Risk of seizures in transcranial magnetic stimulation: a clinical review to inform consent process focused on bupropion

Figures & data

Table 1 Summary table of rTMS induced accidental seizures including the author, type of TMS, location, medications, risk factors, type of seizure, and diagnosis

ID	Author	Type of TMS	Location	Medication	Risk factor	Type of seizure	Diagnosis
1	Chervyakov et al^Citation42	SP	L-MC	NR	Pre-existing condition	Secondarily generalized	Stroke
2	Chervyakov et al^Citation42	HF	R-MC	NR	Pre-existing condition	Secondarily generalized	Stroke
3	Chiramberro et al^Citation24	HF	L-DLPFC	SRT, OLZ, HDX	High blood alcohol, multiple medications, over OLZ recommended dose	Asymmetric twitching of both arms	MDD
4	Bagati et al^Citation25	HF	L-DLPFC	PRX, DVF	Multiple medications	Generalized	MDD
5	Hu et al^Citation26	HF	L-PFC	SRT	Youth	Generalized	Adolescent onset MDD
6	Harel et al^Citation27	HF	L-PFC	Li	No risk factors	Generalized	BD
7	Gomez et al^Citation28	HF	R-MC	CZX	Pre-existing condition, frequent alcohol use (withdrawal)	Jacksonian	Stroke –MCA
8	Oberman and Pascual-leone^Citation39	cTBS	L-MC	None	No risk factors	Generalized	Healthy
9	Sakkas et al^Citation30	HF	R-PFC	QTP, DZP, GP	Multiple medications	Jacksonian	BD: Type I
10	Rosa et al^Citation29	HF	L-MC	NR	Pre-existing condition	Generalized	Complex pain regional syndrome
11	Tharayil et al^Citation35	SP	R-MC	Li, CPZ	Sleep deprived	Generalized	BD- current hypomania
12	Prikryl and Kucerova^Citation31	HF	L-DLPFC	NR	Sleep deprived	Generalized	MDD
13	Bernabeu et al^Citation32	HF	MC	FLX	Pre-existing condition, multiple medications	Secondarily generalized	Possible Traumatic Brain Injury
14	Conca et al^Citation33	HF	L-DLPFC	VFX, TZD, LOR, THR	History of seizure	Frontal lobe complex partial seizure	Mixed depressive-anxious state, dependent personality, hypothyroid
15	Brogmus^Citation40	NR	NR	NR	NR	Secondarily generalized	Hydrocephalus and chronic inflammatory CNS process
16	(NINDS) Wassermann^Citation23	HF	MC	NR	NR	Secondarily generalized	Healthy
17	Wassermann et al^Citation34	HF	L-PFC	NR	NR	Generalized	Healthy
18	Wassermann et al^Citation34	HF	MC	NR	NR	Generalized	Healthy
19	Pascual-leone et al^Citation41	HF	L-MC	None	Family history of seizures	Generalized	Healthy
20	Fauth et al^Citation36	SP	MC	NR	Pre-existing condition	Jacksonian	Stroke
21	Kandler^Citation38	HF	MC	None	Pre-existing condition	Jacksonian	Multiple sclerosis
22	Kandler^Citation38	HF	MC	None	Pre-existing condition	2 generalized same day	Multiple sclerosis
23	Homberg and Netz^Citation37	SP	MC	NR	Pre-existing condition	Generalized	Large ischaemic scar after MCA infarction
24	Wassermann^Citation23	HF	MC	NR	NR	Partial motor	Healthy
25	Pascual-Leone not published (reported Wasserman^Citation23)	HF	PFC	AMT, HLD	Investigators unaware of medications	Secondary generalized	Psychotic depression

Abbreviations: HF, High Frequency; SP, Single Pulse; cTBS, continuous theta burst stimulation; MC, Motor Cortex; PFC, Prefrontal cortex; DLPFC, dorsolateral prefrontal cortex; L-, Left; R-, Right; MDD, Major Depressive Disorder; BD, Bipolar Depression; MCA, Middle Cerebral Artery; NR, Not Reported; AMT, Amitryptiline; CPZ, Chlorpromazine; CZX, Chlordiazepoxide; DVF, Desvenlafaxine; DZP, Diazepam; GP, Gabapentin; FLX, Fluoxetine; HLD, Haloperidol; HDX, Hydroxyzine; Li, Lithium; LOR, Lorazepam; OLZ, Olanzapine; PRX, paroxetine; QTP, Quetiapine; SRT, Sertraline; THR, Thyroxin; TZD, Trazodone; VFC, Venlafaxine.

