TMS vs Conventional Therapy for the Treatment of Functional Neurological Non Epileptic Seizure Disorder

Controlled Clinical Trial of Transcranial Magnetic Stimulation Versus Conventional Therapy for the Treatment of Functional Neurological Non-Epileptic Seizure Disorder: A Pilot Study

The aim of the study is to compare the effect of Transcranial Magnetic Stimulation (TMS) versus treatment with selective serotonin reuptake inhibitors (SSRIs), in patients with diagnosis of Functional Neurological Non Epileptic Seizure Disorder (PNES).

Study Overview

• Status: Completed
• Conditions: Psychogenic Non-Epileptic Seizure
• Intervention / Treatment: Device: Transcranial Magnetic Stimulation; Device: Sham Transcranial Magnetic Stimulation coil

Detailed Description

This study consists of a single-blind Randomized Controlled Clinical Trial comprised of 20 patients with diagnosis of Psychogenic Non Epileptic Seizures (PNES), distributed in 2 arms of 10 patients each.

Patients (n=20) will be randomly assigned (using the block randomization method) to one of the groups. Both groups of patients will be receiving their usual medical treatment (SSRIs), one group will receive in addition a therapeutic scheme with active TMS, while the second group will receive the same scheme, but with a sham TMS coil to decrease the bias of placebo effect.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Mexico
  • Ciudad De Mexico
    • Mexico, Ciudad De Mexico, Mexico, 14269
      • Instituto Nacional de Neurologia Y Neurocirugia Mvs

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with a diagnosis of PNES, based on the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) and the ILAE, confirmed by video recording and/or V-EEG monitoring, and who have a monthly seizure frequency greater than 3.
2. Patients who have a record at the institute with the diagnosis of PNES.
3. Patients with an encephalic MRI.
4. Patients who give their written consent to participate in the protocol.
5. Patients who have not had any changes in the pharmacological treatment in the last 6 weeks.

Exclusion Criteria:

