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Transcranial Magnetic Stimulation (TMS) Safety with Respect to Seizures: A Literature Review

Abstract Transcranial magnetic stimulation is an increasingly popular FDA-approved treatment for resistant depression, migraines, and OCD. Research is also underway for its use in various other psychiatric and medical disorders. Although rare, seizures are a potential adverse event of TMS treatment. In this article, we discuss TMS-related seizures with the various coils used to deliver TMS, the risk factors associated with seizures, the differential diagnosis of its presentations, the effects of sleep deprivation and alcohol use on seizures, as well as seizure risks with protocols for traditional TMS, theta-burst stimulation, and accelerated TMS. A discussion is presented comparing the potential risk of seizures with various psychotropic medications versus TMS. Included are case reports of TMS seizures in the child/adolescent patient, bipolar disorder patients, patients with a history of a traumatic brain injury, and those with epilepsy. Reports are also shared on TMS use without seizures in patients with a history of head injuries and TMS’s continued use if patients have a seizure during their TMS treatment. Findings generated in this review suggest the following. Seizures, if present, are usually self-limiting. Most treatment recommendations for TMS-related seizures are supportive in nature. The risk of TMS-related seizures is <1% overall. TMS has successfully been used in patients with epilepsy, traumatic brain injuries, and those with a prior TMS-related seizure. The rate of TMS-related seizures is comparable to that of most psychotropic medications. While having a seizure is a rare but serious adverse effect of TMS, the benefits of treating refractory depression with TMS may outweigh the risk of suicidal ideation and other significant complications of depression.


Introduction
Transcranial Magnetic Stimulation (TMS) is FDA approved for depression, migraines, and OCD, with other symptoms and disorders being aggressively studied for benefit. Lefaucheur et al 2020 1 have an extensive review of the evidence-based use of rTMS in other disorders such as stroke, multiple sclerosis, tinnitus, anxiety, schizophrenia, substance abuse, Alzheimer's, ALS, epilepsy, panic, PTSD, and others. TMS uses an electromagnetic coil placed on varying areas of the scalp. This coil generates magnetic pulses and stimulates different brain areas to create the desired pathophysiologic and clinical outcome. TMS was first approved for depression in 2008; 2 since that time, various coils have been created, altering the area and depth stimulated. It has been suggested that the different coils may have variations in side effects and the possible frequency of the adverse event of a seizure. There are also different protocols of stimulation used with TMS, with the most recent advances called theta-burst stimulation and accelerated treatment. Theta-burst stimulation uses three magnetic pulses 20 ms apart and repeated every 200 ms of 50 Hz stimulation. 3 Accelerated TMS uses multiple TMS stimulation treatments per day. 4 Methodology This paper will focus on the adverse event of a seizure during TMS, which is an abnormal electrical activity and may be due to systemic or local causes. We will also review TMS use in patients with known epilepsy, which is usually due to a structural abnormality of the brain and is that of repeated seizures.
After having a patient who had a seizure during her TMS treatment in 2018, we began looking for all suggestions and references we could find on TMS-related seizures. We had difficulty finding specific information on whether to continue the TMS and what steps to take immediately after the patient had been stabilized from the seizure. From that time forward, we have reviewed articles/books found on PubMed, MEDLINE, Medscape, Cochrane Libray, Scopus, and Google Scholar while collecting information with Mendeley. In this article, we have presented data from 1998 to 2020 (See Table 1). We will discuss the general risk factors associated with seizures, the risks associated with the different TMS coils, reports of seizures with differing TMS protocols, the risk of psychotropic medication alteration on having a seizure, TMS seizures in the child/adolescent population, TMS seizures in bipolar disorder, as well as the possible effects of alcohol use and sleep deprivation on seizures. We will review TMS use with epilepsy and traumatic head injury patients. We will report on continued TMS after a seizure. We will also describe specific steps to take should the patient have a seizure.

