Repeated TMS at Low Frequencies to Reduce Seizure Occurrence

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.

• Low frequency repeated TMS (LF-rTMS) (Device): 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.

Primary outcomes

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

Secondary outcomes

• Interhemispheric EEG Asymmetry Ratio for Alpha Power [8-weeks Post rTMS Treatment]: 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.
• Scalp EEG Functional Connectivity for Alpha Hz [8-weeks Post rTMS Treatment]: 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.
• Abductor Pollicis Brevis (APB)-Evoked Response Threshold [8-weeks Post rTMS treatment]: 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.
• Treatment Response Rate [8-weeks post rTMS treatment]: Count of subjects whose seizure frequency decreased by 50% after rTMS treatment
• Intrahemispheric EEG Asymmetry Ratio for Alpha Power [8-weeks Post rTMS Treatment]: 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.

Sex: All, ages: 18 Years to 80 Years

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)

Participant flow

Outcome results

• Average Weekly Seizure Frequency (Primary), Mean, average seizure frequency per week: Group 1: Weekly TMS 22 (21 to 23); Group 2: Monthly TMS ; Group 3: Sham TMS ; Short-term Protocol
• Scalp EEG: Number of Interictal Epileptiform Discharges (Primary), Number, Interictal discharges: Group 1: Weekly TMS 0; Group 2: Monthly TMS ; Group 3: Sham TMS ; Short-term Protocol
• Seizure Duration Proxy for Seizure Severity (Primary), Mean, seconds: Group 1: Weekly TMS 34.54 +/- 26.14; Group 2: Monthly TMS ; Group 3: Sham TMS ; Short-term Protocol
• Interhemispheric EEG Asymmetry Ratio for Alpha Power (Secondary), Number, Ratio: Group 1: Weekly TMS 0.45; Group 2: Monthly TMS ; Group 3: Sham TMS ; Short-term Protocol
• Scalp EEG Functional Connectivity for Alpha Hz (Secondary), Number, Standardized EEG connections: Group 1: Weekly TMS 0.4; Group 2: Monthly TMS ; Group 3: Sham TMS ; Short-term Protocol
• Abductor Pollicis Brevis (APB)-Evoked Response Threshold (Secondary)
• Treatment Response Rate (Secondary), Count of participants, Participants: Group 1: Weekly TMS 0; Group 2: Monthly TMS ; Group 3: Sham TMS ; Short-term Protocol
• Intrahemispheric EEG Asymmetry Ratio for Alpha Power (Secondary), Number, Ratio: Group 1: Weekly TMS 0.095; Group 2: Monthly TMS ; Group 3: Sham TMS ; Short-term Protocol

Adverse events

Time frame: 1 year

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• Study Protocol and Statistical Analysis Plan (PDF, 2021-09-21)

• Alberto Pinzon, M.D., Ph.D., Principal investigator, Baptist Health South Florida