1. Patients who cannot answer the scales and other clinimetric instruments.
2. Patients with a history of previous or current epilepsy.
3. Patients with other major neurological comorbidities (tumor, cerebrovascular event (CVE), cranioencephalic trauma (TBI)).
4. Patients currently taking medications that lower the seizure threshold (Bupropion).
5. Patients with psychiatric comorbidities such as psychosis/bipolar disorder/substance abuse.
6. Patients with certain implanted metallic devices (pacemakers).
7. Pregnant women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Transcranial Magnetic Stimulation + usual treatment with SSRIs; Transcranial Magnetic Stimulation + SSRIs The TMS group will be comprised of 10 patients, each subject will receive 12 sessions of low frequency (1 Hz) rTMS over right dorsolateral prefrontal cortex with a total of 1500 each session. All patients will continue with the usual treatment established by their treating physician. Those who do not have a previous pharmacological treatment will start a protocol with sertraline, which should be started at a 50 mg/day dosage.	Device: Transcranial Magnetic Stimulation; The TMS group will be comprised of 10 patients, each subject will receive 12 sessions of low frequency (1 Hz) rTMS over the right dorsolateral prefrontal cortex with a total of 1500 pulses in each session. Each session will last approximately 30 minutes. There will be one session per day, five sessions per week. The total duration of the treatment will be four weeks. All patients will continue with the usual treatment established by their treating physician. Those who do not have a previous pharmacological treatment will start a protocol with sertraline, which should be started at a 50 mg/day dosage.; Other Names: rTMS
Sham Comparator: Sham TMS coil + usual treatment with SSRIs; The sham TMS coil group will be comprised of 10 patients, sham TMS stimulation will be performed with the B-65 coil, which has similar sound and scalp contact to those experienced during active stimulation. The duration of treatment will be the same as in the experimental arm. All patients will continue with the usual treatment established by their treating physician. Those who do not have a previous pharmacological treatment will start a protocol with sertraline, which should be started at a 50 mg/day dosage.	Device: Sham Transcranial Magnetic Stimulation coil; Simulated TMS stimulation will be performed with a Sham TMS coil, which has a sound and scalp contact similar to those experienced during active stimulation. The duration of the treatment will be the same as in the experimental arm. All patients will continue with the usual treatment established by their treating physician. Those who do not have a previous pharmacological treatment will start a protocol with sertraline, which should be started at a 50 mg/day dosage.; Other Names: Sham TMS coil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PNES count (1/4)	Participants in both groups will registered in a specific chart, daily psychogenic non-epileptic seizure activity.	Baseline PNES count (Starting 1 month before TMS treatment)
PNES count (2/4)	Participants in both groups will registered in a specific chart, daily psychogenic non-epileptic seizure activity.	Change from Baseline PNES count (immediately after the session 12th -last session-)
PNES count (3/4)	Participants in both groups will registered in a specific chart, daily psychogenic non-epileptic seizure activity.	Change from Baseline PNES count at month 1 post treatment
PNES count (4/4)	Participants in both groups will registered in a specific chart, daily psychogenic non-epileptic seizure activity.	Change from Baseline PNES count at month 2 post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Psychometric self-assessment scales (BDI-II) 1/4	1.0) Mood: Beck Depression Inventory-II (BDI-II) Minimum score: 0 Maximum score: 63 1-10: These ups and downs are considered normal 11-16: Mild mood disturbance 17-20: Borderline clinical depression 21-30: Moderate depression 31-40: Severe depression over 40: Extreme depression *Higher scores mean a worse outcome.	Baseline score (1 month before TMS treatment)
Psychometric self-assessment scales (BDI-II) 2/4	1.1) Mood: Beck Depression Inventory-II (BDI-II) Minimum score: 0 Maximum score: 63 1-10: These ups and downs are considered normal 11-16: Mild mood disturbance 17-20: Borderline clinical depression 21-30: Moderate depression 31-40: Severe depression over 40: Extreme depression *Higher scores mean a worse outcome.	Change from Baseline score (immediately after the 12th session -last session-)
