Theta burst transcranial magnetic stimulation to induce seizures in an epilepsy monitoring unit

Epilepsy is a common neurological disorder affecting about 1% of the population [[1]Fiest K.M. Sauro K.M. Wiebe S. Patten S.B. Kwon C.S. Dykeman J. Pringsheim T. Lorenzetti D.L. Jetté N. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies.Neurology. 2017; 88: 296-303https://doi.org/10.1212/WNL.0000000000003509Crossref PubMed Scopus (760) Google Scholar]. Although medications effectively control seizures in many patients, 20–40% of patients are refractory to antiepileptic medications [[2]Janmohamed M. Brodie M.J. Kwan P. Pharmacoresistance - epidemiology, mechanisms, and impact on epilepsy treatment.Neuropharmacology. 2020; 168: 107790https://doi.org/10.1016/j.neuropharm.2019.107790Crossref PubMed Scopus (52) Google Scholar]. Many such medically intractable patients may benefit from surgical removal of an accurately identified epileptic focus [[3]Sheng J. Liu S. Qin H. Li B. Zhang X. Drug-Resistant epilepsy and surgery.Curr Neuropharmacol. 2018; 16: 17-28https://doi.org/10.2174/1570159X15666170504123316Crossref PubMed Scopus (64) Google Scholar]. The efficacy of epilepsy surgery depends on the precise localization of the epileptic focus [[4]Spencer D.D. Pappas C.T. Surgical decisions regarding medically intractable epilepsy.Clin Neurosurg. 1992; 38 (PMID: 1537203): 548-566PubMed Google Scholar], and for this patients are typically admitted to an epilepsy monitoring unit (EMU) for continuous video-EEG recording. EMU length of stay depends on the number of seizures recorded and may extend more than a week in many cases [[5]Celik S.Y. Headley A.J. Shih J.J. Clinical characteristics of video-EEG patients: limited utility of prolonging VEEG study duration beyond 5 days for spell classification.Epilepsy Behav. 2020; 103106827https://doi.org/10.1016/j.yebeh.2019.106827Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar], with the failure to record a sufficient number of seizures being the leading cause of prolonged EMU stay [[6]Moseley B.D. Dewar S. Haneef Z. Eliashiv D. Stern J.M. Reasons for prolonged length of stay in the epilepsy monitoring unit.Epilepsy Res. 2016; 127: 175-178https://doi.org/10.1016/j.eplepsyres.2016.08.030Crossref PubMed Scopus (10) Google Scholar]. Considerable waiting lists for EMU admissions imply that reducing average EMU length of stay could have major benefits in overall patient care. Typically, hastening seizure occurrence in an EMU relies mainly on tapering anti-epileptic medications [[7]Keller A.E. Bradbury L. Wang L. Yau I. Donner E.J. Effectiveness of antiepileptic drug tapering in the pediatric epilepsy monitoring unit.Epilepsy Behav. 2018; 87: 83-88https://doi.org/10.1016/j.yebeh.2018.08.007Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar], and, to a lesser extent, on non-invasive measures such as sleep deprivation, hyperventilation or photic stimulation [[8]Gogia B. Rai P.K. Matthys S.A. Mong E.R. Rodriguez R. Yassin A. Patel K. Patel C. Todd M. Use of noninvasive induction techniques in the diagnosis of PNES.Epilepsy Behav. 2019; 99: 106491https://doi.org/10.1016/j.yebeh.2019.106491Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. Another non-invasive method, transcranial magnetic stimulation (TMS), can be used to increase cortical excitability [[9]Chen R. Udupa K. Measurement and modulation of plasticity of the motor system in humans using transcranial magnetic stimulation.Mot Contr. 2009; 13: 442-453https://doi.org/10.1123/mcj.13.4.442Crossref PubMed Scopus (46) Google Scholar] and thus could potentially be used to purposefully induce seizures in patients with epilepsy, although TMS has not been studied for this purpose. By increasing cortical excitability, TMS could trigger seizures in an epileptic focus [[10]Kratz O. Studer P. Barth W. Wangler S. Hoegl T. Heinrich H. Moll G.H. Seizure in a nonpredisposed individual induced by single-pulse transcranial magnetic stimulation.J ECT. 2011; 27: 48-50https://doi.org/10.1097/YCT.0b013e3181d2ef85Crossref PubMed Scopus (25) Google Scholar,[11]Janicak P. Heart K. McGugan B. 166 post market rate of seizures during TMS treatment with NeuroStar® system Appears to Be lower than previously estimated.CNS Spectr. 