Epilepsies, Partial
Conditions
Keywords
Epilepsies, Partial, Transcranial Magnetic Stimulation
Brief summary
The investigators will treat patients with fully characterized refractory unifocal neocortical epilepsy with a technique that delivers magnetic waves (transcranial magnetic stimulation, TMS) to the region that causes the epilepsy. Active rTMS applied over the epileptogenic focus will reduce seizure frequency compared with sham rTMS.
Detailed description
1. Background and study aims Epilepsy is a disease that causes repetitive seizures. In 60% of people with epilepsy, these seizures start in a small zone of the brain (focal or partial epilepsy). This zone can be in the depth of the temporal lobe (mesial temporal lobe epilepsy) or in another brain region (neocortical epilepsy). Even with optimal medical care, up to 30% of people with epilepsy continue to have seizures. The investigators will treat people with neocortical partial epilepsy with a technique that delivers magnetic waves (transcranial magnetic stimulation, TMS) to the region that causes the epilepsy. The investigators have good reasons to believe that there will be fewer seizures during several weeks after treatment. 2. Who can participate? You have neocortical focal epilepsy. A doctor who specializes in epilepsy made this diagnosis. You had at least one seizure recorded while in an epilepsy monitoring unit. You had an MRI scan of the brain. You can deliver us all the results of the tests you had. You continue to have more than 4 seizures a month. You tried a least two different schemes of anti-epileptic drugs as prescribed by your doctor and those schemes were well tolerated. Nevertheless this never cured the seizures. You are older than 16 years. You don't plan to become pregnant during the study. You need to faithfully continue your treatment as prescribed by your doctor and don't change the drugs you take from at least 4 weeks before the study until 8 weeks after the last TMS session. You need to be able to keep a diary of your seizures. 3. What does the study involve? You will need to come to the hospital every weekday during two consecutive weeks, every three months during nine months for the TMS-treatment. So you will have three treatment sessions. You will have a brain scan (FDG-PET) before the first treatment and after each session. The magnetic pulses will be delivered differently during each of the three treatment sessions: once on a rather small area of the brain, once on a larger brain area and once using a dummy coil, i.e. you will have two active treatment sessions and one dummy or placebo session. The investigators will not tell in which order they deliver the treatments. 4. What are the possible benefits and risks of participating? The investigators have good reasons to believe you will have fewer seizures in the weeks following the active treatment.
Interventions
DEVICEfigure-of-eight active rTMS coil
navigated rTMS over epileptogenic focus using figure-of-eight active rTMS coil
DEVICEround active rTMS coil
navigated rTMS over epileptogenic focus using round active rTMS coil
DEVICEsham rTMS coil (figure-of-eight)
commercially available placebo coil that provides slight sensory stimulation and discharge noise without stimulating cortical tissue
Sponsors
Universitaire Ziekenhuizen KU Leuven
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* fully characterized refractory unifocal 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… * pacemaker, implantable cardioverter-defibrillator (ICD) * psychogenic non-epileptic seizures and other non-epileptic spells
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 50% Responder Rate After Active rTMS Treatment Compared With Placebo Treatment | week 12 after each intervention | Number of participants achieving a 50% or greater reduction in seizure frequency from baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Seizure Frequency After Active rTMS Treatment Compared With Placebo Treatment | week 12 after each treatment | Seizure frequency was recorded in patient diaries and reviewed with the neurologist/epileptologist (outcomes assessor) at visits 12 weeks (+/- 1 week) after each intervention. The average weekly seizure rate was calculated and compared to baseline frequency over all participants. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | before the first treatment of each session and at the last evaluation visit | * Quality of life in epilepsy (QOLIE-31): self-report (if cognitive faculties allowed) questionnaire of emotional well-being, social functioning, energy/ fatigue, cognitive functioning, seizure worry, medication effects & overall quality of life. Range 0-100, with higher numbers indicating better quality of life. * Global impression of change-scales (score 1-7, with 4 no change and lower/higher numbers implying grade of improvement/worsening) and Visual analogue scale (0-10: no problem to horrible): self-report or parent report about effect of treatment * Columbia Suicide Severity Rating Scale (CSSR): structured interview about suicidal risk * change in QOLIE scores considered better/worse are based on cut-off reported in DOI 10.1016/j.yebeh.2011.12.023 For global impression of change, the scoring was \<4, 4 or \>4. |