Figure 1 Patients with an rTMS-induced seizure categorized by area of cortex stimulated (cortex), sex, type of TMS administered, and possible risk factors.

Abbreviations: rTMS, repetitive transcranial magnetic stimulation; TMS, transcranial magnetic stimulation; HF, high frequency; LF, low frequency; SP, single pulse; TBS, theta-burst stimulation; MC, preexisting medical condition; Meds, medications; Sleep, sleep deprived; Sz Hx, history of seizures; Alcohol, influence of alcohol.

Figure 2 The number and combination of medications that each of the patients (n=25) was taking during the time of accidental rTMS-induced seizure: including no medication (none, n=4, 16%), one medication (n=4, 16%), two medications (n=3, 12%), three medications or more (n=3, 12%), and medications not reported (n=11, 44%).

Abbreviation: rTMS, repetitive transcranial magnetic stimulation.

Table 2 Seizure incidence rates (in percent) for popular antidepressants and antipsychotics based in the literature

Antidepressant	Source	Dose (mg/d)	Seizure rate (%)
Bupropion SR	US Food and Drug Administration^Citation12	100–300	0.1
Bupropion IR	US Food and Drug Administration^Citation12	300–450	0.4
Citalopram	Lundbeck Canada Inc.^Citation53		0.25 (vs 0.23 placebo)
Duloxetine	Eli Lilly and Company^Citation51		0.2
Fluoxetine	Eli Lilly and Company^Citation48	20–60	0.2
Fluvoxamine	Edwards et al^Citation52	<100	0.2
Mirtazapine	GenMed PC^Citation49		0.04
Paroxetine	GlaxoSmithKline Inc.^Citation54		0.1
Sertraline	Pfizer-Roerig^Citation47		0.0–0.2
Venlafaxine	Pfizer^Citation50	<150	0.3
Venlafaxine XR	Pfizer^Citation50		0
Tricyclics	Preskorn & Fast^Citation56		0.1–0.4
Antipsychotic	US Food and Drug Administration; Alper et al^Citation55
Olanzapine			0.9
Quetiapine			0.8
Aripiprazole			0.4 (vs 0.1 placebo)
Ziprasidone			0.4
Risperidone			0.3

Note: Dosing information is available for some of the medications.

Abbreviations: IR, immediate release; SR, sustained release; XR, extended release.

Figure S1 PRISMA flow diagram.¹

Abbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table S1 rTMS characteristics and information on seizures