2020; 25: 306Crossref Scopus (2) Google Scholar]. High frequency bursts of TMS known as theta burst stimulation (TBS) are known to alter cortical excitability in such a way that continuous TBS (cTBS) decreases cortical excitability whereas intermittent TBS (iTBS) increases cortical excitability [[12]Huang Y.Z. Edwards M.J. Rounis E. Bhatia K.P. Rothwell J.C. Theta burst stimulation of the human motor cortex.Neuron. 2005; 45: 201-206https://doi.org/10.1016/j.neuron.2004.12.033Abstract Full Text Full Text PDF PubMed Scopus (2575) Google Scholar]. Seizure induction with cTBS has been reported in a healthy subject without risk factors for epilepsy [[13]Oberman L.M. Pascual-Leone A. Report of seizure induced by continuous theta burst stimulation.Brain Stimul. 2009; 2: 246-247https://doi.org/10.1016/j.brs.2009.03.003Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar], and in a study of 18 healthy individuals cTBS applied to the right operculo-insular cortex was reported to induce one confirmed generalized seizure and one suspected partial seizure [[14]Lenoir C. Algoet M. Vanderclausen C. Peeters A. Santos S.F. Mouraux A. Report of one confirmed generalized seizure and one suspected partial seizure induced by deep continuous theta burst stimulation of the right operculo-insular cortex.Brain Stimul. 2018; 11: 1187-1188https://doi.org/10.1016/j.brs.2018.05.004Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. However, this protocol has not been studied in patients with epilepsy to induce seizures. Hence, we investigated the effects of cTBS as well as iTBS in patients during their EMU stay with the objective of determining whether seizures could be reliably induced using TBS protocols. The study was carried out in the EMU of the Toronto Western Hospital. The University Health Network (UHN) Research Ethics board (REB) approved the study (UHN REB 13-7224-B). Seven patients undergoing video-EEG recording in the EMU with presumptive localization of a single principal epileptic focus (based on history and EEG recordings) were recruited. The patients were admitted to the EMU to capture seizures as part of their routine pre-surgical investigation and were recruited for the study after consenting and evaluation by an epileptologist (PT, DA or RW). Patients with suspicion of non-epileptic seizures or thought to have multifocal epileptiform abnormalities were excluded, as were patients with contraindications for TMS such as metallic implants, cardiac pacemakers and pregnancy. The two hemispheres were alternately stimulated in random order of TBS. [See Supplementary materials for details of TMS procedure and protocols used]. The resting motor threshold (RMT) of the 7 patients was 64 ± 5.4% stimulator output (range 55–70%, Table 1). The stimulus intensities were set at 65% stimulator output as higher intensities would quickly switch off the stimulator due to coil heating. The intensities used as percentage of RMT are listed in Table 1. No seizures or EEG changes were induced immediately after these protocols and continuous EEG recording was acquired for at least 2 days after each experiment. One patient developed seizures 10 hours after TMS was applied, but this was with prolonged admission off antiepileptic medications and thus the relationship of these seizures to TMS is unclear. Three of the seven patients developed slight pain over the stimulated regions likely due to scalp muscle contractions, which resolved with rest and analgesics by 1 h after completion of the protocol.Table 1Demographic and clinical characteristics of the patients investigated in this study.Sl. No.AgeSexDuration of epilepsy (yr)Interictal abnormalitiesSeizures at current EMU stayMedicationsRMT (% stimulatoutput)TBS intensity as % of RMT173M7Left > right temporal sharp waves.No seizures recordedNo AEDs62104222M3Rare right temporal sharp transients.One aura with right temporal changes. No other seizures recordedphenytoin valproic acid, lamotrigine55118329F3Rare bifrontal sharp thetaOne seizure recorded 6 days after TMS.topiramate, lacosamide6797447M2NoneNonelamotrigine, levetiracetam7093541F30Left temporal sharp wavesNo seizures recordedtopiramate, clobazam62104632F16Bifrontal