| Alteration of Brain Activation as Measured by 18-2-fluoro-2-deoxy-D-glucose Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) on Individual Patient Level | within one week after the last treatment day of each session | Alterations were assessed by visual inspection of PET scans generated by subtracting the baseline individual PET scan from each of the follow-up scans. The subtraction PET scans were overlayed on the anatomical MRI of the patient and the focus of stimulation determined and an sphere with a 1cm radius around this point was analysed. |
| Adverse Event Rate | during the 9 months of the study | — |
| Drop Out-rate | during the 9 months of the study | exclusion by investigator was due to necessity to change drug regimen due to toxicity |
| Difference in Seizure Reduction Using Different Coil Types | 9 months | any difference between the four conditions (baseline/ figure-of-eight treatment/ round coil treatment/ sham treatment) based in negative binomial model for count data |
Countries
Belgium
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants description of the patients at the onset of the study | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Age, Continuous | 35 years |
| baseline seizure frequency per week | 24.9 seizures/week |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 9 | 3 / 10 | 3 / 9 |
| serious Total, serious adverse events | 2 / 9 | 1 / 10 | 0 / 9 |
Outcome results
Primary
50% Responder Rate After Active rTMS Treatment Compared With Placebo Treatment
Number of participants achieving a 50% or greater reduction in seizure frequency from baseline
Time frame: week 12 after each intervention
Population: Besides the reported participants that went through whole protocol, one supplementary participant underwent the first rTMS session of the first protocol and one supplementary participant underwent the first rTMS session of the second protocol
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | 50% Responder Rate After Active rTMS Treatment Compared With Placebo Treatment | 50% seizure reduction over any of three periods | 0 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | 50% Responder Rate After Active rTMS Treatment Compared With Placebo Treatment | 50% seizure reduction over whole study | 0 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | 50% Responder Rate After Active rTMS Treatment Compared With Placebo Treatment | 50% seizure reduction over any of three periods | 0 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | 50% Responder Rate After Active rTMS Treatment Compared With Placebo Treatment | 50% seizure reduction over whole study | 0 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | 50% Responder Rate After Active rTMS Treatment Compared With Placebo Treatment | 50% seizure reduction over any of three periods | 0 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | 50% Responder Rate After Active rTMS Treatment Compared With Placebo Treatment | 50% seizure reduction over whole study | 0 participants |
Secondary
Seizure Frequency After Active rTMS Treatment Compared With Placebo Treatment
Seizure frequency was recorded in patient diaries and reviewed with the neurologist/epileptologist (outcomes assessor) at visits 12 weeks (+/- 1 week) after each intervention. The average weekly seizure rate was calculated and compared to baseline frequency over all participants.
Time frame: week 12 after each treatment
Population: baseline weekly seizure frequency over all participants was 24.8 (95% confidence interval 8.2-76.1)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Seizure Frequency After Active rTMS Treatment Compared With Placebo Treatment | 25.7 seizures/week |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Seizure Frequency After Active rTMS Treatment Compared With Placebo Treatment | 23.5 seizures/week |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Seizure Frequency After Active rTMS Treatment Compared With Placebo Treatment | 28.6 seizures/week |
Other Pre-specified
Adverse Event Rate
Time frame: during the 9 months of the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Adverse Event Rate | worsening seizures | 2 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Adverse Event Rate | hearing problems | 1 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Adverse Event Rate | fatigue | 2 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Adverse Event Rate | concentration difficulties | 1 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Adverse Event Rate | concentration difficulties | 1 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Adverse Event Rate | worsening seizures | 1 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Adverse Event Rate | fatigue | 2 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Adverse Event Rate | hearing problems | 1 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Adverse Event Rate | concentration difficulties | 1 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Adverse Event Rate | hearing problems | 0 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Adverse Event Rate | fatigue | 2 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Adverse Event Rate | worsening seizures | 0 participants |
Other Pre-specified
Alteration of Brain Activation as Measured by 18-2-fluoro-2-deoxy-D-glucose Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) on Individual Patient Level
Alterations were assessed by visual inspection of PET scans generated by subtracting the baseline individual PET scan from each of the follow-up scans. The subtraction PET scans were overlayed on the anatomical MRI of the patient and the focus of stimulation determined and an sphere with a 1cm radius around this point was analysed.