Psychometric self-assessment scales (BDI-II) 3/4	1.2) Mood: Beck Depression Inventory-II (BDI-II) Minimum score: 0 Maximum score: 63 1-10: These ups and downs are considered normal 11-16: Mild mood disturbance 17-20: Borderline clinical depression 21-30: Moderate depression 31-40: Severe depression over 40: Extreme depression *Higher scores mean a worse outcome.	Change from Baseline score at month 1 post treatment
Psychometric self-assessment scales (BDI-II) 4/4	1.3) Mood: Beck Depression Inventory-II (BDI-II) Minimum score: 0 Maximum score: 63 1-10: These ups and downs are considered normal 11-16: Mild mood disturbance 17-20: Borderline clinical depression 21-30: Moderate depression 31-40: Severe depression over 40: Extreme depression *Higher scores mean a worse outcome.	Change from Baseline score at month 2 post treatment
Psychometric self-assessment scales (DES) 1/4	2.0) Dissociation : Dissociative Experience Scale (DES). Minimum score: 0 Maximum score: 100 High levels of dissociation are indicated by scores of 30 or more, scores under 30 indicate low levels. *Higher scores mean a worse outcome.	Baseline score (1 month before TMS treatment)
Psychometric self-assessment scales (DES) 2/4	2.1) Dissociation : Dissociative Experience Scale (DES). Minimum score: 0 Maximum score: 100 High levels of dissociation are indicated by scores of 30 or more, scores under 30 indicate low levels. *Higher scores mean a worse outcome.	Change from Baseline score (immediately after the 12th session -last session-)
Psychometric self-assessment scales (DES) 3/4	2.2) Dissociation : Dissociative Experience Scale (DES). Minimum score: 0 Maximum score: 100 High levels of dissociation are indicated by scores of 30 or more, scores under 30 indicate low levels. *Higher scores mean a worse outcome.	Change from Baseline score at month 1 post treatment
Psychometric self-assessment scales (DES) 4/4	2.3) Dissociation : Dissociative Experience Scale (DES). Minimum score: 0 Maximum score: 100 High levels of dissociation are indicated by scores of 30 or more, scores under 30 indicate low levels. *Higher scores mean a worse outcome.	Change from Baseline score at month 2 post treatment
Psychometric self-assessment scales (PTSD) 1/4	3.0) PTSD/Trauma/Resilience: PTSD Symptom Severity Scale. Minimum score: 0 Maximum score: 80 *Higher scores mean a worse outcome.	Baseline score (1 month before TMS treatment)
Psychometric self-assessment scales (PTSD) 2/4	3.1) PTSD/Trauma/Resilience: PTSD Symptom Severity Scale. Minimum score: 0 Maximum score: 80 *Higher scores mean a worse outcome.	Change from Baseline score (immediately after the 12th session -last session-)
Psychometric self-assessment scales (PTSD) 3/4	3.2) PTSD/Trauma/Resilience: PTSD Symptom Severity Scale. Minimum score: 0 Maximum score: 80 *Higher scores mean a worse outcome.	Change from Baseline score at month 1 post treatment
Psychometric self-assessment scales (PTSD) 4/4	3.3) PTSD/Trauma/Resilience: PTSD Symptom Severity Scale. Minimum score: 0 Maximum score: 80 *Higher scores mean a worse outcome.	Change from Baseline score at month 2 post treatment
Psychometric self-assessment scales (MoCA) 1/4	4.0) Education and Cognition: Montreal Cognitive Assessment (MoCA). Minimum score: 0 Maximum score: 30 Normal score: 26-30 Probable Neurocognitive Dissorder: 0-25 *Higher scores mean a better outcome.	Baseline score (1 month before TMS treatment)
Psychometric self-assessment scales (MoCA) 2/4	4.1) Education and Cognition: Montreal Cognitive Assessment (MoCA). Minimum score: 0 Maximum score: 30 Normal score: 26-30 Probable Neurocognitive Dissorder: 0-25 *Higher scores mean a better outcome.	Change from Baseline score (immediately after the 12th session -last session-)
Psychometric self-assessment scales (MoCA) 3/4	4.2) Education and Cognition: Montreal Cognitive Assessment (MoCA). Minimum score: 0 Maximum score: 30 Normal score: 26-30 Probable Neurocognitive Dissorder: 0-25 *Higher scores mean a better outcome.	Change from Baseline score at month 1 post treatment
Psychometric self-assessment scales (MoCA) 4/4	4.3) Education and Cognition: Montreal Cognitive Assessment (MoCA). Minimum score: 0 Maximum score: 30 Normal score: 26-30 Probable Neurocognitive Dissorder: 0-25 *Higher scores mean a better outcome.	Change from Baseline score at month 2 post treatment
Psychometric self-assessment scales (WHOQOL-BREF) 1/4	5.0) Quality of life: WHOQOL-BREF (World Health Organization Quality of Life-BREF). Minimum score: 0 Maximum score: 100 *Higher scores mean a better outcome.	Baseline score (1 month before TMS treatment)
Psychometric self-assessment scales (WHOQOL-BREF) 2/4	5.1) Quality of life: WHOQOL-BREF (World Health Organization Quality of Life-BREF). Minimum score: 0 Maximum score: 100 *Higher scores mean a better outcome.	Change from Baseline score (immediately after the 12th session -last session-)
