Transcranial Magnetic Stimulation (rTMS) for Refractory Focal Epilepsy

Transcranial Magnetic Stimulation (rTMS) for the Treatment of Focal Refractory Epilepsy: Neuropsychological and Electrophysiological Evaluation.

Epilepsy as a brain disease is characterised by enhanced brain excitability. Low frequency repetitive transcranial magnetic stimulation (rTMS) can be an effective treatment for refractory focal epilepsy. Today different ways of stimulation were used, the best protocol of rTMS in refractory focal epilepsy is under evaluation. The aim of our study is neuropsychological and electrophysiological evaluation before and after rTMS sessions, the results of rTMS will be compared with VNS outcome in patients, who undergoes VNS implantation after rTMS.

Study Overview

• Status: Active, not recruiting
• Conditions: Focal Epilepsy; Transcranial Magnetis Stimulation
• Intervention / Treatment: Device: figure-of-eight active rTMS coil device; Device: figure-of-eight sham rTMS coil device

Detailed Description

1. Background Epilepsy is a chronic disease that causes repetitive seizures. In 60% to 70% of people with epilepsy (PWE) , these seizures start in a small part of the brain (focal epilepsy). Up to 30% of people with epilepsy continue to have seizures despite optimal pharmacological care. Invasive methods - called epilepsy surgery are the choice of treatment for this group of the patients. New non- invasive non- pharmacological methods are on the way.
2. Aim of the study Treatment the people with focal epilepsy with non- invasive transcranial magnetic stimulation (rTMS) to the region that causes the epilepsy. A part of the patients will after that be treated with invasive VNS implantation. The aim is to evaluate neuropsychological and electrophysiological out come in non- invasive arm and in combined arm (VNS after rTMS).
3. Inclusion criteria The patients with neocortical focal epilepsy older than 18 years, not controlled with antiseizure drugs, with confirmed refractory epilepsy.

4. Study methodology The seizure frequency will be controlled with seizure diaries, patients will be evaluated in tertiary epilepsy centre. The patients will be on stable dose of drugs 4 week before and at least 8 weeks after last TMS session. They will be evaluated by battery of neuropsychological tests (cognition, emotions, personality) and electrophysiological methods ( QEEG, SEP n. medianus) before rTMS sessions and after rTMS session and a month later. A part of the patient, who will continue to VNS implantation will be evaluated before VNS implantation and 6 month later again.

   The magnetic pulses will be delivered in a active session or in a placebo session ( sham). The investigators will not tell in which order they deliver the treatments.

5. What are the possible benefits and risks of participating? The investigators believe, that the patients will have fewer seizures in the weeks following the active treatment and that the improvement could be detected in neuropsychological evaluations and in electrophysiology. It is not known, if the results of rTMS could predict the response of the patients to VNS stimulation.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Slovakia
  • Slovak Republic
    • Bratislava, Slovak Republic, Slovakia, 83305
      • 2nd Department of Neurology, Faculty of Medicine COMENIUS UNIVERSITY BRATISLAVA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

- fully characterized refractory focal neocortical epilepsy (i.e. the epileptogenic zone is well defined) on a stable drug regimen for at least one month, able to complete a seizure dairy either by the patient or by a significant other

Exclusion Criteria:

- Metal in the head including deep brain stimulators, aneurysmal clips, ventricular shunts, cochlear implants, ossicular reconstruction of the middle ear, VNS implants pacemaker, implantable cardioverter-defibrillator (ICD) psychogenic non-epileptic seizures and other non-epileptic spells

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention/treatment; figure-of-eight active rTMS coil rTMS is administered using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains with a total of 15000 pulses during 5 weekdays at low frequency 0,5Hz Device: figure-of-eight active rTMS coil navigated rTMS over epileptogenic focus using figure-of-eight active rTMS coil, optic navigation system	Device: figure-of-eight active rTMS coil device; rTMS is administered using the figure-of-eight active coil, at 90% of the resting motor threshold over the epileptogenic region, in trains with a total of 15000 pulses during 5 weekdays at low frequency 0,5Hz Device: figure-of-eight active rTMS coil navigated rTMS over epileptogenic focus using figure-of-eight active rTMS coil, optic navigation system
Sham Comparator: Control arm; figure-of-eight active rTMS coil rTMS is administered using the figure-of-eight sham coil, at 90% of the resting motor threshold over the epileptogenic region, in trains with a total of 15000 pulses during 5 weekdays at sham stimulation Device: figure-of-eight sham rTMS coil navigated rTMS over epileptogenic focus using figure-of-eight sham rTMS coil, optic navigation system	Device: figure-of-eight sham rTMS coil device; rTMS is administered using the figure-of-eight sham coil, in trains with a total of 15000 pulses during 5 weekdays Device: figure-of-eight sham rTMS coil navigated rTMS over epileptogenic focus using figure-of-eight sham rTMS coil, optic navigation system

