Repeated TMS at Low Frequencies to Reduce Seizure Occurrence

Study Overview
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Brief Summary
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Perform non-invasive neuro-navigated repeated Transcranial Magnetic Stimulation (rTMS) at low frequencies (LF) with the intent to reduce the occurrence of seizures over time (long-term protocol). Seizure reduction and improvements in the quality of life in patients with epilepsy will be associated with increased cortical inhibition resulting from the LF-rTMS sessions over time. This procedure using rTMS at low frequencies (LF-rTMS) between 0.5 and 1 Hz is a safe and painless method for noninvasive focal cortical brain stimulation, which will be evaluated in its efficacy at reducing/suppressing seizures. Accordingly, we propose a clinical trial in patients with epilepsy to test whether LF-rTMS can improve seizure suppression. The location of the presumed 3D source in the brain will be stimulated for few minutes (10 to 15 min.). With the same rTMS modality, we will also perform motor threshold mapping in conjunction with its fully integrated and compatible electroencephalography (EEG) module. Up to 100 individuals 18 to 80 years with epilepsy will be enrolled. In addition, a short-term protocol has been added to test whether LF-rTMS can reduce or suppress status epilepticus in medically refractory participants.

Detailed Description
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Long term protocol: Perform non-invasive neuro-navigated repeated Transcranial Magnetic Stimulation (rTMS) at low frequencies (LF) with to reduce the occurrence of seizures over time. Seizure reduction and improvements in the quality of life in patients with epilepsy will be associated with increased cortical inhibition resulting from the LF-rTMS sessions over time. This procedure using rTMS at low frequencies (LF-rTMS) between 0.5 and 1 Hz is a safe and painless method for noninvasive focal cortical brain stimulation, which will be evaluated in its efficacy at reducing/suppressing seizures. Accordingly, we propose a clinical trial in patients with epilepsy to test whether LF-rTMS can improve seizure suppression. The location of the presumed 3D source in the brain will be stimulated for few minutes (10 to 15 min.). Using a double-blinded, sham-controlled design, we will enroll up to 100 participants aged 18-80 with focal and generalized retractable epilepsy. Baseline data will include a detailed seizure diary over 4 weeks, psychometric testing/neuropsychology evaluation, and 20-minute EEG recordings. Each patient will then begin treatment with 14 minute sessions of 1 Hz rTMS or sham rTMS, 120%MT, and 800 stimuli on the position of the calculated 3D source using EEG, MRI, and digitized electrode locations. The protocol will be divided in 3 groups (Groups 1, 2 and 3) as follows: Groups 1, 2, and 3: LF-rTMS for 2 weeks (5 days per week for total of 10 days). Group 1: protocol total duration: 1 year: LF-rTMS 1 session/week for 1 month (4 days), and LF-rTMS 1 session/month for 11 months Group 2: protocol total duration: 1 year: LF-rTMS 1 session/month for 12 months Group 3 (placebo protocol, total duration: 1 year): LF-rTMS 1 session/week for 1 month (4 days); and LF-rTMS 1session/month. During each session EEG may be recorded. Also, we will obtain the number, frequency, and duration of seizure events from an ongoing seizure diary. Psychometric testing will be performed at the beginning of study, 3 months, and at the end of the study. Thus, each patient will have rTMS testing, psychometrics, and EEG recordings. With the same rTMS modality, we will also perform motor threshold mapping in conjunction with its fully integrated and compatible electroencephalography (EEG) module. Short-term protocol: Use LF-rTMS protocol as described but for up to 5 days in 10 participants with medically refractory status epilepticus. During each session EEG will be recorded.

Official Title
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Repeated TMS at Low Frequencies to Reduce Seizure Occurrence

Conditions
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Epilepsy, Status Epilepticus, Epilepsia Partialis Continua, Epilepsia Partialis Continua, Refractory (Medically)

Intervention / Treatment
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* Device: Low frequency repeated TMS (LF-rTMS)


