The influence of Perampanel on Cortical Inhibition in People with Epilepsy: Assessment with Transcranial Magnetic Stimulation

A biomarker to predict long-term seizure control shortly after initiation of
antiepileptic drug treatment (AED) could speed up the process of finding the
AED appropriate for that person with epilepsy. A prospective study in newly
diagnosed people with epilepsy demonstrated that transcranial magnetic
stimulation (TMS) responses measured shortly after the start of AED treatment
can predict long-term seizure control. Perampanel is a newly licensed AED for
people with localization-related epilepsy, with or without secondary
generalization. Perampanel selectively blocks AMPA receptor-mediated synaptic
transmission, reducing neuronal excitation. This proposed study aims to
investigate the effect of perampanel on cortical excitability in people with
medically refractory epilepsy.

Main Objectives:

To assess the effect of perampanel on cortical excitability in people with
medically refractory epilepsy.

Secondary Objectives;

To investigate the predictive value of TMS-EMG/EEG for long-term seizure
control after starting perampanel therapy.

We aim to conduct a within-subject controlled longitudinal study to investigate
the effect of perampanel on cortical excitability measured by TMS-EMG/EEG. To
assess the effect of perampanel on cortical excitability, people with
refractory localization-related epilepsy will be recruited. Doses of concurrent
medication are kept constant for at least 6 weeks before the baseline
measurement and during the study, if possible. Participants will be asked to
keep a seizure diary starting 6 weeks before the baseline measurement of the
study and during the study. If such data is available retrospectively and
reliable, participants can start immediately with the baseline T0 measurement.
In the case of low seizure frequency (<1 seizure per month), seizure frequency
will be determined anamnestically. Titration of perampanel will follow the
baseline measurement according to standard clinical practice and is at the
discretion of the person*s neurologist. A normal titration schedule would start
with a dosage of 2mg daily with increases of 2 mg per two weeks up to 8-12 mg
daily, but deviations from the scheme are allowed. Phase II studies showed that
once-daily doses of perampanel at 8 and 12 mg were effective, safe, and
tolerability was acceptable.7,8 TMS measurements will performed before starting
titration (T0), at 4 mg dose (T1), and after reaching the maximum effective but
tolerated dose (T2). The participants will be asked to continue with their
seizure diary for a follow-up of three months.

TMS is non-invasive and few seizures have been reported with single- or paired
pulse TMS (much less than with repetitive TMS), and most occurred in patients
with underlying brain pathology or taking neuro-active medication. In people
with epilepsy, seizure occurrence due to TMS stimulation is about 0-3.6%.
Seizures occurred most frequently (3.6%) in people with temporal lobe epilepsy
who were undergoing pre-surgical evaluation. The setting however is different,
as pre-surgical evaluation aims at inducing seizures for ictal measurements.
Therefore, we expect seizures in relation to TMS to occur less frequently in
our subject group.

With this study we investigate the changes induced by perampanel treatment on
cortical excitability. A change in intracortical inhibition at the 250 ms
interval can potentially be used to predict long-term seizure control for
perampanel, thereby accelerating the process of finding the AED appropriate for
individual person with refractory epilepsy and limiting exposure to
non-effective AEDs and their side-effects.