polyspikes, R > LNo seizures recordedcarbamazepine, perampanel, pamotrigine7093728F16Left posterior temporal sharp wavesSeizures recorded after 12th day of admission ∼10 hours after TMScarbamazepine, levetiracetam, lacosamide62104AED: anti-epileptic drug; EMU: epilepsy monitoring unit; RMT: resting motor threshold; TBS: theta burst stimulation. TMS: transcranial magnetic stimulation. TBS intensity was set at 65% stimulator output. Open table in a new tab AED: anti-epileptic drug; EMU: epilepsy monitoring unit; RMT: resting motor threshold; TBS: theta burst stimulation. TMS: transcranial magnetic stimulation. TBS intensity was set at 65% stimulator output. In this cohort of 7 patients with refractory epilepsy, we showed that the TBS protocols used (cTBS and iTBS at about 100% RMT) appear to be safe and were insufficient to induce seizures. There are many reports of accidental seizure induction in healthy subjects as well as in epilepsy patients using single or patterned stimuli [[10]Kratz O. Studer P. Barth W. Wangler S. Hoegl T. Heinrich H. Moll G.H. Seizure in a nonpredisposed individual induced by single-pulse transcranial magnetic stimulation.J ECT. 2011; 27: 48-50https://doi.org/10.1097/YCT.0b013e3181d2ef85Crossref PubMed Scopus (25) Google Scholar,[11]Janicak P. Heart K. McGugan B. 166 post market rate of seizures during TMS treatment with NeuroStar® system Appears to Be lower than previously estimated.CNS Spectr. 2020; 25: 306Crossref Scopus (2) Google Scholar,13Oberman L.M. Pascual-Leone A. Report of seizure induced by continuous theta burst stimulation.Brain Stimul. 2009; 2: 246-247https://doi.org/10.1016/j.brs.2009.03.003Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 14Lenoir C. Algoet M. Vanderclausen C. Peeters A. Santos S.F. Mouraux A. Report of one confirmed generalized seizure and one suspected partial seizure induced by deep continuous theta burst stimulation of the right operculo-insular cortex.Brain Stimul. 2018; 11: 1187-1188https://doi.org/10.1016/j.brs.2018.05.004Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 15Rossi S. Hallett M. Rossini P.M. Pascual-Leone A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research.Clin Neurophysiol. 2009; 120: 2008-2039https://doi.org/10.1016/j.clinph.2009.08.016Crossref PubMed Scopus (3578) Google Scholar]. Some of these cases may have been related to stimulation parameters exceeding safety guidelines [[15]Rossi S. Hallett M. Rossini P.M. Pascual-Leone A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research.Clin Neurophysiol. 2009; 120: 2008-2039https://doi.org/10.1016/j.clinph.2009.08.016Crossref PubMed Scopus (3578) Google Scholar], biological predisposition to seizures, or non-epileptic events such as syncope or psychogenic seizures [[11]Janicak P. Heart K. McGugan B. 166 post market rate of seizures during TMS treatment with NeuroStar® system Appears to Be lower than previously estimated.CNS Spectr. 2020; 25: 306Crossref Scopus (2) Google Scholar]. Most previous studies on rTMS in epilepsy patients were designed to treat seizures [[16]Sun W. Mao W. Meng X. Wang D. Qiao L. Tao W. Li L. Jia X. Han C. Fu M. Tong X. Wu X. Wang Y. Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: a controlled clinical study.Epilepsia. 2012; 53: 1782-1789https://doi.org/10.1111/j.1528-1167.2012.03626.xCrossref PubMed Scopus (120) Google Scholar]. These studies used protocols to reduce cortical excitability and showed an approximately 13% reduction in seizure frequency with low (0.5 Hz) frequency stimulation for 2 weeks [[16]Sun W. Mao W. Meng X. Wang D. Qiao L. Tao W. Li L. Jia X. Han C. Fu M. Tong X. Wu X. Wang Y. Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: a controlled clinical study.Epilepsia. 2012; 53: 1782-1789https://doi.org/10.1111/j.1528-1167.2012.03626.xCrossref PubMed Scopus (120) Google Scholar]. We used an excitatory protocol (iTBS) to potentially induce seizures. Given that previous studies reported that cTBS [[13]Oberman L.M. Pascual-Leone A. Report of seizure induced by continuous theta burst stimulation.Brain Stimul. 