ID	Patient	Type of TMS	Location	Medication	Sleep hx	Session number	Other risk factors	Outcome of seizure	Type of seizure	Diagnosis	Others
1	F	SP, diagnostic mapping	L-MC	NR	NR	Map (1)	Stroke patient and no hx of seizures	Developed symptomatic poststroke epilepsy	Secondarily GEN	Stroke, left MCA	Epileptiform signs seen on EEG during screening
2	NR	10 Hz, 80% MT 2-second stimulation, 58 second-rest-8 session	R-MC	NR	NR	1	Stroke patient and no hx of seizures		Secondarily GEN	Stroke, right MCA	Epileptiform signs seen on EEG during screening
3	16 yo F	10 Hz, 60 trains of 5 seconds, intertrain intervals of 25 seconds and 3,000 stimuli/d; 5 days a week for 4 weeks	L-DLPFC	SRT (150 mg/d), OLZ (75 mg/d), and HDX (24 mg/d)	NR	12	0.20% alcohol concentration on the 12th session	Neurological examination, blood work, and EKG fine	Asymmetric twitching of both arms	MDD	Alcohol complication, outside range of OLZ dosage
4	44 yo male	15 Hz, 110% of motor threshold, 35 pulses/train, 35 trains/session, intertrain interval 26 seconds, 1,225 pulses/d	L-DLPFC	PRX (37.5 mg), DVF (100 mg), and etizolam (2 mg/d)	NR	4	Not any known	Showed diffuse, mild cerebral atrophy on MRI	GEN	MDD	Resumed rTMS at subthreshold power level (90% of MT) under sodium valproate coverage
5	15 yo F	20 trains per session with the coil turned on for 4 seconds at a frequency of 10 Hz and MT intensity of 80% and then turned off for 26 seconds (ie, one train lasted 30 seconds in total)	L-PFC	SRT (100 mg/d)	NR	1	ECG, EEG, MRI, and blood tests all came back fine during screening	No abnormality in neurological examination; EEG did not indicate any focal lesions or epileptiform discharge, hypomania first night	GEN	Adolescent onset MDD	Sertraline use continued
6	F	20 Hz at 120% MT. 42 trains with a 2-second duration for each and a 20-second intertrain interval (total 1,680 pulses/session)	L-PFC	Li (900 mg/d) (blood level of 0.79 mEq/L before entering study)	NR	12	No risk factors	No lasting effects determined by cognitive examination	GEN	BD	Limited information on this case
7	58 yo M	10 trains, 10 Hz of rTMS with 2-second duration each train, at 90% of RMT	R-MC	CZX (10 mg at night) for a slight anxiety disorder, acetyl salicylic acid	NR	1	Chronic stroke patient, MCA; frequent alcohol use; current withdrawal; and no hx of seizures	Abnormal EEG 1 hour after	Jacksonian	Stroke, MCA	Frequent alcohol consumer, eliminated intake for 2 weeks before
8	33 yo M	50 trains of cTBS at RMT	L-MC	None	Yes	NR	No	MRI, neurological examination and blood tests normal; no EEG done	GEN	Healthy	Recent large time zone change
9	30 yo F	100% MT; constant frequency (20 Hz), duration of each train (2 seconds), ~40 trains, with an intertrain interval of 1 minute	R-PFC	QTP (600 mg/d), DZP (20 mg/d), and GP (150 mg/d)		9th	No hx of epilepsy and normal MRI	EEG normal	Jacksonian, left arm	BD: type I	Patient decided to go off diazepam for it was made her sleepy. Unknown to staff. Continued treatment when back on diazepam
10	24 yo F	25 trains per session, intensity of 100% MT, frequency of 10 Hz, 10 seconds turned on and 20 seconds turned off (total of 2,500 pulses/d)	L-MC	NR	NR	1st	No hx of seizures or other risk factors	Clinical and neurological examinations, blood work, EEG, and CT all normal	GEN	Complex pain regional syndrome
11	35 yo M	Single pulse, 58% delivered the stimulus at the same spot twice 60 seconds apart	R-MC	Li (900 mg/d) and CPZ (50 mg/d)	Yes	1st	No hx or seizures or risk factors and no hx drugs/alcohol	Found out after brother had one episode of convulsions; EEG showed mostly alpha waves	GEN	BD-current hypomania	Lack of sleep due to hypomania
12	45 yo M	15 Hz, 100% MT, 10-second train, 30-second intertrain	L-DLPFC	NR	Yes	6th	Healthy	Free of health problem and EEG normal	Grand mal	MDD	Did not sleep over week-end
13	28 yo F	Single 2-second train of 20 Hz at 110% MT	MC	FLX (20 mg for anxiety 3 days prior)	NR	1st	Normal physical and neurological examinations	Neurological examination, MRI, and EEG normal	Secondarily GEN	Possible traumatic brain injury	Fluoxetine was unknown to staff
14	36 yo F	Underwent 110% of MT with 20 Hz, 10-second duration and ten trains with an intertrain interval of 60 seconds	L-DLPFC	VFX (112.5 mg/d), TZD (500 mg/d), LOR (3 mg/d), and THR (100 µg/d)	NR	First session of second protocol	Yes. EEG showed mild generalized slowing	EEG recorded bifrontopolar paroxysmal delta activities and abnormal SPECt scan	Frontal lobe complex partial seizure	Mixed depressive ± anxious state; codiagnosed dependent personality, hypothyroidism	Add-on antidepressant strategy. One maprotiline-induced generalized seizure in 1996
15	66 yo F		NR	NR					Secondarily GEN	Hydrocephalus and chronic inflammatory process in CNS
16	26 yo F	120% MT, 15 Hz, 2.5 seconds, intertrain 120 seconds	MC	None	NR	NR	NR	No lasting effects	Secondarily GEN	Healthy
17	27 yo F	1%–5%, 15 Hz, three trains ×0.75 seconds, intertrain interval 250 ms	L-PFC	None	NR	1	Neurological examination fine	EEG, neurological, pulse, and cognitive tests normal	GEN	Healthy
18	39 yo F	110%, 25 Hz, four trains ×0.8 seconds, intertrain interval 1 second	MC	None	NR	1	Neurological examination fine	EEG, neurological, pulse, cognitive tests normal	GEN	Healthy
19	35 yo F	10 seconds, frequency 25 Hz, intensity of 2.5× the MEP threshold	L-MC	None	Slept well	Possibly Day 1	Found out after had a first degree relative with hx of seizures	Neurological examination, EEG, and neuropsychological tests normal. Anxiety about having another seizure	GEN	Healthy
20	62 yo M	Intensity (30%, 40%, and 50% maximum), 51 stimuli given 5–30 seconds apart with a stimulus intensity of 70%	MC	NR	NR	Possibly Day 1	No hx of seizures and EEG and CT normal	Postictal paresis resolved in 4 days, two further seizures on days 7 and 15	Jacksonian	Stroke
21	60 yo M	24 cortical stimuli, <3 Hz	MC	None	NR	After 4 weeks	NR	NR	Jacksonian	Multiple sclerosis
22	30 yo F	50 cortical stimuli, <3 Hz	MC	None	NR	After 3 weeks	NR	EEG high voltage rhythmic and sharp activities suggest low epileptic threshold	Two GEN same day	Multiple sclerosis	Session before convulsions she had 50 stimuli. This was her fifth series of tests; on four earlier ones over the past 5 months, 40 stimuli had been given
23	57 yo M	Single pulse. 40% maximum intensity of stimulator output (2 T pulsed for 100 ns) at intervals of 2 minutes	MC	NR	NR	First	No hx of seizures; EEG and CT demonstrated the MCA infarction	2 seizures 4 weeks later, seizure free since taking phenytoin (100 mg three times per day)	GEN	Large ischemic scar after MCA infarction
24	M	130% intensity, 3 Hz, 7 seconds, “long” intertrain interval	MC	None	NR	NR	NR	No lasting effects	Partial motor	Healthy
25	F	10-second trains, rTMS, frequency 10 Hz, intensity 0.9× MEP threshold, intertrain interval 1 minute	PFC	AMT and HLD		Several		No lasting effects	Secondarily GEN	Psychotic depression	Investigators were unaware that she was on medications