Psychometric self-assessment scales (WHOQOL-BREF) 3/4	5.2) Quality of life: WHOQOL-BREF (World Health Organization Quality of Life-BREF). Minimum score: 0 Maximum score: 100 *Higher scores mean a better outcome.	Change from Baseline score at month 1 post treatment
Psychometric self-assessment scales (WHOQOL-BREF) 4/4	5.3) Quality of life: WHOQOL-BREF (World Health Organization Quality of Life-BREF). Minimum score: 0 Maximum score: 100 *Higher scores mean a better outcome.	Change from Baseline score at month 2 post treatment
Psychometric self-assessment scales (King's) 1/4	6.0) King's Internalized Stigma Scale. Minimum score: 0 Maximum score: 112 *Higher scores mean a worse outcome.	Baseline score (1 month before TMS treatment)
Psychometric self-assessment scales (King's) 2/4	6.1) King's Internalized Stigma Scale. Minimum score: 0 Maximum score: 112 *Higher scores mean a worse outcome.	Change from Baseline score (immediately after the 12th session -last session-)
Psychometric self-assessment scales (King's) 3/4	6.2) King's Internalized Stigma Scale. Minimum score: 0 Maximum score: 112 *Higher scores mean a worse outcome.	Change from Baseline score at month 1 post treatment
Psychometric self-assessment scales (King's) 4/4	6.3) King's Internalized Stigma Scale. Minimum score: 0 Maximum score: 112 *Higher scores mean a worse outcome.	Change from Baseline score at month 2 post treatment
Psychometric self-assessment scales (OCI-R) 1/4	7.0) Obsessions/compulsions: The Obsessive-Compulsive Inventory Short Version (OCI-R) Minimum score: 0 Maximum score: 72 *Higher scores mean a worse outcome.	Baseline score (1 month before TMS treatment)
Psychometric self-assessment scales (OCI-R) 2/4	7.1) Obsessions/compulsions: The Obsessive-Compulsive Inventory Short Version (OCI-R) Minimum score: 0 Maximum score: 72 *Higher scores mean a worse outcome.	Change from Baseline score (immediately after the 12th session -last session-)
Psychometric self-assessment scales (OCI-R) 3/4	7.2) Obsessions/compulsions: The Obsessive-Compulsive Inventory Short Version (OCI-R) Minimum score: 0 Maximum score: 72 *Higher scores mean a worse outcome.	Change from Baseline score at month 1 post treatment
Psychometric self-assessment scales (OCI-R) 4/4	7.3) Obsessions/compulsions: The Obsessive-Compulsive Inventory Short Version (OCI-R) Minimum score: 0 Maximum score: 72 *Higher scores mean a worse outcome.	Change from Baseline score at month 2 post treatment
Psychometric self-assessment scales (BAI) 1/4	8.0) Beck Anxiety Inventory (BAI). Minimum score: 0 Maximum score: 63 Minimal: 0 - 7 Mild: 8 - 15 Moderate: 16 - 25 Severe: 26 - 63 *Higher scores mean a worse outcome.	Baseline score (1 month before TMS treatment)
Psychometric self-assessment scales (BAI) 2/4	8.1) Beck Anxiety Inventory (BAI). Minimum score: 0 Maximum score: 63 Minimal: 0 - 7 Mild: 8 - 15 Moderate: 16 - 25 Severe: 26 - 63 *Higher scores mean a worse outcome.	Change from Baseline score (immediately after the 12th session -last session-)
Psychometric self-assessment scales (BAI) 3/4	8.2) Beck Anxiety Inventory (BAI). Minimum score: 0 Maximum score: 63 Minimal: 0 - 7 Mild: 8 - 15 Moderate: 16 - 25 Severe: 26 - 63 *Higher scores mean a worse outcome.	Change from Baseline score at month 1 post treatment
Psychometric self-assessment scales (BAI) 4/4	8.3) Beck Anxiety Inventory (BAI). Minimum score: 0 Maximum score: 63 Minimal: 0 - 7 Mild: 8 - 15 Moderate: 16 - 25 Severe: 26 - 63 *Higher scores mean a worse outcome.	Change from Baseline score at month 2 post treatment
Psychometric self-assessment scales (HADS) 1/4	9.0) Anxiety: Hospital Anxiety and Depression Scale (HADS). Depression (D): Minimum score: 0 Maximum score: 21 Anxiety (A): Minimum score: 0 Maximum score: 21 *Higher scores mean a worse outcome.	Baseline score (1 month before TMS treatment)
Psychometric self-assessment scales (HADS) 2/4	9.1) Anxiety: Hospital Anxiety and Depression Scale (HADS). Depression (D): Minimum score: 0 Maximum score: 21 Anxiety (A): Minimum score: 0 Maximum score: 21 *Higher scores mean a worse outcome.	Change from Baseline score (immediately after the 12th session -last session-)
Psychometric self-assessment scales (HADS) 3/4	9.2) Anxiety: Hospital Anxiety and Depression Scale (HADS). Depression (D): Minimum score: 0 Maximum score: 21 Anxiety (A): Minimum score: 0 Maximum score: 21 *Higher scores mean a worse outcome.	Change from Baseline score at month 1 post treatment
Psychometric self-assessment scales (HADS) 4/4	9.3) Anxiety: Hospital Anxiety and Depression Scale (HADS). Depression (D): Minimum score: 0 Maximum score: 21 Anxiety (A): Minimum score: 0 Maximum score: 21 *Higher scores mean a worse outcome.	Change from Baseline score at month 2 post treatment

