Accelerated TMS for Seizure-Type Functional Neurologic Disorders

Официальное название

Accelerated, Left Prefrontal Transcranial Magnetic Stimulation for Functional Seizures; An Open-Label Exploration of Feasibility, Tolerability, and Preliminary Efficacy

Обзор

The purpose of this project is to assess the feasibility, tolerability, and preliminary efficacy of using an accelerated, intermittent theta burst stimulation (a-iTBS-rTMS) protocol targeting the left dorsolateral prefrontal cortex (l-dlPFC) for Psychogenic Non-Epileptic Seizures (PNES) or Seizure-Type Functional Neurologic Disorder (FND-seiz) in an open-label fashion. Following screening, consent, and enrollment, participants will receive 6-to-10 iTBS-rTMS sessions per day (i.e., theta burst; 600 pulses per session; 6000 pulses per day) over a 3-to-5 treatment days with a target of 30 total sessions (18,000 total pulses). TMS will be targeted to Beam F3 for comparison to the bulk of the literature and to most mimic replicable and clinical use. This proposed iTBS-rTMS protocol was chosen given its previously shown safety, tolerability, and effectiveness in other conditions, but also as it has the potential to shorten treatment to only 3 days, which investigators theorize will be more feasible for patients with FND-seiz. Feasibility will be measured as the percentage of participants who receive at least 20 treatment sessions within the 3-to-5-day window. Other than self-assessments used in the safety screening process or to monitor TMS benefits and risks, secondary subjective measures will assess previously investigated FND-seiz-specific outcomes, which will be obtained prior to intervention and 4-weeks post-intervention. In addition to monthly seizure frequency, this will include validated measures regarding stigma, health-related QOL, depression, PTSD, somatic symptoms, psychosocial functioning, psychological distress, and clinical and participant impression of improvement and satisfaction. Sub-analysis will further divide participants with mild to no depression and/or PTSD versus moderate to severe depression and/or PTSD to further assess how the TMS effects known to effect other highly comorbid disorders with FND-seiz, may indirectly affect FND-seiz outcomes.

Подробное описание

Seizure-Type Functional Neurologic Disorders (FND-seiz) are strikingly prevalent-accounting for 5-15% of epilepsy center referrals and up to 40% of epilepsy monitoring unit admissions-when considering the associated barriers to treatment and dismal outcomes. Due to resource-intensive requirements, diagnosis is often delayed by years. In the interim, patients frequently receive inappropriate antiseizure medications and have high utilization of emergency services. Years after diagnosis, many FND-seiz patients continue to experience non-epileptic seizures (NS) and have high rates of disability. Due to stigma and psychosocial barriers, engagement and responses to the standard of care, Cognitive Behavioral Therapy (CBT), are inconsistent. As many patients are told they may have epilepsy prior to receiving an accurate diagnosis, there is an obvious disconnect between the recommended psychological treatment and the physical nature of their symptoms, which can limit acceptance of the diagnosis and subsequently CBT engagement. Furthermore, the only powered RCT (the CODES trial) examining CBT in FND-seiz failed to show a significant seizure reduction at 12 months follow up and the overall effect size was lower than previously thought highlighting the limitations of a "one-size-fits-all" model for a highly comorbid disorder. Ultimately, patients with FND-seiz have been found to have a poorer overall quality of life compared to epilepsy and a standardized mortality rate 2.5 times greater the general population and comparable to that of drug-resistant epilepsy

Together these factors underscore the need for alternate treatments capable of addressing psychosocial challenges unique to FND-seiz or further investigating the underlying neurobiology. Investigators theorize that offering a brain-network based approach may reduce stigma associated with confusion over the "psychological" rather than "neurological" etiologic conception of FND-seiz, which if effective, may be a more feasible for some patients. Brain-imaging research and prior reports of benefit with neurostimulation suggests TMS to the left dorsolateral prefrontal cortex (l-dlPFC) has the potential to improve cortico-limbic or cortico-sensorimotor governance, which Investigators theorize in FND-seiz may decrease NS frequency or improve quality of life. Thus, Investigators aim to investigate the feasibility and tolerability of an accelerated, intermittent theta-burst TMS protocol in FND-seiz to best mimic current clinical trends and optimize TMS feasibility, which may have several applications for the FND-seiz population.

In clinical practice, the known, but rare risk of inducing an epileptic seizure with TMS and the difficulty differentiating epileptic from non-epileptic seizures, may decrease the comfort of TMS providers to use TMS in FND-seiz patients when indicated for other disabling disorders. In tandem with exploring the feasibility and tolerability of this intervention, Investigators hope to employ and investigate an informed safety protocol, with input from experts in the fields of epilepsy and brain stimulation. Helping providers safely screen patients, more decisively exclude patients with an inaccurate diagnosis or concomitant epilepsy and having a protocol to follow when treating FND-seiz patients who experience a NS during TMS stimulation may increase TMS access for FND-seiz patients with other TMS indications. Finally, as preliminary evidence here at MUSC also suggests combining TMS with CBT for other indications may have a synergistic effect and improve attrition with CBT, if TMS is preliminarily efficacious alone in FND-seiz specific outcomes in a small, open-label sample, this investigation may also help optimize future methodologies examining the use of TMS in FND-seiz.