Time frame: within one week after the last treatment day of each session
Population: patients of whom seizure journals were incomplete also included (one participant who went through all 3 trials and one patient of whom journals were not available from the sham session, that was reported by the patient as ineffective)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Alteration of Brain Activation as Measured by 18-2-fluoro-2-deoxy-D-glucose Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) on Individual Patient Level | hypermetabolism compared to baseline | 1 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Alteration of Brain Activation as Measured by 18-2-fluoro-2-deoxy-D-glucose Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) on Individual Patient Level | hypometabolism compared to baseline | 3 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Alteration of Brain Activation as Measured by 18-2-fluoro-2-deoxy-D-glucose Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) on Individual Patient Level | hypermetabolism compared to baseline | 3 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Alteration of Brain Activation as Measured by 18-2-fluoro-2-deoxy-D-glucose Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) on Individual Patient Level | hypometabolism compared to baseline | 3 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Alteration of Brain Activation as Measured by 18-2-fluoro-2-deoxy-D-glucose Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) on Individual Patient Level | hypermetabolism compared to baseline | 2 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Alteration of Brain Activation as Measured by 18-2-fluoro-2-deoxy-D-glucose Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) on Individual Patient Level | hypometabolism compared to baseline | 3 participants |
Other Pre-specified
Difference in Seizure Reduction Using Different Coil Types
any difference between the four conditions (baseline/ figure-of-eight treatment/ round coil treatment/ sham treatment) based in negative binomial model for count data
Time frame: 9 months
Population: averaged weekly seizure count per condition is given for all patients combined
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Difference in Seizure Reduction Using Different Coil Types | seizures in condition 1 (baseline) | 25 number of seizures per week |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Difference in Seizure Reduction Using Different Coil Types | seizures in condition 2 (figure-8) | 26 number of seizures per week |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Difference in Seizure Reduction Using Different Coil Types | seizures in condition 3 (round) | 24 number of seizures per week |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Difference in Seizure Reduction Using Different Coil Types | seizures in condition 4 (sham) | 29 number of seizures per week |
p-value: 0.9819negative binomial model + overdispersion
Other Pre-specified
Drop Out-rate
exclusion by investigator was due to necessity to change drug regimen due to toxicity
Time frame: during the 9 months of the study
Population: for this analysis, all patients randomised were included; this includes one patient in the second arm that was not included in any of the other outcome measures, due to lack of reliable outcome parameters
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Drop Out-rate | excluded by investigator from concluding study | 0 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Drop Out-rate | stopped due to seizure worsening | 1 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Drop Out-rate | stopped due to intolerance/ inefficiency | 0 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Drop Out-rate | excluded by investigator from concluding study | 1 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Drop Out-rate | stopped due to intolerance/ inefficiency | 1 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Drop Out-rate | stopped due to seizure worsening | 0 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Drop Out-rate | excluded by investigator from concluding study | 0 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Drop Out-rate | stopped due to seizure worsening | 0 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Drop Out-rate | stopped due to intolerance/ inefficiency | 0 participants |
Other Pre-specified
Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale
* Quality of life in epilepsy (QOLIE-31): self-report (if cognitive faculties allowed) questionnaire of emotional well-being, social functioning, energy/ fatigue, cognitive functioning, seizure worry, medication effects & overall quality of life. Range 0-100, with higher numbers indicating better quality of life. * Global impression of change-scales (score 1-7, with 4 no change and lower/higher numbers implying grade of improvement/worsening) and Visual analogue scale (0-10: no problem to horrible): self-report or parent report about effect of treatment * Columbia Suicide Severity Rating Scale (CSSR): structured interview about suicidal risk * change in QOLIE scores considered better/worse are based on cut-off reported in DOI 10.1016/j.yebeh.2011.12.023 For global impression of change, the scoring was \<4, 4 or \>4.
Time frame: before the first treatment of each session and at the last evaluation visit
Population: \* Self-reporting questionnaires could only be filled in by 7 participants For global impression of change scales, the score reached by consensus between the patient and caregiver(s) was used if patient was unable to fill in questionaires: for the three arms, we thus have 7/8/6 scores for each arm respectively
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | worse QOLIE score | 0 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | Global impression of change: better | 1 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | Global impression of change: worse | 1 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | better QOLIE score | 3 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | CSSR-scale increased suicidality | 0 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | Global impression change: first better, then worse | 1 participants |
| Figure-of-eight Active Coil; Then Round Active Coil; Then Sham | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | Global impression of change: no change | 4 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | Global impression of change: worse | 1 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | better QOLIE score | 3 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | worse QOLIE score | 1 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | Global impression of change: no change | 5 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | Global impression of change: better | 1 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | Global impression change: first better, then worse | 1 participants |
| Round Active Coil; Then Sham; Then Figure-of-eight Active Coil | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | CSSR-scale increased suicidality | 0 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | Global impression of change: better | 0 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | worse QOLIE score | 1 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | CSSR-scale increased suicidality | 0 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | Global impression change: first better, then worse | 0 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | Global impression of change: worse | 1 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | Global impression of change: no change | 5 participants |
| Sham Coil; Then Figure-of-eight Active Coil; Then Round Active | Questionnaires: Quality of Life in Epilepsy (QOLIE-31), Global Impression of Change-scales, Visual Analogue Scale, Columbia Suicide Severity Rating Scale | better QOLIE score | 1 participants |