining a low level of excitation in a general condition of hyperexcitability determined by the primary epileptogenic dysfunction.

Introduction

Focal epilepsies are characterized by the functional disarrangement of a restricted population of cortical cells that, for various reasons, suffer a condition of increased excitability. The diverse patterns of epileptiform activity commonly observed in focal epilepsies represent the expression of dynamic changes in excitation and synchronization within the aggregate of ‘epileptic’ neurons. The characterization and the brain location of interictal EEG features observed between seizures in human epilepsies are crucial to identify different epileptic syndromes, and therefore to properly determine the treatment and the prognosis of the epileptic disorder. Interictal discharges in both experimental and human focal epilepsies, are expressed by high-amplitude (>50 μV), fast electroencephalographic (EEG) transients, defined as interictal spikes (ISs), habitually followed by a slow wave that lasts several hundreds of milliseconds (Fig. 1). The term IS includes rapid potentials designated as proper spikes (synchronous events faster then 50 ms) and slower potentials (50–200 ms duration) named sharp waves (Kooi, 1966, Chatrian et al., 1974, Gotman, 1980, Walczac and Jayakar, 1997). ISs show the tendency to recur periodically (Fig. 2A; Chatrian et al., 1964) and often cluster in brief paroxysms that either remain localized in space (arrow in Fig. 2B, left panel) or determine a secondary diffusion to the entire cortical mantle via mechanisms that probably involve subcortical structures (Fig. 2B, right panel). ISs occurring between ictal events should not be considered as simple pre-ictal phenomena since, as a general rule, ictal discharges are not the expression of a reinforcement and acceleration of interictal spiking, but are characterized by a completely different EEG pattern (Fig. 2C) in part mediated by different neuronal mechanisms.

In the present review the relationship between ISs and ictal activities in focal epilepsies is analyzed, specifically addressing the issue of whether ISs are causally involved in or protective against the transition toward an ictal discharge. We will first review the extensive experimental literature that describes the cellular and network mechanisms that subtend generation, propagation and termination of ISs (2 Cellular mechanisms of IS generation and synchronization, 3 Cortical propagation of ISs, 4 Synchronized post-IS inhibition and IS periodicity, 5 The afterdischarge (AD)). The suitability of the mechanisms identified in acute models for the chronic condition and for human epilepsy will be examined in Section 6. Based on the reviewed data, it will be discussed whether focal ISs can be interpreted as protecting events that control of neuronal activity and prevent ictal discharges in a condition of epileptic hyperexcitability. The abnormal phenomena responsible for interictal and ictal activities in focal epilepsies differ from those identified in generalized epilepsies (see de Curtis and Avanzini, 1994, Snead, 1995, Danober et al., 1998, Seidenbecher et al., 1998) that are excluded by the present review. Previous reports surveyed the basic mechanisms of focal epilepsy (Pedley, 1978, Prince, 1985, Jefferys, 1990, Delgado-Escueta et al., 1999) and IS generation (Ajmone-Marsan and Zivin, 1970, Ayala et al., 1973).

Section snippets

Cellular mechanisms of IS generation and synchronization

The IS represents the extracellular correlate of the synchronous and excessive discharge of a cortical neuronal ensemble. The cellular and network mechanisms that determine interictal spiking have been extensively studied by analyzing the IS and the post-IS period with extracellular and intracellular recordings in various animal models. It has long been demonstrated that a single IS is associated with a burst discharge characterized by a rapid sequence of fast action potentials at 200–500 Hz,

Cortical propagation of ISs

As discussed in Section 2.2, associative synaptic connections contribute to the propagation of synchronous epileptiform potentials. In different models of neocortical epileptogenesis ‘vertical’ propagation of ISs across layers (Ebersole and Chatt, 1984, Pockberger et al., 1984, Albowitz and Kuhnt, 1995) and ‘tangential’ propagation within the supragranular layers (Barth et al., 1990, Albowitz and Kuhnt, 1995, Telfeian and Connors, 1998) were demonstrated. Tangential propagation is mostly

Synchronized post-IS inhibition and IS periodicity

ISs are terminated by a transitory depression that follows and is associated with the massive synchronous neuronal discharge established during the IS itself. Enhanced neurotransmitter-mediated inhibition and changes in the intracellular–extracellular environment might account for the post-IS inhibition. In several lesional models of epilepsy GABAergic inhibition was found to be reduced (for review see Jefferys, 1990, Sloviter, 1994). Whether such decrease in inhibition is a consequence of the

The afterdischarge (AD)

A particular interictal discharge pattern, named AD, can be easily induced by electrical stimulation in animal models of focal epilepsy (see Traub et al., 1996), but is hardly observed in humans. Characterized by repeated, fast-at-onset PDSs gradually declining in frequency to circa 2–10 Hz (Fig. 15), the AD has been interpreted as a pre-ictal event or subclinical ‘embryo seizure’ (Ralston, 1958), even if its general discharge pattern is substantially different from that observed during a

Interictal discharges in human focal epilepsies

In order to study interictal activity in human focal epilepsy one has to rely on diagnostic tools that allow to discriminate and to locate in space the brain area that produce interictal spikes (irritative area) within the epileptogenic region. EEG recording from the scalp is a fundamental and irreplaceable diagnostic tool for identifying and classifying pathological brain activity in epilepsies; however, its use in defining the topography of the cortical areas that generate interictal events

Do ISs play a role in the interictal-to-ictal transition?

The studies reviewed in the previous Sections bring up to the possibility that IS and ictal discharges in focal epilepsies represent independent events generated at different sites, possibly through different cellular and network mechanisms. There is a tendency to believe that a reinforcement and/or a progressive increase in frequency and in spatial diffusion of ISs is necessary to determine a condition favorable for the generation of ictal discharges. Such an assumption is sustained by little

Conclusions

Based on the evidences discussed, one can agree with Gotman (1991), who proposed that ISs have little direct effect on seizure generation and that the rate of spiking is ‘more a reflection of past seizures than an indication of the likelihood of impending seizures’. The indications deriving from the experimental studies and from the demonstration of a reverse relationship between the rate of ISs and the susceptibility to generate ictal events rule against the attribution of a pro-convulsive

Acknowledgements

We would like to thank Dr Gerardo Biella and Dr Laura Librizzi for contributing to the original experiments described in the present review.

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