Generalized seizure induced by continuous theta-burst stimulation (cTBS) in a patient with bipolar depression: A case report

Dear Editor,

Theta burst stimulation (TBS) is increasingly used to treat major depression. Here we report, for the first time, a generalized seizure induced by continuous TBS delivered over the right DLPFC.

Mr. A, a 24-year-old right-handed male was referred to a tertiary brain stimulation center due to a depressive episode with marked suicidal ideation in the context of a bipolar affective disorder type 2.

The patient reported symptoms of depressed mood, anhedonia, easy fatigability, and significant suicidal ideation for the past 2 weeks with a background of 8 years of complex mood disorder. He scored 19 on the 17-item Hamilton’s Depression Rating scale [1]. Mr. A had a history of numerous brief-lasting episodes of hypomania and a history of three episodes of severe depression in past. He had failed adequate trials of sertraline and venlafaxine in previous episodes. He had developed an affective switch while on escitalopram in a prior depressive episode. The current relapse in depressive symptoms occurred despite maintenance treatment with lithium 1350mg/day (level was 0.8mEq/L) and 200mg of lamotrigine.

The patient was admitted to hospital and the lithium and lamotrigine were continued at the same doses. A trial of Quetiapine up to 200mg was initiated for 2 weeks and a partial improvement in depressive symptoms was seen. He was then referred to the brain stimulation center for consideration of rTMS as an augmentation treatment to which Mr. A consented.

He was assessed for safety using the TMS adult safety screening (TASS) questionnaire. We delivered TMS with a MagPro X100 stimulator (Magventure, Inc., Denmark) delivering biphasic pulses via a figure-of-8 coil (Model MCF-B70). The coil was held tangential to the scalp with the handle pointing posteriorly making an angle of 45° to the mid-sagittal plane. We delivered a sequential bilateral dorsolateral prefrontal cortex (DLPFC) protocol with the stimulation target localized using the “6 cm rule” [2]. The stimulator intensity was based on the resting motor threshold (RMT) for each hemisphere defined as the lowest stimulus intensity (percentage of Maximum Stimulator Output- MSO) required for contraction in the contralateral first dorsal interosseous muscle (calculated as 43% on left and 45% on the right side). Stimulation intensity was set at 90% of the RMT for the initial week and increased to 100% after confirming the patient’s tolerability. The stimulation protocol involved sequential bilateral stimulation of left DLPFC with intermittent TBS followed by right DLPFC with continuous TBS using 1800 pulses on each side with theta-burst pattern (3 biphasic pulses delivered at a frequency of 50 Hz repeated every 200 msecs) [3]. The TMS administrator had extensive prior experience with TMS in both investigational and therapeutic applications.

The patient was sitting in a chair in a fully equipped brain stimulation laboratory within the hospital premises. The patient had received 6 sessions in the previous week (1 session each day from Monday to Saturday). The event occurred during the 7th session (the 1st session with 100% RMT) after completing the iTBS over the left DLPFC and approximately 5–10 seconds after beginning the cTBS over the right DLPFC. The TMS operator first noted a contraction of the left hand and wrist muscles, which spread up the arm and eventually also involved facial muscle contractions. The patient lost consciousness and had generalized tonic-clonic movements of all four limbs. He was transferred to the floor, in the left lateral supine position to reduce the risk of aspiration and his jaw was supported throughout the event and he was observed to have a seizure for about 45 seconds. The responsible physician was on-site and observed the end of the seizure. He was shifted to a bed for observation, there was post-ictal confusion lasting about 45 minutes. He had no tongue bite or sphincter incontinence. In the postictal period, his pulse was 84, the BP was stable at 140/80 mm of Hg and his respiratory rate was 18/minute. He was transferred to the neurology emergency ward where routine blood work (blood sugar levels, hemogram, liver, and renal function tests) was done which was within normal limits. A CT scan of the brain showed no obvious lesion. The EEG done after a week of this incident showed bi-frontal sharp and slow waves with a normal background.

To our knowledge, this is the first case of cTBS-induced seizure in a clinical sample with a diagnosis of depression, with stimulation given using a figure of eight coil over the right DLPFC. A previous report detailed a seizure induced with cTBS using the a double cone coil (Magventure DB-80) over the right opercular insular cortex [4]. A cTBS-induced seizure was previously reported in a healthy adult after stimulation of the motor cortex [5]. While cTBS is postulated to have inhibitory effects on cortical excitability, there is large individual variability in response and it may have excitatory effects in some individuals [6]. Similarly paradoxical excitability responses have been previously noted for low-frequency rTMS as well [7]. With non-patterned rTMS averaged data demonstrate frequency-dependent rise in cortical excitability, individuals can experience different modulatory effects at different TMS frequencies [8]. Moreover, the cortical excitability is known to be state-dependent and influenced by various intra-individual factors affecting the recent history of neural activity [9]. Hence, we ruled out possible risk factors for the development of new seizures like substance use or withdrawal, sleep deprivation, and nutritional deficiencies. However, the finding of sharp and slow waves on the EEG after a week of the incident may indicate the possibility of an underlying epileptogenic focus [10,11]. Although, the CT scan ruled out gross structural anomalies, a high resolution MRI would have been the ideal imaging modality.

In clinical practice, most TBS reports of seizure have occurred with cTBS. As the stimulation intensity used for TBS ranges from 80% to the FDA cleared 120% for iTBS, the uninterrupted train of 40s or longer might be related to increased risk of seizures in predisposed individuals or who have increase in the cortical excitability in the underlying tissue [12]. While the post stimulation effect of cTBS may induce strong cortical inhibition, practitioners should be aware of the potential for seizure due to the uninterrupted train duration of this protocol.