Interictal spikes: harbingers or causes of epilepsy?

Abstract

Interictal spikes are brief paroxysmal electrographic discharges observed between spontaneous recurrent seizures in epileptic patients. The relationship between interictal spikes and the seizures that define acquired epilepsy has been debated for decades. Recent studies using long-term continuous electrographic recordings from the hippocampus and cortex in rats with kainate-induced epilepsy suggest that electrographic spikes, with waveforms similar to interictal spikes, precede the occurrence of the first spontaneous epileptic seizure. These data raise the possibility that spikes might serve as a surrogate marker of ongoing chronic epileptogenesis. Additionally, electrographic spikes might actually contribute to the development and maintenance of the epileptic state (i.e., the increased probability of spontaneous recurrent seizures). Correlational evidence for such a causal relationship has recently also been obtained in an in vitro model of epileptogenesis using organotypic hippocampal slices. Testing for a causal relationship will ultimately require selective anti-spike medications. Although no such agents currently exist, this new preparation is amenable to moderate-throughput screening, which should accelerate their discovery. Anti-spike agents may also be of benefit in ameliorating the cognitive dysfunctions associated with epilepsy, to which spike activity may contribute.

Figure 1

Time course of electrographic spikes and seizures in rats after convulsive status epilepticus induced by kainate [34]. Times given in the figure represent ranges for the duration of each interval. The top timeline describes spike observations. High-frequency epileptiform discharges (HFED) (i.e. spiking) occurred shortly after status epilepticus; subsequently, the spikes gradually decreased in frequency (low-frequency epileptiform discharges, LFED). Individual spikes and spike clusters persisted for the life of the animal. The lower timeline describes the time course of seizure activity. Convulsive seizures appeared during kainate treatment, and then disappeared within 24 h (bottom timeline). After a seizure-free interval, seizures occurred again, but initially at a low frequency. Seizure activity increased slowly and then increased more rapidly, after which it often began to show a plateau. In all rats with convulsive status epilepticus (n=9), spike clusters occurred prior to the end of the seizure-free interval. The transition phase was defined as the time from the first kainate treatment until 10 seizures were observed per day for 2 consecutive days.

Figure 2

The time course of spikes and spontaneous recurrent seizures following after kainate-induced status epilepticus. (A) The frequency of interictal spikes and seizures after kainate treatment. Data are shown as mean normalized frequencies of spikes or seizures versus time since kainate treatment, which has been normalized to the time of maximum seizure frequency. The data were normalized in order to illustrate that the frequency of interictal spikes was high and increased before seizure frequency began to increase, and the increase in spike versus seizure frequency was independent of the time course of seizure frequency. (B) The number of EEG spikes per day and the percent of time spent in seizures are plotted in this figure for rats with latent periods of at least 2 weeks. The data from each rat is shown in a different color. Closed circles illustrate seizure time (left y-axis) and open circles show the number of spikes per day (right y-axis). In six of seven rats, rapid increases in spikes preceded similar rises in seizure time. Reprinted with permission from reference .