Continuous Thetaburst Stimulation for the Treatment of Refractory Epilepsy - Safety, Feasibility and Proof-of-concept

Study Overview
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Brief Summary
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The purpose of this study is to investigate a novel stimulation protocol of repetitive transcranial magnetic stimulation (rTMS) for the treatment of unifocal neocortical epilepsy, namely continuous thetaburst stimulation (cTBS). As this is a pilot study, the primary endpoint is on safety and tolerability of the treatment. However, information on clinical efficacy and mechanism of action will also be collected.

Detailed Description
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Study design: This is an open label prospective pilot trial of continuous thetaburst stimulation (cTBS) in patients with unifocal neocortical epilepsy. The study comprises a 13-week period, consisting of 4 weeks baseline seizure frequency assessment, a one-week treatment period with baseline assessments on Monday (T0) and stimulation sessions from Tuesday to Friday (T1-T4), and an 8-week follow-up period with short-term assessments immediately after the final stimulation session on Friday afternoon (T4) and long-term assessments after 2 weeks (FU2) and 8 weeks (FU8). Objectives: The primary objective is to assess the feasibility, safety and tolerability of cTBS in refractory epilepsy patients. The secondary objectives are to assess the clinical efficacy and associated mechanism of action of cTBS in unifocal neocortical epilepsy. Rationale: An open label prospective design allows to make a first estimate on the safety, feasibility and tolerability of cTBS in refractory epilepsy patients. There are currently no reports available of cTBS performed in epilepsy patients. The ultimate aim is to assess clinical efficacy of cTBS with regard to seizure frequency, but a feasibility and safety study is a prerequisite in order to achieve this goal.

Official Title
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Continuous Thetaburst Stimulation for the Treatment of Refractory Epilepsy - Safety, Feasibility and Proof-of-concept

Conditions
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Epilepsies, Partial

