Seizure produced by 15Hz transcranial magnetic stimulation in a healthy subject following static magnetic stimulation and single pulse stimulation

We report the occurrence of a TMS-related seizure in a healthy 19-year-old man with no history of neurological or psychiatric disorder. The participant had no family history of epilepsy, febrile seizures, or close head injury. After the episode, the participant reported past occurrences of loss of consciousness in the context of orthopaedic injuries. On the day of the event, the participant did not have additional risk factors; he did not take any medication at the moment of testing nor in the prior days and his sleep pattern did not change. He reported no illicit drug use, substance abuse, or taking high doses of caffeine. There was no unusual event in the preceding days. This was his first session of TMS. The event occurred in a research lab at the Research Center of Sherbrooke University Hospital. The session involved 30 minutes of static magnetic stimulation (SMS), tracking of corticospinal excitability (CSE) with single-pulse TMS, and repetitive TMS (rTMS). The session started with the measure of the resting motor threshold (RMT) assessed with electromyography from the first dorsal interosseus using the 5 out of 10 motor evoked potentials (MEPs) of >50μV criterion. Thirty single-pulse evoked MEPs were acquired with an intensity of 120% of RMT at baseline. SMS was performed using a nickel-plated neodymium disc magnet (N52, 50mm diameter, 25mm thickness, axially magnetized) placed for 30 minutes over the left primary motor cortex (M1) while the participant was at rest, a procedure presumed to reduce cortical excitability and hence, seizure susceptibility. The magnet was then removed, and thirty MEPs induced by single-pulse TMS at 120% of RMT were acquired at eight-minute intervals for 40 minutes, with interstimulus intervals varying between 5 and 7 seconds. At that point, the participant had received 210 single pulses of TMS; he was feeling well and did not report any side effects. The seizure occurred subsequently, while rTMS was being applied to the left M1 with a figure-of-eight coil oriented at 45o of midline and connected to a Rapid-2 stimulator (MagStim, Whitland, UK ®). The current was biphasic, and the stimulation parameters were the following: 15 Hz trains for 2 seconds (30 pulses), separated by an inter-train interval of 18.6 seconds, with an intensity set at 130% of RMT. The subject was sitting in a reclining chair (70o), and the experimenter was standing behind him. The seizure started during the second or third train of stimulation; a clonic movement appeared in the right hand, and gradually extended to the forearm, bicep, and shoulder, propagated to the contralateral side, and generalized into symmetric tonic-clonic activity. The patient convulsed for approximately 3 min before the seizure self-terminated. Oxygen saturation level and blood pressure could be measured, and the experimenter could not confirm the presence of eye deviation or head turning. There was no tongue biting or incontinence, but the patient suffered from a small scalp laceration during the convulsive episode. Postictal confusion lasted approximately 15 minutes and the patient had no recollection of the event. Close-by medical staff were immediately called in, and the patient was quickly transferred to the emergency room. A brain computerized tomography (CT) scan revealed no anomaly, and the patient was discharged 2 h after his admission. Five days after the event, the patient was seen by a neurologist who performed a complete neurological exam and awake electroencephalography recordings. No abnormality was noted. The clinical diagnosis of this event was TMS-induced focal to bilateral tonic-clonic seizure (secondary generalized seizure). The clinical presentation with regards to the site of onset and propagation pattern of the clonic movements, the duration of generalized convulsions, and the presence of postictal confusion strongly support this hypothesis over alternative diagnoses such as a syncopal episode or psychogenic non-epileptic seizure. This is the first report of the event, and it has not been listed elsewhere. Of note, the use of rTMS as reported here was an infringement of the approved study protocol. This ethical breach and the details of the event were communicated to the institution's review board within 24h. We obtained informed consent from the participant to publish this specific event as part of a scientific communication. A unique feature of this case is the presence of CSE measurements over an extensive period preceding the seizure. A close examination of the single pulse MEPs collected suggests that the application of SMS at the beginning of the session did not alter durably CSE, but that rTMS was applied during a period of enhanced excitability (Fig. 1). There is at least one report of seizures induced by high frequency rTMS during a situation of increased cortical excitability [[1]Edwardson M. Fetz E.E. Avery D.H. Seizure produced by 20Hz transcranial magnetic stimulation during isometric muscle contraction in a healthy subject.Clin Neurophysiol. 2011; 122: 2326-2327https://doi.org/10.1016/j.clinph.2011.04.005Crossref PubMed Scopus (11) Google Scholar], where 20Hz rTMS (90% RMT) was applied to the M1 during the performance of an isometric contraction, provoking a generalized seizure in a healthy participant without known risk factors. The authors postulated that the increase in CSE induced by the muscle contraction may have contributed to the cortical spread and lowering of the seizure threshold. Whether the presence of enhanced excitability played a determinant role in the present case is uncertain, as the intensity and train duration used could have been sufficient to induce a seizure in themselves. Nonetheless, researchers should be cautious when combining high frequency rTMS with interventions believed to increase cortical excitability. TMS studies conducted in these circumstances – or in any novel stimulation protocol – should use EMG to monitor the spread of excitation and afterdischarges in proximal muscles in order to interrupt stimulation when such manifestations occur [[2]Rossi S. Antal A. Bestmann S. Bikson M. Brewer C. Brockmöller J. et al.Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: expert Guidelines.Clin Neurophysiol. 2021; 132 (Wassermann E, Cohen L, Flitman S): 269-306https://doi.org/10.1016/j.clinph.2020.10.003Crossref PubMed Scopus (279) Google Scholar]. To our knowledge, 15 Hz rTMS with intensities above the RMT induced seizures in at least two other instances in individuals without known risk factors (105% and 120% RMT; >2.5-s trains) [[3]Chen R. Hallett M. Seizures in healthy people with repeated “safe” trains of transcranial magnetic stimuli.Lancet. 1996; 347: 825-826https://doi.org/10.5555/uri:pii:S0140673696908983Abstract Google Scholar,[4]Wassermann E.M. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the international workshop on the safety of repetitive transcranial magnetic stimulation, june 5-7, 1996.Electroencephalogr Clin Neurophysiol. 1998; 108: 1-16https://doi.org/10.1016/s0168-5597(97)00096-8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], and in one individual with major depression that was sleep deprived [[5]Prikryl R. Kucerova H. Occurrence of epileptic paroxysm during repetitive transcranial magnetic stimulation treatment.J Psychopharmacol. 2005; 19: 313https://doi.org/10.1177/0269881105051545Crossref PubMed Scopus (18) Google Scholar] (110% RMT; 10-s trains). While current guidelines do not address specifically the safe settings for 15 Hz stimulation (1, 5, 10, 20, and 25Hz are discussed) [[2]Rossi S. Antal A. Bestmann S. Bikson M. Brewer C. Brockmöller J. et al.Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: expert Guidelines.Clin Neurophysiol. 2021; 132 (Wassermann E, Cohen L, Flitman S): 269-306https://doi.org/10.1016/j.clinph.2020.10.003Crossref PubMed Scopus (279) Google Scholar], we would like to note that all reported seizures using 15 Hz occurred when using settings exceeding the safety guidelines for 10 Hz stimulation. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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