TMS and Coils
The general risks of a seizure with TMS have been reported to be <1/30,000 (<0.003%) by Rossi et al 2009. 5 The risk of seizure with theta burst is estimated at 0.02% by Oberman et al 2011. 6 With the Figure-8 coil, the risk of seizure has been estimated by Carpenter et al 2012 7 to be 3/1000 or <1% overall. Janicak et al 2020 8 reported postmarketing seizure rates with the Neurostar coil are even lower than previously reported. Tendler et al 2018 9 reviewed available data for the Brainsway H1-Coil and reported a seizure rate of 0.087%. They reviewed 31 reported cases of seizures with the H1-Coil and felt most were due to the motor threshold (MT) not being rechecked weekly, as recommended by the company. Six seizures were due to stimulation with intensity >120% of the Motor Threshold. No seizures were reported with the first TMS treatment. Nine seizures were associated with medication issues, increased alcohol intake was reported with six patients, and three seizures were associated with sleep issues. While most seizures occur during or around the time of treatment, Cavinato et al 2012 10 reported on a patient with a traumatic brain injury who had a seizure 3 hours after his TMS treatment. Also, Koudijs et al 2010 11 reported an increased frequency of seizures for up to 3 days in four children with known epilepsy who had TMS treatment.
Lerner et al 2019 12 reviewed surveys from 174 providers from 2012 to 2016, revealing 24 seizures out of 318,560 TMS sessions. They reported the risk of seizures with TMS was 0.08/1000 and that "TMS delivered within published guidelines to individuals without risk factors appears to cause fewer than one seizure per 60,000 sessions." In their review, 62% of seizures occurred on the first exposure to TMS and 75% within the first three treatments. Of the 24 seizures, seven occurred in patients with congenital epilepsy, all of whom were on anti-epileptic medication at the time. Two patients were described as having refractory epilepsy. Lerner et al described the seizure risk for the different coil types as follows: 0.08/1000 for conventional figure-8 coils, double cone coils of 0.12/1000 and 0.43/1000 for H-coils. Only three seizures were reported with the H-coil, but only 7577 (2%) of the 318,560 TMS sessions were completed using the H-coil. The smaller sample size may have made the H-coil numbers appear higher.

Rossi et al 2009 5 conveyed
Seizures are caused by hyper synchronized discharges of groups of neurons in the gray matter, mainly due to an imbalance between inhibitory and excitatory synaptic activity in favor of the latter. Seizures can be induced by rTMS when pulses are applied with relatively highfrequencies and short interval periods between trains of stimulation.
Wasserman 1998 13 stated that "Intervals between series less than 20 seconds were associated with increased seizures". (       the risk of tonic-clonic seizure, a rare event during rTMS, is related to the direct stimulation of motor cortex or stimulation of the adjacent brain areas with spread of neuronal excitation to the motor cortex. Inspection of the contralateral hand for signs of twitching or movement during stimulation may ensure that stimulation does not spread from prefrontal to primary motor cortex, which can lead to generalized seizure induction with tonic-clonic movement pattern.
McClintock also stated, "seizures can occur within safety guidelines, even in patients who present with no known risk factors." The risk factors associated with TMS-related seizures were discussed in the book entitled "Transcranial Magnetic Stimulation in Neuropsychiatry" (George and Belmaker 2007 14 ). They reported on the increased risk of seizures with focal or generalized encephalopathy, severe head trauma, non-treated epilepsy, family history of epilepsy in first-degree relatives, heavy alcohol use, severe

Differential Diagnosis of TMS Seizures
Concerning the differential diagnosis, a distinction must be made between vasovagal syncope and seizure during an episode. Vasovagal syncope symptoms include a transient rapid onset, self-limited loss of consciousness associated with lightheadedness, pale skin, yawning, blurred vision, and a feeling of being warm, cold, clammy, or sweaty (Sheldon et al 2002 15 ). Jerky myoclonic movements have also been reported with both vasovagal syncope and seizures. TMS seizures can be generalized or partial. Kinback in 2018 16 described a partial tonic seizure in a 42-year-old white female using the H1 coil during treatment 21, where she developed tense jaw and arm muscles, fixed gaze, unresponsiveness, and bilateral upper extremity flexion with clinched wrists. She had slight spine arching but no lower extremity involvement. She stayed fully aware without incontinence or LOC.

Theta-Burst TMS and Seizures
As previously stated, theta-burst TMS has been associated with an estimated seizure risk of 0.02%. 6

Accelerated TMS and Seizures
Kallel and Brunelin 2020 21 described an 18-year-old female with major depression receiving a protocol of 5 sessions per day during four consecutive working days over the left dorsolateral prefrontal cortex using the MagPro X30 figure-eight coil. The patient developed a seizure on the third session of the second day. The seizure underwent secondary generalization and was associated with urinary incontinence and postictal confusion. Twelve days later, the patient agreed to additional TMS given at 1-Hz right DLPFC treatment with one session per day for 30 additional sessions. She also had maintenance TMS scheduled every 2 weeks afterwards and had no seizure activity during her continued or maintenance treatments.