Intervention / Treatment
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* Device: continuous thetaburst stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Refractory unifocal neocortical epilepsy with a well-defined ictal onset zone based on a standardized presurgical evaluation ≥ 4 seizures/month, for at least six months On a stable drug regimen for at least 2 months IQ >70 Reliable completion of a seizure diary by patient or caretakers Therapeutic compliance in the past Informed consent signed Exclusion Criteria: Pregnancy, short-term birth wish or childbearing age without adequate birth control History of psychogenic non-epileptic seizures Intracranial metal hardware (excluding dental filling): surgical clips, shrapnell, electrodes under the stimulation area Presence of pacemaker, implantable cardioverter-defibrillator (ICD), permanent medication pumps, cochlear implants or deep brain stimulation (DBS) Patients with a vagus nerve stimulator are not excluded, provided that adequate distance between the coil and the implanted material can be maintained. As the short duration of the study will not interfere with an ongoing presurgical evaluation and/or its eventual conclusion, the patients in the course of the evaluation or awaiting surgery are also eligible for inclusion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: continuous thetaburst stimulation<br>Transcranial magnetic stimulation over the epileptogenic focus using a cTBS stimulation protocol. | Device: continuous thetaburst stimulation<br>* On 4 consecutive days patients receive 5 cTBS trains with a 10min intertrain-interval. One cTBS train consists of 600 pulses delivered in bursts at theta frequency (200ms) during 40s. Each burst comprises 3 pulses at 50Hz. Focal stimulation occurs over the epileptogenic focus (EF), perpendicular to the local gyral geometry, using online neuronavigation. Stimulation intensity is set relative to the resting motor threshold (rMT) determined at baseline (80% rMT). Stimulation intensity is further adjusted to the coil-cortex distance at the EF with the following formula: adjusted MT% (AdjMT) = rMT + 2,7*(DEF-DM1) [DEF = distance over EF; DM1 = distance over M1]. If rMT exceeds the capacity of the stimulator output, stimulation intensity is 100% of maximal stimulator output (MSO).<br>* Other names: cTBS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seizure induction | Induction of epileptic seizures during or in-between rTMS stimulation trains as a measure of safety | Throughout stimulation, 4 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seizure diary | Self-reported seizure frequency throughout the study as a measure of clinical efficacy. Four separate seizure diaries are provided: Baseline period: 4 weeks prior to treatment Treatment week: from monday to friday evening Follow-up part 1: two weeks following the treatment week Follow-up part 2: week 3 to week 8 following treatment Patients note down if the seizure was habitual, atypical or if it was an episode of uncertain etiology (eg. non-epileptic) | Throughout the study, lasting 13 weeks | 
| Adverse events diary | Description of all experienced adverse event during the study as a measure of safety and tolerability. | Throughout the study, lasting 13 weeks | 
| Number of interictal epileptiform discharges (IEDs) on hd-EEG | A 15min hd-EEG is recorded and IEDs are counted during acquisition. Comparison of number of IEDs between the different time points as a measure of clinical efficacy. | Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up), 2 weeks after stimulation and 8 weeks after stimulation (long-term follow-up) | 
| Number of interictal epileptiform discharges (IEDs) on normal EEG | Fifteen min EEG with 21 scalp electrodes is recorded immediately before and following each stimulation session. Number of IEDs are counted and compared between pre- and post acquisition as a measure of clinical efficacy. | Throughout the study, lasting 13 weeks: assessment immediately before and after each treatment session | 
| Cortical resting motor threshold (rMT) | Cortical resting motor threshold is determined using single-pulse TMS over the primary motor cortex (M1) (ipsilateral to epileptogenic focus). Motor-evoked potential (MEP) is measured over the first dorsal interosseus (FDI) of the contralateral hand. Using a threshold tracking tool (Adaptive PEST) the minimally required stimulation intensity that elicits an MEP of 50 microvolt is determined. RMT at different time points throughout the study is compared to assess the effect of the treatment on cortical excitability as a measure of mechanism of action. | Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up), 2 weeks after stimulation and 8 weeks after stimulation (long-term follow-up) | 
| TMS-EEG evoked potentials (TEPs) | TMS-EEG evoked potentials are measured over the epileptogenic focus and the primary motor cortex by performing single-pulse TMS (100 consecutive pulses jittered around an interval of 5s) with continuous EEG acquisition. The EEG is processed in order to obtain quantitative and comparable TEPs measures that reflect cortical excitability. These TEP measures obtained at different time points throughout the study are compared to assess the effect of the treatment on cortical excitability as a measure of mechanism of action. | Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up), 2 weeks after stimulation and 8 weeks after stimulation (long-term follow-up) | 
| Magnetic resonance imaging (MRI) | Resting-state functional MRI (rs-fMRI) is acquired at the four main time points of the study to assess the effects of treatment on functional connectivity as a measure of mechanism of action. | Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up), 2 weeks after stimulation and 8 weeks after stimulation (long-term follow-up) | 
| High-density EEG (hd-EEG) | A 128-channel EEG for resting-state EEG acquisition is obtained at the four main time points of the study to assess the effects of treatment on functional connectivity as a measure of mechanism of action. | Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up), 2 weeks after stimulation and 8 weeks after stimulation (long-term follow-up) | 
| Change in Montreal Cognitive Assessment score (MoCA) | Score ranging from 0 [worst cognitive state] to 30 [best cognitive state], with a score of 26 or higher reflecting normal cognitive function. Cognitive assessment as a measure of safety: comparison at different time points throughout the study using MoCA version 7, 7.2 and 7.3 respectively. | Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up) and 8 weeks after stimulation (long-term follow-up) | 
| Change in Computerized Visual Searching Task (CVST) | A 24-figure task assessing mean trial time [the faster the better] and number of errors [the lower the better] Assessment of mental flexibility and information processing as a measure of safety: comparison at different time points throughout the study. | Throughout the study, lasting 13 weeks: baseline (before treatment), following final stimulation session (short-term follow-up), 2 weeks after stimulation and 8 weeks after stimulation (long-term follow-up) | 
| Change in Quality of life in epilepsy-31 (QOLIE-31) | Questionnaire scoring quality of life (QoL) ranged from 0 [lowest QoL] to 100 [highest QoL] (with associated T-value per score) as a measure of well-being. | Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up) | 
| Change in Beck depression inventory (BDI-II) | Questionnaire scoring depression ranged from 0 to 63 as a measure of well-being. | Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up) | 
| Change in Positive affect negative affect schedule (PANAS) | Questionnaire scoring affect as a measure of well-being. | Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up) | 
| Change in State-trait anxiety inventory (STAI) | Questionnaire scoring anxiety as a state (now) or a trait (more generally) separately, ranged from 20 [less anxious] - 80 [more anxious] as a measure of well-being. | Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up) | 
| Change in Visual analogue scale (VAS) of general well-being | Score ranged from 0 [lowest well-being] to 100 [highest well-being] as a measure of well-being. | Throughout the study, lasting 13 weeks: baseline (before treatment) and 8 weeks after stimulation (long-term follow-up) | 
| Change in Visual analogue scale (VAS) of tolerability of the treatment | Score ranged from 0 [absolutely tolerable] -100 [absolutely intolerable] as a measure of tolerability and feasibility. | Throughout the study: after each treatment session and at the end of the study (8 weeks after stimulation) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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partial epilepsy, unifocal neocortical, treatment resistant, transcranial magnetic stimulation, thetaburst stimulation