Repeated TMS at Low Frequencies to Reduce Seizure Occurrence

Epilepsy Clinical Trial

Official title:

Repeated TMS at Low Frequencies to Reduce Seizure Occurrence

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03154307
• Other study ID #: 15-135
• Status: Terminated
• Phase: N/A
• Start date: February 19, 2016
• Est. completion date: August 23, 2019

Study information

• Verified date: May 2023
• Source: Baptist Health South Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: August 23, 2019
• Est. primary completion date: August 23, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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)

Related Conditions & MeSH terms

• Epilepsia Partialis Continua
• Epilepsy
• Seizures
• Status Epilepticus

Intervention

Device:
• 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.

Locations

Country	Name	City	State
United States	Baptist Hospital of Miami	Miami	Florida

Sponsors (3)

Lead Sponsor	Collaborator
Baptist Health South Florida	Florida International University, U.S. National Science Foundation

Country where clinical trial is conducted

United States, 

References & Publications (7)

Fox MD, Liu H, Pascual-Leone A. Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity. Neuroimage. 2013 Feb 1;66:151-60. doi: 10.1016/j.neuroimage.2012.10.082. Epub 2012 Nov 7. — View Citation

Hallett M. Transcranial magnetic stimulation and the human brain. Nature. 2000 Jul 13;406(6792):147-50. doi: 10.1038/35018000. — View Citation

Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol. 2003 Mar;2(3):145-56. doi: 10.1016/s1474-4422(03)00321-1. — View Citation

Plewnia C, Pasqualetti P, Grosse S, Schlipf S, Wasserka B, Zwissler B, Fallgatter A. Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. J Affect Disord. 2014 Mar;156:219-23. doi: 10.1016/j.jad.2013.12.025. Epub 2013 Dec 28. — View Citation

Rossini PM, Rossi S. Transcranial magnetic stimulation: diagnostic, therapeutic, and research potential. Neurology. 2007 Feb 13;68(7):484-8. doi: 10.1212/01.wnl.0000250268.13789.b2. — View Citation

Siebner HR, Hartwigsen G, Kassuba T, Rothwell JC. How does transcranial magnetic stimulation modify neuronal activity in the brain? Implications for studies of cognition. Cortex. 2009 Oct;45(9):1035-42. doi: 10.1016/j.cortex.2009.02.007. Epub 2009 Mar 3. — View Citation

Udupa K, Sathyaprabha TN, Thirthalli J, Kishore KR, Raju TR, Gangadhar BN. Modulation of cardiac autonomic functions in patients with major depression treated with repetitive transcranial magnetic stimulation. J Affect Disord. 2007 Dec;104(1-3):231-6. doi: 10.1016/j.jad.2007.04.002. Epub 2007 May 8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
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.	6-7-weeks post rTMS treatment
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.	8-weeks Post rTMS Treatment
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.	8-weeks Post rTMS Treatment
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.	8-weeks Post rTMS treatment
Secondary	Treatment Response Rate	Count of subjects whose seizure frequency decreased by 50% after rTMS treatment	8-weeks post rTMS treatment
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.	8-weeks Post rTMS Treatment