TMS, Psychotropic Medications, and Seizures
Over the years, various medications have been used during which a TMS-related seizure has occurred, but we have found no absolute contraindication with any specific medication to date. Rossi et al 5 in their safety article of 2009 listed several medications described as having either a strong potential for hazard or a relative hazard for interactions with TMS. They also included medications that if withdrawn could create a strong relative hazard. (Please see their article for a complete list of medications listed.) Since their 2009 article, many of these substances have been used during TMS without incident.
There has been discussion about changing medications during the TMS treatment, and Loo et al 2008 22 stated, If medications are altered during the TMS course, the motor threshold should be re-measured and the stimulus intensity adjusted accordingly. This is based on the premise that medications which alter seizure threshold could also alter motor cortical threshold.
Dobek et al 2015 23 while studying bupropion treatment with TMS and after an extensive literature review reported the following seizure incidence rates in percent for psychotropic medications independent of TMS use: Bupropion SR 0.1%, Bupropion IR 0.  25 revealed studies with antipsychotics are associated with 0.5% to 1.2% risk of seizures, and also reported clozapine appears to increase the risk the most. The above information reveals that the rates of seizures for psychotropic medications are similar or higher than the general TMS rates of <0.003% to 0.087% mentioned previously. Dobek et al 23 also stated that TMS-induced seizure data are not associated with any particular antidepressant, and bupropion is not a contraindication to TMS. Thanki et al 2020 26 even reported on using rTMS in a 60-year-old male with a history of hyponatremic seizures with antidepressants on two different occasions while on sertraline 50 mg and then later on venlafaxine 75 mg, who was later successfully treated with 1 Hz TMS to the right dorsolateral prefrontal cortex at 90% of the resting motor threshold without having a seizure. In the transition years to adulthood ages (18)(19)(20), Muir et al 2019 31 reviewed six patients and presented a case of one seizure using the H 1 coil at 120% MT with the risk factors of autism, multiple head injuries, and the discontinuation of oxcarbazepine during the week before TMS initiation. They felt the spontaneous discontinuation of oxcarbazepine was the most likely cause. Most recently, Zewdie et al 2019 32 reviewed the results of 384 children over ten years that underwent TMS or direct current stimulation (tDCS). Neuromodulation TMS occurred in 119 of the patients with a median age of 14. "Despite 221 (58%) of the patients having some sort of brain injury/or epilepsy, no seizures occurred with single, paired, or rTMS or with tCDS."

TMS in Traumatic Brain Injury Patients
Head injuries are another situation associated with an increased risk of seizures. Dhaliwal et al 2015 37 stated, "patients with severe TBI do show an increased risk of unprovoked seizures," and there is a strong connection between the severity of a brain injury and the subsequent risk of seizures; individuals with mild to moderate TBI have a substantially lower seizure risk than those with severe TBI.
Reti et al 2015 38 indicated, TBI is associated with an increased risk of both early and late spontaneous seizures, a significant consideration in Neuropsychiatric Disease and Treatment 2020:16 submit your manuscript | www.dovepress.com DovePress evaluating rTMS as a potential treatment for TBI depression. Whilst the risk from rTMS is low; underlying neuropathology may somewhat increase that risk.
They suggested that low-frequency rTMS might be less likely to trigger a seizure.
Various reports of patients with a history of a head injury having a TMS-related seizure have been described. Bernabeu et al 2004 39 reported a seizure in a TBI patient on fluoxetine but was using a brief interstimulus interval. Cavinato et al 2012 10 described a 31year-old male with a history of a severe TBI 8 months before TMS initiation. He had a secondary generalized seizure on the 4th of 10 daily sessions. TMS was delivered at 90% MT, 20 Hz, 1s train duration, and 1-minute inter-train interval to the dorsolateral prefrontal cortex (DLPFC). The seizure developed 3 hours after treatment. Pape et al 2014 40 reported on a 32-year-old male who had a TBI 9 years before TMS initiation who had an EEG identified seizure during the treatment with no clinical expression. Boes et al 2016 41 reported on a 27year-old male with MDE, GAD, alcohol use, and a history of 4 prior head injuries. He was also sleep deprived. He developed a seizure during the 12th treatment session. As described previously, Muir et al 2019 29 presented a patient with a history of oxcarbazepine withdrawal the week before, autism, and multiple head injuries who had a seizure.

TMS Treatment Without Seizures in Patients with Head Injuries
Transcranial Magnetic Stimulation has also been used successfully without seizures in patients with a history of brain injury.  45 reported on a 48-year-old man with a severe TBI history 5 years before TMS was administered with lowfrequency right dorsolateral prefrontal cortex stimulation daily for 6 weeks. The patient demonstrated a 49% improvement in his Hamilton Depression Rating Scale 46 with treatment. In their article, they set forth that those who have not had a seizure within 2 years of injury have a 90% lower risk of seizure based on work by Englander et al 2003. 47 Koski et al 2015 48

TMS Seizures and Alcohol
Excessive alcohol use and withdrawal can precipitate seizures and has been found to possibly increase the risk of TMS-related seizures. Tendler et al 2018 9 indicated 6 of the 31 patients reviewed with TMS-related seizures using the H1 coil had a history of increased alcohol intake. Alcohol use was also reported in TMS seizure patients' history by Boes et al 2016 41 and Chiramberro et al 2013. 28 These cases are described elsewhere in this report.