Collaborators and Investigators

• Sponsor: El Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez
• Investigators: Principal Investigator: Édgar Daniel Crail Meléndez, MD, Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez

Publications and helpful links

General Publications

• Kanemoto K, LaFrance WC Jr, Duncan R, Gigineishvili D, Park SP, Tadokoro Y, Ikeda H, Paul R, Zhou D, Taniguchi G, Kerr M, Oshima T, Jin K, Reuber M. PNES around the world: Where we are now and how we can close the diagnosis and treatment gaps-an ILAE PNES Task Force report. Epilepsia Open. 2017 Jun 23;2(3):307-316. doi: 10.1002/epi4.12060. eCollection 2017 Sep. Erratum In: Epilepsia Open. 2019 Jan 07;4(1):219.
• LaFrance WC Jr, Keitner GI, Papandonatos GD, Blum AS, Machan JT, Ryan CE, Miller IW. Pilot pharmacologic randomized controlled trial for psychogenic nonepileptic seizures. Neurology. 2010 Sep 28;75(13):1166-73. doi: 10.1212/WNL.0b013e3181f4d5a9. Epub 2010 Aug 25.
• Varia I, Logue E, O'connor C, Newby K, Wagner HR, Davenport C, Rathey K, Krishnan KR. Randomized trial of sertraline in patients with unexplained chest pain of noncardiac origin. Am Heart J. 2000 Sep;140(3):367-72. doi: 10.1067/mhj.2000.108514.
• Duncan R, Razvi S, Mulhern S. Newly presenting psychogenic nonepileptic seizures: incidence, population characteristics, and early outcome from a prospective audit of a first seizure clinic. Epilepsy Behav. 2011 Feb;20(2):308-11. doi: 10.1016/j.yebeh.2010.10.022. Epub 2010 Dec 30.
• Dafotakis M, Ameli M, Vitinius F, Weber R, Albus C, Fink GR, Nowak DA. [Transcranial magnetic stimulation for psychogenic tremor - a pilot study]. Fortschr Neurol Psychiatr. 2011 Apr;79(4):226-33. doi: 10.1055/s-0029-1246094. Epub 2011 Apr 8. German.
• Benbadis SR, Allen Hauser W. An estimate of the prevalence of psychogenic non-epileptic seizures. Seizure. 2000 Jun;9(4):280-1. doi: 10.1053/seiz.2000.0409.
• Agarwal R, Garg S, Tikka SK, Khatri S, Goel D. Successful use of theta burst stimulation (TBS) for treating psychogenic non epileptic seizures (PNES) in a pregnant woman. Asian J Psychiatr. 2019 Jun;43:121-122. doi: 10.1016/j.ajp.2019.05.013. Epub 2019 May 8. No abstract available.
• LaFrance, W., & Blumer, D. (2018). Pharmacological Treatments for Psychogenic Nonepileptic Seizures. University of Warwick. Retrieved from: https://www.cambridge.org/core.
• Peterson, K., et al. (2017). Transcranial Magnetic Stimulation in the treatment of non-epileptic seizures: A Case Series. Max Rady College of Medicine. University of Manitoba.
• Peterson KT, Kosior R, Meek BP, Ng M, Perez DL, Modirrousta M. Right Temporoparietal Junction Transcranial Magnetic Stimulation in the Treatment of Psychogenic Nonepileptic Seizures: A Case Series. Psychosomatics. 2018 Nov;59(6):601-606. doi: 10.1016/j.psym.2018.03.001. Epub 2018 Mar 7.
• Pollak TA, Nicholson TR, Edwards MJ, David AS. A systematic review of transcranial magnetic stimulation in the treatment of functional (conversion) neurological symptoms. J Neurol Neurosurg Psychiatry. 2014 Feb;85(2):191-7. doi: 10.1136/jnnp-2012-304181. Epub 2013 Jan 8.
• van der Kruijs SJ, Bodde NM, Vaessen MJ, Lazeron RH, Vonck K, Boon P, Hofman PA, Backes WH, Aldenkamp AP, Jansen JF. Functional connectivity of dissociation in patients with psychogenic non-epileptic seizures. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):239-47. doi: 10.1136/jnnp-2011-300776. Epub 2011 Nov 5.
• van der Kruijs SJ, Jagannathan SR, Bodde NM, Besseling RM, Lazeron RH, Vonck KE, Boon PA, Cluitmans PJ, Hofman PA, Backes WH, Aldenkamp AP, Jansen JF. Resting-state networks and dissociation in psychogenic non-epileptic seizures. J Psychiatr Res. 2014 Jul;54:126-33. doi: 10.1016/j.jpsychires.2014.03.010. Epub 2014 Mar 21.
• Parain D, Chastan N. Large-field repetitive transcranial magnetic stimulation with circular coil in the treatment of functional neurological symptoms. Neurophysiol Clin. 2014 Oct;44(4):425-31. doi: 10.1016/j.neucli.2014.04.004. Epub 2014 May 15.
• Nightscales R, McCartney L, Auvrez C, Tao G, Barnard S, Malpas CB, Perucca P, McIntosh A, Chen Z, Sivathamboo S, Ignatiadis S, Jones S, Adams S, Cook MJ, Kwan P, Velakoulis D, D'Souza W, Berkovic SF, O'Brien TJ. Mortality in patients with psychogenic nonepileptic seizures. Neurology. 2020 Aug 11;95(6):e643-e652. doi: 10.1212/WNL.0000000000009855. Epub 2020 Jul 20.

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2022
• Primary Completion (Actual): May 20, 2023
• Study Completion (Actual): July 31, 2023

Study Registration Dates

• First Submitted: January 20, 2022
• First Submitted That Met QC Criteria: February 11, 2022
• First Posted (Actual): February 15, 2022

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 27, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Transcranial Magnetic Stimulation; Selective Serotonin Reuptake Inhibitor; Functional Neurological Disorder
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Epilepsy; Seizures; Psychogenic Nonepileptic Seizures
• Other Study ID Numbers: 16/21

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.: Yes