Participation Criteria
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Eligibility Criteria
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Long-term protocol: Inclusion Criteria: Experience ≥ 3 seizures/month in the month prior to starting study (any type of seizure will count) No status epilepticus in the last 12 months No change in medication in last 30 days Exclusion Criteria: Presence of implanted electronic devices (e.g., pacemaker, medication pump, brain or vagus nerve stimulator, cochlear implant) Presence of intracranial metal (e.g., aneurysm clip) Unable to cooperate with non-sedated, navigated TMS testing Short-term protocol: Inclusion Criteria: Epilepsia partialis continua or status epilepticus At least 2 medications failed At least 24 hours of acute phase Exclusion Criteria: Presence of implanted electronic devices (e.g., pacemaker, medication pump, brain or vagus nerve stimulator, cochlear implant) Presence of intracranial metal (e.g., aneurysm clip)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Weekly TMS<br>LF-rTMS intervention for 2 weeks (5 days per week for total of 10 days) , LF-rTMS 1 session/week for 1 month (4 days), and LF-rTMS 1 session/month for 11 months | Device: Low frequency repeated TMS (LF-rTMS)<br>* Each patient will then begin treatment with 14 minute sessions of 1 Hz rTMS or sham rTMS, 120% minimum threshold (MT), and 800 stimuli on the position of the calculated 3D source using EEG, MRI, and digitized electrode locations. Two different timelines of delivering the rTMS will be compared against a sham/delayed treatment group.<br>|
| Experimental: Group 2: Monthly TMS<br>LF-rTMS intervention for 2 weeks (5 days per week for total of 10 days), LF-rTMS 1 session/month for 12 months | Device: Low frequency repeated TMS (LF-rTMS)<br>* Each patient will then begin treatment with 14 minute sessions of 1 Hz rTMS or sham rTMS, 120% minimum threshold (MT), and 800 stimuli on the position of the calculated 3D source using EEG, MRI, and digitized electrode locations. Two different timelines of delivering the rTMS will be compared against a sham/delayed treatment group.<br>|
| Sham Comparator: Group 3: Sham TMS<br>Sham LF-rTMS for 2 weeks (5 days per week for a total of 10 days), sham LF-rTMS 1 session/week for 1 month (4 days), and sham LF-rTMS 1 session/month for 1 month. After the sham stimulation real LF-rTMS intervention sessions will be delivered as follows: 50% of placebo group will follow group 1 protocol and the other 50% will follow group 2 protocol | Device: Low frequency repeated TMS (LF-rTMS)<br>* Each patient will then begin treatment with 14 minute sessions of 1 Hz rTMS or sham rTMS, 120% minimum threshold (MT), and 800 stimuli on the position of the calculated 3D source using EEG, MRI, and digitized electrode locations. Two different timelines of delivering the rTMS will be compared against a sham/delayed treatment group.<br>|
| Experimental: Short-term protocol<br>LF-rTMS intervention daily for up to 5 days in medically refractory status epilepticus participants only | Device: Low frequency repeated TMS (LF-rTMS)<br>* Each patient will then begin treatment with 14 minute sessions of 1 Hz rTMS or sham rTMS, 120% minimum threshold (MT), and 800 stimuli on the position of the calculated 3D source using EEG, MRI, and digitized electrode locations. Two different timelines of delivering the rTMS will be compared against a sham/delayed treatment group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Weekly Seizure Frequency | Seizure frequency was recorded by the caregiver in a journal at weeks 6 and 7 post rTMS treatment. | 6 and 7 weeks post rTMS treatment | 
| Scalp EEG: Number of Interictal Epileptiform Discharges | Interictal discharges are common in those with epilepsy and tends to decrease with treatment. | From start of intervention through 5 days of treatment | 
| Seizure Duration Proxy for Seizure Severity | Care provider journaled the seizure duration over the coure of a 2-week period beginning on week 6 post rTMS treatment. | 6-7-weeks post rTMS treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interhemispheric EEG Asymmetry Ratio for Alpha Power | Expresses the ratio of laterality for the corresponding electrode pairs between the left and right hemispheres, where the left hemisphere electrodes are divided by the right hemisphere electrodes. | 8-weeks Post rTMS Treatment | 
| Scalp EEG Functional Connectivity for Alpha Hz | Standardized functional scalp EEG connection per of region (anterior, posterior, right, and left). Calculations required EEG electrode activity of 80% for a minimum of 20 epochs to be included. All area electrode counts were then divided by the threshold providing a normalized value per brain region. Scalp EEG connectivity was collected 8-weeks post rTMS treatment. | 8-weeks Post rTMS Treatment | 
| Abductor Pollicis Brevis (APB)-Evoked Response Threshold | The motor evoked potential (MEP) will be calculated using the Nexstim system's 6-channel EMG module (SR=1450 Hz, cut-off frequency of 350 Hz for the low pass filter) as the APB is stimulated to find the threshold for each individual. Listed values represent the percentage of the maximum Tesla output of the Nexstim system. | 8-weeks Post rTMS treatment | 
| Treatment Response Rate | Count of subjects whose seizure frequency decreased by 50% after rTMS treatment | 8-weeks post rTMS treatment | 
| Intrahemispheric EEG Asymmetry Ratio for Alpha Power | Expresses the asymmetry power ratio for the corresponding electrode pairs between the posterior and anterior brain regions, where the left posterior electrodes are divided by the anterior electrodes. | 8-weeks Post rTMS Treatment |