TMS Seizures and Sleep Deprivation
Sleep deprivation has long been identified as a precipitant to having a seizure in epilepsy patients and may increase the risk of a TMS-related seizure. Nakken et al 2005 56 reported on 1677 patients with epilepsy revealing 53% reported at least one seizure precipitant, with 30% reporting two or more factors had contributed at times to having a seizure. The three most common seizure-precipitating factors were emotional stress, sleep deprivation, and tiredness. Patients having generalized seizures were reported to be more sensitive to sleep deprivation. Ferlisi and Shorvon 2014 57 studied 104 patients at a tertiary-care adult epilepsy clinic to identify triggering factors to their epilepsy. Ninety-seven percent cited at least one precipitant, with stress, sleep deprivation, and fatigue being the most commonly reported. Those with idiopathic generalized epilepsy were more sensitive to seizures during wake periods and sleep deprivation, with those having extratemporal epilepsy reporting more seizures during sleep.
There are reports of patients having a seizure during TMS in which sleep deprivation may have played a role. Prikryl and Kucerova 2005 58 described a seizure in a sleep-deprived depressed patient at 110% MT, 15 Hz, and train duration of 10 seconds. Tendler et al 2018 9 reported that of the 31 patients they reviewed having had a seizure with the H1 coil; three had sleep issues. Oberman and Pascual-Leon 2009 17 reported on a 33-year-old male who had flown from London to Boston and may have been sleep-deprived before the TMS in which he had a seizure.

Continued TMS After a Seizure
If the patient does have a seizure, then the question is that of whether to continue treatment. Bagati et al 2012 64 described a patient who developed a seizure during treatment session #4, and while using valproate to cover for seizures, he finished TMS. Stultz 2019 65 reported previously on a patient who had a seizure during treatment session #11 but was then able to continue TMS without additional seizures or additional medications. The patient received 39 treatment sessions in total. In the accelerated TMS article referenced previously by Kalle and Brunelin 21 , the patient continued treatment and later maintenance treatment after having a seizure.

DovePress
Most treatment recommendations for TMS seizures are supportive, with ensuring patient safety, avoiding aspiration, and monitoring blood pressure if possible. Currently, there are no specific recommendations for oxygen or suctioning during the seizure.
As seizures are usually a rare occurrence in the outpatient psychiatric office, one must also debrief the staff and may use the episode as a teachable moment to review seizure protocols with the staff and emphasize the need to be discussing sleep hygiene continually, alcohol use, medication change, etc., with patients daily before their TMS treatment. Concerning documentation, always include the date of occurrence, TMS treatment number, train, placement, motor threshold, and device used. A detailed description of the seizure, how it first presented and then progressed should be described. Documentation should include any identifiable risk factors and the absence of others. List all medications the patient was taking at the time of the seizure, including non-psychotropic meds. Review with the patient any changes they may have had before the seizure concerning sleep, medications, or alcohol/caffeine use. The risk of not treating severe depression versus the risk of another seizure must be discussed with the patient and the family if TMS is to be continued. While not always necessary, some practitioners have added antiepileptic medications to the treatment regimen before continuing TMS treatment. The seizure should be reported to the FDA and the manufacturer of the TMS unit. Also, one should consider a letter to the editor of a journal to help keep others informed of potential risks and outcomes.

Conclusion
In summary, while TMS has a risk of seizure that is generally <1% overall, some situations may increase that risk, such as alcohol use, brain injury, sleep deprivation, family history, etc. Various case studies have been described in this article in which these situations may have been contributing factors. Traditional TMS, theta burst, accelerated TMS, and child/adolescent TMS use have been reviewed with similar risks for seizures. Comparable seizure rates are reported with both TMS and various psychotropic medications we prescribe daily. (TMS has a lower risk than some of the medications.) We have described successful continued TMS use in patients having had a seizure during TMS and in those with a history of head injury/concussion. TMS use in patients with known epilepsy has also been reviewed. While seizure is a potentially serious adverse event of TMS and must be discussed with the patient, the benefit of treating refractory depression and possibly suicidal ideation may outweigh the risk.

Disclosure
The authors have no conflict of interests to report.