Epilepsia Partialis Continua, Epilepsia Partialis Continua, Refractory (Medically), Epilepsy, Status Epilepticus
Conditions
Brief summary
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
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.
Interventions
DEVICELow frequency repeated TMS (LF-rTMS)
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.
Sponsors
U.S. National Science Foundation
Florida International University
Baptist Health South Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Participant and outcomes assessor will be masked in the 3 arms of the long-term protocol. However, the short-term arm will be open label.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Treatment Response Rate | 8-weeks post rTMS treatment | Count of subjects whose seizure frequency decreased by 50% after rTMS treatment |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1: Weekly TMS 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
Low frequency repeated TMS (LF-rTMS): 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. | 1 |
| Group 2: Monthly TMS LF-rTMS intervention for 2 weeks (5 days per week for total of 10 days), LF-rTMS 1 session/month for 12 months
Low frequency repeated TMS (LF-rTMS): 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. | 0 |
| Group 3: Sham TMS 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
Low frequency repeated TMS (LF-rTMS): 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. | 0 |
| Short-term Protocol LF-rTMS intervention daily for up to 5 days in medically refractory status epilepticus participants only
Low frequency repeated TMS (LF-rTMS): 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. | 0 |
| Total | 1 |
Baseline characteristics
| Characteristic | Total | Group 1: Weekly TMS | Group 3: Sham TMS | Short-term Protocol | Group 2: Monthly TMS |
|---|---|---|---|---|---|
| Abductor Pollicis Brevis (APB)-evoked response threshold | 40 percentage of max Telsa | 40 percentage of max Telsa | — | — | — |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Baseline Seizure Duration Proxy for Seizure Severity | 26.08 seconds STANDARD_DEVIATION 28.97 | 26.08 seconds STANDARD_DEVIATION 28.97 | — | — | — |
| Baseline Seizure frequency per week | 37 seizures per week | 37 seizures per week | — | — | — |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Interhemispheric EEG Asymmetry Ratio for Alpha power | 1.26 Ratio | 1.26 Ratio | — | — | — |
| Intrahemispheric EEG Asymmetry Ratio for Alpha power | 1.28 Ratio | 1.28 Ratio | — | — | — |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Scalp EEG Functional Connectivity for Alpha Hz Anterior | 2.44 Standardized EEG connections | 2.44 Standardized EEG connections | — | — | — |
| Scalp EEG Functional Connectivity for Alpha Hz Left | 0.63 Standardized EEG connections | 0.63 Standardized EEG connections | — | — | — |
| Scalp EEG Functional Connectivity for Alpha Hz Posterior | 1.0 Standardized EEG connections | 1.0 Standardized EEG connections | — | — | — |
| Scalp EEG Functional Connectivity for Alpha Hz Right | 2.425 Standardized EEG connections | 2.425 Standardized EEG connections | — | — | — |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 0 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 2 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 2 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Average Weekly Seizure Frequency
Seizure frequency was recorded by the caregiver in a journal at weeks 6 and 7 post rTMS treatment.
Time frame: 6 and 7 weeks post rTMS treatment
Population: Post rTMS seizure journal
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group 1: Weekly TMS | Average Weekly Seizure Frequency | 22 average seizure frequency per week |
Primary
Scalp EEG: Number of Interictal Epileptiform Discharges
Interictal discharges are common in those with epilepsy and tends to decrease with treatment.
Time frame: From start of intervention through 5 days of treatment
Population: No interictal discharges were observed during baseline or post-treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Weekly TMS | Scalp EEG: Number of Interictal Epileptiform Discharges | 0 Interictal discharges |
Primary
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.
Time frame: 6-7-weeks post rTMS treatment
Population: Post rTMS seizure journal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Weekly TMS | Seizure Duration Proxy for Seizure Severity | 34.54 seconds | Standard Deviation 26.14 |
Secondary
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.
Time frame: 8-weeks Post rTMS treatment
Population: Post APB-evoked response was not collected, therefore cannot be analyzed.
Secondary
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.
Time frame: 8-weeks Post rTMS Treatment
Population: left hemisphere electrodes are divided by the right hemisphere electrodes
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Weekly TMS | Interhemispheric EEG Asymmetry Ratio for Alpha Power | 0.45 Ratio |
Secondary
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.
Time frame: 8-weeks Post rTMS Treatment
Population: left posterior electrodes are divided by the anterior electrodes
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Weekly TMS | Intrahemispheric EEG Asymmetry Ratio for Alpha Power | 0.095 Ratio |
Secondary
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.
Time frame: 8-weeks Post rTMS Treatment
Population: Data was based on standardized threshold of 80% across 20 Epochs
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: Weekly TMS | Scalp EEG Functional Connectivity for Alpha Hz | Anterior | 0.4 Standardized EEG connections |
| Group 1: Weekly TMS | Scalp EEG Functional Connectivity for Alpha Hz | Posterior | 0.455 Standardized EEG connections |
| Group 1: Weekly TMS | Scalp EEG Functional Connectivity for Alpha Hz | Right | 0.375 Standardized EEG connections |
| Group 1: Weekly TMS | Scalp EEG Functional Connectivity for Alpha Hz | Left | 0.255 Standardized EEG connections |
Secondary
Treatment Response Rate
Count of subjects whose seizure frequency decreased by 50% after rTMS treatment
Time frame: 8-weeks post rTMS treatment
Population: The only subject to complete the study was assigned the group 1. Due to lack of enrollment no subjects were assigned to group 2, 3, or the short-term group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: Weekly TMS | Treatment Response Rate | Responder (> 50%) | 0 Participants |
| Group 1: Weekly TMS | Treatment Response Rate | Non-Responder (<50%) | 1 Participants |