Вмешательства

• Устройство Transcranial Magnetic Stimulation
  Participants will receive 6 to 10 sessions per day (i.e., theta burst; 600 pulses per session; 6000 pulses per day) over 3 to 5 treatment days using a MagVenture MagPro TMS System. Treatment will consist of a total of 30 sessions (18,000 total pulses). A single session is defined as 600 pulses at 50 Hz for 2s (i.e., 5 Hz triplets) and repeated every 10s for a total of 190s per session to l-dlPFC at 120% rMT with 15-minute intersession intervals. TMS will be targeted to Beam F3 for comparison to

Первичные конечные точки

• Percentage of Participants Completing TMS Sessions [Срок оценки: Assessed daily from Day 1 to Day 5 of the TMS treatment period and summarized at the 4-week follow-up visit.]
• Session Delivery Patterns [Срок оценки: Recorded daily from Day 1 to Day 5 of the TMS treatment period and summarized at the 4-week follow-up visit.]
• Adverse Event Rate [Срок оценки: Assessed daily from Day 1 to Day 5 of the TMS treatment period, at the initial screening visit (baseline), and at the 4-week follow-up visit.]
• Serious Adverse Event Rate [Срок оценки: Assessed daily from Day 1 to Day 5 of the TMS treatment period, at the initial screening visit (baseline), and at the 4-week follow-up visit.]
• Pulses per Session Delivery Patterns [Срок оценки: Recorded daily from Day 1 to Day 5 of the TMS treatment period and summarized at the 4-week follow-up visit.]

Вторичные конечные точки (11)

• Non-epileptic Seizure Frequency (NES) [Срок оценки: Assessed prior to intervention at visit 1, 2-4 weeks prior to starting the 3-5 day TMS treatment protocol, and at the final follow up visit 4 weeks after completing the TMS treatment protocol.]
• Chronic Illness Anticipated Stigma Scale (CIASS) [Срок оценки: Assessed at initial visit (time point 0 at visit 1, 2-4 weeks pre-TMS) and at post-intervention follow-up (4 weeks post-TMS).]
• Montgomery-Asberg Depression Rating Scale (MADRS) [Срок оценки: Assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS).]
• Post-Traumatic Stress Disorder Checklist for DSM-5 (PCL-5) [Срок оценки: Assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS).]
• PROMIS®-29+2 Profile v2.1 (PROPr) [Срок оценки: Assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS).]
• Patient Health Questionnaire-15 (PHQ-15) [Срок оценки: Assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS).]
• Clinical Outcomes in Routine Evaluation (CORE-10) [Срок оценки: Assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS).]
• Clinical Global Impression-Improvement and Severity (CGI-I and CGI-S) [Срок оценки: Time Frame: CGI-S assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS); CGI-I assessed only at follow-up (4 weeks post-TMS).]
• The National Hospital Seizure Severity Scale (NHS3) [Срок оценки: Assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS).]
• Participants with Complete NES Remission [Срок оценки: Assessed at follow-up (4 weeks post-TMS).]
• Participants with >50% Reduction in NES Frequency [Срок оценки: Assessed at follow-up (4 weeks post-TMS).]

Критерии участия

Критерии включения

• >18 years old and <65 years old
• English Speaking, can read and write, and able to provide informed consent
• Diagnosis of "documented" Functional Seizures as made by an MUSC epileptologist or neurologist using the ILAE recommendations: "by clinician experienced in diagnosis of seizure disorders (on video or in person), showing semiology of typical of FND-seiz, while on EEG plus no epileptiform activity on routine or ambulatory ictal EEG during a typical ictus/event in which the semiology would make ictal epileptiform EEG activity expected during equivalent epileptic seizures"2
• In addition to meeting ILAE minimum requirements for FND-seiz diagnosis, must have previously undergone and documented in the electronic medical record a minimum of 24-hours of otherwise normal video EEG without interictal epileptiform findings
• Duration of symptoms >3 months and continuing to experience NES at least monthly
• Not currently undergoing any psychotherapeutic intervention, agree to forgo any psychotherapeutic intervention during the study, and if previously completed any psychotherapeutic intervention continue to experience monthly non-epileptic seizures
• If on psychotropic medications may choose to continue during the duration of the study at current doses, but consent to not modifying medication doses or switching to alternative psychotropic regimens during the trial
• In good general health, as ascertained by medical history
• Females of reproductive age (ages 18 to 50) must have a negative urine pregnancy test, performed onsite, and documented in the study record within 72 hours prior to the first TMS session