2009; 2: 246-247https://doi.org/10.1016/j.brs.2009.03.003Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] or deep cTBS [[14]Lenoir C. Algoet M. Vanderclausen C. Peeters A. Santos S.F. Mouraux A. Report of one confirmed generalized seizure and one suspected partial seizure induced by deep continuous theta burst stimulation of the right operculo-insular cortex.Brain Stimul. 2018; 11: 1187-1188https://doi.org/10.1016/j.brs.2018.05.004Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] induced seizures in healthy participants, we also tested cTBS protocol [[12]Huang Y.Z. Edwards M.J. Rounis E. Bhatia K.P. Rothwell J.C. Theta burst stimulation of the human motor cortex.Neuron. 2005; 45: 201-206https://doi.org/10.1016/j.neuron.2004.12.033Abstract Full Text Full Text PDF PubMed Scopus (2575) Google Scholar,[13]Oberman L.M. Pascual-Leone A. Report of seizure induced by continuous theta burst stimulation.Brain Stimul. 2009; 2: 246-247https://doi.org/10.1016/j.brs.2009.03.003Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. Based on these pilot data, commonly used rTMS machines are probably not sufficient to reliably induce seizures in epilepsy patients for diagnostic purposes. The patients studied had focal epilepsies of different localizations and etiologies, and tapering dosages of different antiepileptic medications, such that neither clinical phenotype nor medical treatments are likely to have been primarily responsible for the inability to induce seizures. It would appear that higher intensities than we used would be needed, but such intensities were not feasible in our study due to coil heating and machine limitations. There are TMS machines capable of producing much higher output designed for magnetic seizure therapy to treat refractory depression [[17]Hoy K.E. Fitzgerald P.B. Magnetic seizure therapy for treatment-resistant depression.Expet Rev Med Dev. 2011; 8: 723-732https://doi.org/10.1586/erd.11.55Crossref PubMed Scopus (12) Google Scholar], which results in comparable ictal characteristics to those induced by electroconvulsive therapy [[18]Kayser S. Bewernick B.H. Hurlemann R. Soehle M. Schlaepfer T.E. Comparable seizure characteristics in magnetic seizure therapy and electroconvulsive therapy for major depression.Eur Neuropsychopharmacol. 2013; 23: 1541-1550https://doi.org/10.1016/j.euroneuro.2013.04.011Crossref PubMed Scopus (27) Google Scholar]. However, that approach is likely to induce seizures that have different origins and characteristics compared to the patients’ spontaneous seizures. Accordingly, we used protocols that are being routinely used in plasticity [[9]Chen R. Udupa K. Measurement and modulation of plasticity of the motor system in humans using transcranial magnetic stimulation.Mot Contr. 2009; 13: 442-453https://doi.org/10.1123/mcj.13.4.442Crossref PubMed Scopus (46) Google Scholar] and treatment regimens [[11]Janicak P. Heart K. McGugan B. 166 post market rate of seizures during TMS treatment with NeuroStar® system Appears to Be lower than previously estimated.CNS Spectr. 2020; 25: 306Crossref Scopus (2) Google Scholar,[15]Rossi S. Hallett M. Rossini P.M. Pascual-Leone A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research.Clin Neurophysiol. 2009; 120: 2008-2039https://doi.org/10.1016/j.clinph.2009.08.016Crossref PubMed Scopus (3578) Google Scholar]. These TBS protocols appear to be safe in epilepsy patients, consistent with published TMS safety reviews in epilepsy [[19]Pereira L.S. Müller V.T. da Mota Gomes M. Rotenberg A. Fregni F. Safety of repetitive transcranial magnetic stimulation in patients with epilepsy: a systematic review.Epilepsy Behav. 2016; 57: 167-176https://doi.org/10.1016/j.yebeh.2016.01.015Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar]. More intensive protocols that may be attempted in the future using different TMS machines, higher stimulus intensity, greater pulse number, high frequency or deep stimulation with special coils may be needed to induce seizures for diagnostic purposes in the EMU. All authors declare no conflicts of interest related to this study. This study was funded by New Initiatives Program grant of the Division of Neurology, University of Toronto, to PT and KU. The following is the Supplementary data to this article: Download .docx (.02 MB) Help with docx files Multimedia component 1

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