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Seizure frequency and severity	50% Responder Rate after active rTMS treatment and median of seizure frequency reduction from baseline according seizure diaries of the patients rated per 28 day period	1 hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
QOLIE-31-P measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Questionnaires: Quality of Life in Epilepsy- problems (QOLIE-31-P) change of score	20 min
Electrophysiological evaluation with quantitative EEG	Electrophysiological evaluation with quantitative EEG ( QEEG) as response to rTMS stimulation and correlation with primary outcome measure and neuropsychological outcome measured with neuropsychological batteries change in cordance	30 min
Comparison the data in the group of the patients	Comparison the data in the group of the patients, who will after rTMS continue to VNS implantation, multiregression analysis for possible connection between rTMS response and later VNS efficacy	1 hour
Drop out rate and adverse event profile	Drop out rate and adverse event profile	1 hour
LSSS- measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Liverpool seizure severity scale (LSSS) change in frequency and severity of seizures	10 min
PHQ-9 measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Patients Health Questionnaire ( PHQ-9), change of score	5 min
GAD-7 measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Generalized Anxiety Disorder(GAD-7), change of score	5 min
ROCFT measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Rey-Osterrieth complex figure test ( ROCFT), change of score	10 min
STROOP measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Stroop 1,2,3, change of score	15 min
TMT AB measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Trail making test A,B, (TMT AB), change of score	5 min
DST measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Digit span test (DST), change of score	10 min
AVLT measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Auditory verbal learning test ( AVLT), change of score	10 min
MoCA measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Montreal Cognitive Assessment (MoCA) change of score	20 min
SDMT measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Symbol Digit Modalities Test (SDMT), change of score	10 min
StT measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Story Test (StT), change of score	10 min
WCST measurement of different neuropsychological aspects of epilepsy	measurement of different neuropsychological aspects of epilepsy (cognition, emotions, social well- being and social functioning) in patients before and one month after rTMS: Wisconsin Card Sorting Test (WCST), change of score	10 min
Electrophysiological evaluation with quantitative SEP	Electrophysiological evaluation with SEP (n. medianus amplitude) as response to rTMS stimulation and correlation with primary outcome measure and neuropsychological outcome measured with neuropsychological batteries change of amplitude	1 hour

Collaborators and Investigators

• Sponsor: Comenius University

Publications and helpful links

General Publications

• Sun W, Mao W, Meng X, Wang D, Qiao L, Tao W, Li L, Jia X, Han C, Fu M, Tong X, Wu X, Wang Y. Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: a controlled clinical study. Epilepsia. 2012 Oct;53(10):1782-9. doi: 10.1111/j.1528-1167.2012.03626.x. Epub 2012 Sep 5.
• Fregni F, Otachi PT, Do Valle A, Boggio PS, Thut G, Rigonatti SP, Pascual-Leone A, Valente KD. A randomized clinical trial of repetitive transcranial magnetic stimulation in patients with refractory epilepsy. Ann Neurol. 2006 Oct;60(4):447-55. doi: 10.1002/ana.20950.
• Cantello R, Rossi S, Varrasi C, Ulivelli M, Civardi C, Bartalini S, Vatti G, Cincotta M, Borgheresi A, Zaccara G, Quartarone A, Crupi D, Lagana A, Inghilleri M, Giallonardo AT, Berardelli A, Pacifici L, Ferreri F, Tombini M, Gilio F, Quarato P, Conte A, Manganotti P, Bongiovanni LG, Monaco F, Ferrante D, Rossini PM. Slow repetitive TMS for drug-resistant epilepsy: clinical and EEG findings of a placebo-controlled trial. Epilepsia. 2007 Feb;48(2):366-74. doi: 10.1111/j.1528-1167.2006.00938.x.
• Pereira LS, Muller VT, da Mota Gomes M, Rotenberg A, Fregni F. Safety of repetitive transcranial magnetic stimulation in patients with epilepsy: A systematic review. Epilepsy Behav. 2016 Apr;57(Pt A):167-176. doi: 10.1016/j.yebeh.2016.01.015. Epub 2016 Mar 10.
• Seynaeve L, Devroye A, Dupont P, Van Paesschen W. Randomized crossover sham-controlled clinical trial of targeted low-frequency transcranial magnetic stimulation comparing a figure-8 and a round coil to treat refractory neocortical epilepsy. Epilepsia. 2016 Jan;57(1):141-50. doi: 10.1111/epi.13247. Epub 2015 Dec 8.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2022
• Primary Completion (Estimated): February 28, 2025
• Study Completion (Estimated): April 30, 2025

Study Registration Dates

• First Submitted: September 9, 2022
• First Submitted That Met QC Criteria: November 7, 2024
• First Posted (Estimated): November 8, 2024

Study Record Updates

• Last Update Posted (Estimated): November 8, 2024
• Last Update Submitted That Met QC Criteria: November 7, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Epilepsy, Focal, Partial, Central Nervous System Diseases, Brain Diseases
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Epilepsies, Partial
• Other Study ID Numbers: U-1111-1280-4605; UK/33/2022 (Other Grant/Funding Number: Comenius University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No