Generalized Tonic-Clonic Seizure Following Single-Pulse Transcranial Magnetic Stimulation to the Ipsilesional Primary Motor Cortex in a Participant with Chronic Stroke

Dear Editor:

We report a generalized tonic-clonic seizure following single-pulse transcranial magnetic stimulation (TMS) in a stroke survivor undergoing screening procedures for a research study.

The participant was a 59-year-old right-hand dominant male with a history of hypertension and 18-months following a middle cerebral artery cortical/subcortical ischemic stroke involving the left dominant hemisphere involving the primary motor cortex, basil ganglia, primary somatosensory cortex, and the posterior parietal cortex. He presented with mild aphasia, right hemiparesis, and impaired proprioception of the affected upper limb. Upper extremity motor impairment was significant, with an upper-extremity Fugl-Meyer hand subscore of 4 out of 14, consisting of scores of 1 for mass flexion, 1 for mass extension, and 2 for grasping a cylindrical object. Finger extensor manual muscle test was graded as 2, indicating movement with gravity eliminated across nearly the full range of motion.

He had no prior history of seizure or family history of epilepsy, no history of alcohol or drug use, and was not taking any medications known to lower the seizure threshold. He took warfarin in the morning, and his medication schedule and use were normal. He reported 11.5 hours of sleep the night before, consistent with his usual sleep duration. Six months before this event, he completed participation in research study involving non-invasive brain stimulation at another institute, during which he underwent multiple upper limb therapy and TMS sessions, including single-pulse TMS assessments, without any adverse events. His final 6-month follow-up TMS assessment occurred two weeks before the screening procedures for our study.

On the day of the event, following IRB approved consenting procedures, the participant underwent TMS eligibility assessment to determine the presence or absence of a motor evoked potential (MEP) from the finger extensor and the hand muscle (i.e. extensor digitorum communis and first dorsal interosseous). TMS was delivered using a monophasic Magstim stimulator with a figure-of-eight coil (200² BiStim unit; D70² coil; Magstim Co., Whitland, Dyfed, UK). The coil was positioned over the left (ipsilesional) primary motor cortex with the coil-oriented posterior-anterior at 45° relative to the sagittal plane. Stimulation began at 60% maximum stimulator output (MSO) and was gradually increased to 100% MSO. Approximately 85 single pulses were delivered over a 20-minute period at a frequency of approximately 0.2 Hz (one pulse every five seconds). During the first 60 pulses, TMS was delivered while the participant’s wrists/hands were at rest; during the later pulses, stimulation was delivered during voluntary contraction of the paretic and/or non-paretic wrist and finger extensors. Throughout the procedure, the participant was cheerful and engaged.

Approximately five minutes after the final TMS pulse, the participant verbally reported a tingling and “pulsing” sensation in his right paretic hand and arm. This was followed by a visible tonic muscle contraction that began in the distal arm and hand, progressed proximally up the arm, and eventually involved the entire body, evolving into a generalized tonic-clonic seizure. The participant became unresponsive. The seizure lasted approximately five minutes.

Following the seizure, the participant was awake, but unresponsive, and then went unconscious. He was placed on his side in a recovery position and monitored. Emergency medical services arrived shortly thereafter. The participant had regained awareness when the emergency medical services arrived and was able to verbally answer questions accurately regarding his whereabouts but still appeared disoriented as he was regaining alertness. He was transported to the emergency room. It was reported through medical chart that in route to the emergency room, he experienced an additional one-minute generalized tonic-clonic seizure, and subsequently, two additional seizures upon arrival in the emergency room. Electroencephalogram revealed no epileptiform discharge but revealed focal slowing in the left temporal lobe likely to due to the prior stroke. The participant was admitted to the hospital for observation and was discharged to home 2-days following the event. At discharge, he was ambulatory with assistance and his mentation was improved to almost baseline. The physician notes indicated there was no need to follow up with neurology unless another seizure occurred.

While we, and others (Hamel et al., 2023; Lerner et al., 2019; Rossi et al., 2021; Taylor et al., 2021), report isolated events, TMS is considered a well-tolerated and safe neuromodulation technique. Rossi et al., (2021) in guidelines endorsed by the International Federation of Clinical Neurophysiology, summarize data through 2020 (Chou et al., 2020) and conclude that TMS-induced seizures are exceedingly rare, even among individuals with neurological conditions or taking central nervous system-active medications. Further, the guidelines highlight the work by Lerner et al., (2019) that surveyed 2510 authors of papers using TMS and concluded that single pulse stimulation, paired pulse stimulation, low frequency and high frequency stimulation accounted for a total of 16 seizures in over 200,000 sessions for a standardized risk of 8/100,000 sessions across high and low-risk subjects. Also, they showed that when delivered within recommended safety parameters, single-pulse TMS and repetitive TMS (high and low frequency) carry comparable risk of inducing a seizure. Rossi et al. 2021 also highlight that if a seizure occurs, it is more likely to occur during the first exposure to TMS. Last, In the largest real-world dataset to date, Taylor et al., (2021) surveyed 125 Clinical TMS Society members about seizures in their practices, analyzing 586,656 clinical rTMS sessions. They identified 18 seizures, a rate of 0.31 (95% CI: 0.18–0.48) per 10,000 sessions and 0.71 (95% CI: 0.42–1.11) per 1,000 patients. Rates were lowest with figure-of-eight coils (0.14 per 1,000 patients).

Although rare, seizure is a serious adverse event following TMS, and understanding its circumstances is important for safe implementation in research and clinical practice. Our report describes a generalized tonic-clonic seizure following single-pulse TMS in an individual with prior exposure to TMS without incident and reports the occurrence of seizure clusters. Isolated cases highlight the need for vigilant participant monitoring during sessions as well as transparent reporting to the scientific community to minimize the risk of underreporting bias.