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. 2015 Feb:25:18-25.
doi: 10.1016/j.seizure.2014.11.008. Epub 2014 Nov 26.

The anti-ictogenic effects of levetiracetam are mirrored by interictal spiking and high-frequency oscillation changes in a model of temporal lobe epilepsy

Maxime Lévesque  1 , Charles Behr  1 , Massimo Avoli  2
Affiliations

The anti-ictogenic effects of levetiracetam are mirrored by interictal spiking and high-frequency oscillation changes in a model of temporal lobe epilepsy

Maxime Lévesque et al. Seizure. 2015 Feb.

Abstract

Purpose: Mesial temporal lobe epilepsy (MTLE) is the most prevalent type of partial epileptic disorders. In this study, we have analyzed the impact of levetiracetam (LEV) in the pilocarpine model of MTLE.

Methods: Sprague-Dawley rats (n=19) were injected with pilocarpine (380 mg/kg, i.p.) to induce a status epilepticus. Twelve animals were used as controls and seven were treated with LEV. They were implanted with bipolar electrodes in the CA3 subfield of the hippocampus, entorhinal cortex (EC), dentate gyrus (DG) and subiculum and EEG-video monitored continuously from day 4 to day 14 after SE.

Results: Only 29% of LEV-treated animals had seizures compared to all controls following a latent period that was similar in duration. Seizure rates were lower in LEV-treated animals. In LEV-treated animals without seizures, lower interictal spike rates were found in all regions compared to controls. Analysis of interictal high-frequency oscillations (HFO s) revealed that LEV-treated animals without seizures had lower rates of interictal spikes with ripples (80-200 Hz) in CA3, EC and subiculum (p<0.01), whereas rates of interictal spikes with fast ripples (250-500 Hz) were significantly lower in CA3 and subiculum, compared to controls.

Conclusion: Our findings indicate that the anti-ictogenic properties of LEV are mirrored by decreases of interictal spike rate in temporal lobe regions, and are accompanied by subregion-specific decreases of HFO occurrence in CA3 and subiculum. Overall, this evidence suggest that LEV may inhibit neural network activity in regions that are known to play important roles in MTLE.

Keywords: High-frequency oscillations; Interictal spikes; Levetiracetam; Pilocarpine; Seizures.

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Conflict of interest statement

Conflict of interest statement

M.A. received an investigator initiated grant from UCB Pharma. The remaining authors have no conflict of interest. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

Fig. 1
Fig. 1
(A) Bar graph showing the average duration of the latent period in each group. No significant differences were observed. (B) Average seizure rate per day for each group. Note that in each group seizures tend to occur in a cluster, between the 6th and the 11th days after SE. (C) Bar graph showing the percentage, in each group, of non-convulsive seizures (*p < 0.05). LEV w Sz animals showed significantly more non-convulsive seizures compared to controls. (D) Bar graph showing the average duration of seizures in each group. No significant differences were observed.
Fig. 2
Fig. 2
(A and B) Representative HYP-onset seizures in a control (A) and in a LEV w Sz animal (B). Note the occurrence of multiple spikes preceding the onset of fast activity (arrow) in CA3, EC and subiculum in the control animal and in CA3 and EC in the LEV w Sz animal. Seizure duration was calculated from the onset of fast activity (15–20 Hz) (arrow) to the end of the seizure. (C and D) Representative LVF-onset seizures in a control (C) and in a LEV w Sz animal (D). Note the occurrence of a single pre-ictal spike preceding the onset of fast activity (arrow). (E and F) Pie chart showing the distribution of seizure-onset patterns in controls (E) and LEV w Sz animals (F). Both groups showed a similar distribution of seizure-onset patterns. CA3, CA3 region of the hippocampus; EC, entorhinal cortex; DG, dentate gyrus; Sub, subiculum.
Fig. 3
Fig. 3
(A) Representative recordings showing interictal spikes in a control (A) and in a LEV w/o Sz animal (B). Interictal spikes could occur in any region of the temporal lobe, but they occurred at significantly lower rates in LEV w/o Sz animals. Insets show interictal spikes on an expanded time scale. (C) Bar graph showing the average rates (number of events/s) of interictal spikes in the control group and in the LEV w/o Sz group. Note that in all regions interictal spike rates were lower in LEV w/o Sz animals compared to controls. (D) Average interictal spike rates in all regions over time. Note the difference in interictal spike rate between controls and LEV w/o Sz animals over time (*p < 0.05, **p < 0.01). IIS, interictal spikes.
Fig. 4
Fig. 4
(A) Representative example of an interictal spike (black line) co-occurring with a ripple (red line). The time frequency representation of the activity in the ripple frequency range (80–200 Hz) is also shown. The arrow points to the detected ripple. (B) Bar graph showing the average rate of interictal spikes with ripples in each region for the control and the LEV w/o Sz group. In CA3, EC and subiculum, significantly lower rates of interictal spike rates with ripples were recorded (**p < 0.01). (C) Average interictal spike rates over time. Note the difference between controls and LEV w/o Sz animals over time in CA3, EC and subiculum. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 5
Fig. 5
(A) Representative example of an interictal spike (black line) co-occurring with a fast ripple (red line). The fast ripple is indicated by the arrow in the time frequency representation. (B) Bar graph showing the average rate of interictal spikes with fast ripples in each region for the control and the LEV w/o Sz group. In CA3 and subiculum, significantly lower rates of interictal spike rates with fast ripples were recorded (**p < 0.01). (C) Average rates of interictal spikes with fast ripples over time in CA3 and subiculum. Note the difference between controls and LEV w/o Sz animals over time. (D) Average rates of seizures (bar graph) and of interictal spikes with fast ripples (solid line) in CA3 in controls. Rates of interictal spikes with fast ripples in CA3 were significantly correlated with seizure rates (*p < 0.05). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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