Abbreviations: AMT, amitriptyline; BD, bipolar depression; CNS, central nervous system; CPZ, chlorpromazine; cTBS, continuous theta-burst stimulation; CZX, chlordiazepoxide; DLPFC, dorsolateral prefrontal cortex; DVF, desvenlafaxine; DZP, diazepam; F, female; FLX, fluoxetine; GEN, generalized; GP, gabapentin; HDX, hydroxyzine; HF, high frequency; HLD, haloperidol; hx, history; L, left; LF, low frequency; Li, lithium; LOR, lorazepam; M, male; MC, motor cortex; MCA, middle cerebral artery; MDD, major depressive disorder; NR, not reported; OLZ, olanzapine; PFC, prefrontal cortex; PRX, paroxetine; QTP, quetiapine; R, right; rTMS, repetitive transcranial magnetic stimulation; cTBS, continuous theta-burst stimulation; SP, single pulse; SRT, sertraline; THR, thyroxin; TZD, trazodone; VFX, venlafaxine; yo, year old; RMT, resting motor threshold; TMS, transcranial magnetic stimulation; MT, motor threshold; ECG, electrocardiogram; EEG, electroencephalogram; MRI, magnetic resonance imaging; EKG, electrocardiogram; SPECt, single-photon emission computer tomography; MEP, motor evoked potential; CT, computerized tomography.

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