Критерии исключения

• History of clinical concern for concomitant epileptic seizures or epilepsy
• History of ongoing psychosis, mania, active alcohol or substance use disorder as screened by the PSQ, YMRS, AUDIT, and DAST-10
• History of positive screening urine test for drugs of abuse within the last year: cocaine, amphetamines, barbiturates, opiates
• Active suicidal intent or a score >2 on question 3 of the HAM-D
• Use of medications known to lower the seizure threshold at doses that may increase this risk in the setting of rTMS-iTBS (i.e. buproprion at >300 mg, combinations of tricyclic antidepressants, antipsychotics… as determined by investigators)
• History of central nervous system surgeries or clinically relevant structural brain lesions
• Significant or unstable cardiac, metabolic, oncologic, psychiatric, developmental, or neurologic condition(s) or treatments that may impact safe participation in the study as determined by the study investigators (e.g. poorly-controlled heart failure, current or past cardiac arrhythmia, sustained systolic blood pressure >180, labile diabetes, significant electrolyte abnormality, brain cancer, cognitive impairment, neurodevelopmental disorders, autism spectrum disorder, mania, schizophrenia spectrum or other psychotic disorder, movement disorders, multiple sclerosis, moderate to severe brain injury)
• Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation
• History of TMS exposure
• TMS contraindications (e.g., ferromagnetic implants, cochlear implants, conditions or treat-ments that lower seizure threshold - as determined by study investigators).
• Current pregnancy or desire to become pregnant during study duration without contraceptive plan
• Are a prisoner or in police custody at the time of eligibility screening

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Institute of Psychiatry, Brain Stimulation Department — Charleston

Публикации

• Kan RLD, Padberg F, Giron CG, Lin TTZ, Zhang BBB, Brunoni AR, Kranz GS. Effects of repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex on symptom domains in neuropsychiatric disorders: a systematic review and cross-diagnostic meta-analysis. Lancet Psychiatry. 2023 Apr;10(4):252-259. doi: 10.1016/S2215-0366(23)00026-3. Epub 2023 Mar 7. PMID 36898403
• Wang Y, Gao H, Qi M. Left dorsolateral prefrontal cortex activation can accelerate stress recovery: A repetitive transcranial stimulation study. Psychophysiology. 2023 Oct;60(10):e14352. doi: 10.1111/psyp.14352. Epub 2023 May 23. PMID 37221649
• Philip NS, Barredo J, van 't Wout-Frank M, Tyrka AR, Price LH, Carpenter LL. Network Mechanisms of Clinical Response to Transcranial Magnetic Stimulation in Posttraumatic Stress Disorder and Major Depressive Disorder. Biol Psychiatry. 2018 Feb 1;83(3):263-272. doi: 10.1016/j.biopsych.2017.07.021. Epub 2017 Aug 8. PMID 28886760
• Hassa T, Sebastian A, Liepert J, Weiller C, Schmidt R, Tuscher O. Symptom-specific amygdala hyperactivity modulates motor control network in conversion disorder. Neuroimage Clin. 2017 Apr 27;15:143-150. doi: 10.1016/j.nicl.2017.04.004. eCollection 2017. PMID 28529870
• Maurer CW, LaFaver K, Ameli R, Epstein SA, Hallett M, Horovitz SG. Impaired self-agency in functional movement disorders: A resting-state fMRI study. Neurology. 2016 Aug 9;87(6):564-70. doi: 10.1212/WNL.0000000000002940. Epub 2016 Jul 6. PMID 27385746
• Mcsweeney M, Reuber M, Levita L. Neuroimaging studies in patients with psychogenic non-epileptic seizures: A systematic meta-review. Neuroimage Clin. 2017 Jul 27;16:210-221. doi: 10.1016/j.nicl.2017.07.025. eCollection 2017. PMID 28808618
• Perez DL, Dworetzky BA, Dickerson BC, Leung L, Cohn R, Baslet G, Silbersweig DA. An integrative neurocircuit perspective on psychogenic nonepileptic seizures and functional movement disorders: neural functional unawareness. Clin EEG Neurosci. 2015 Jan;46(1):4-15. doi: 10.1177/1550059414555905. Epub 2014 Nov 27. PMID 25432161
• Perez DL, Nicholson TR, Asadi-Pooya AA, Begue I, Butler M, Carson AJ, David AS, Deeley Q, Diez I, Edwards MJ, Espay AJ, Gelauff JM, Hallett M, Horovitz SG, Jungilligens J, Kanaan RAA, Tijssen MAJ, Kozlowska K, LaFaver K, LaFrance WC Jr, Lidstone SC, Marapin RS, Maurer CW, Modirrousta M, Reinders AATS, Sojka P, Staab JP, Stone J, Szaflarski JP, Aybek S. Neuroimaging in Functional Neurological Disor PMID 34215138

Идентификаторы

NCT: NCT07059325 · Pro00144502

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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