REVIEW URRENT C OPINION
Transcranial magnetic stimulation for the diagnosis and treatment of epilepsy Vasilios K. Kimiskidis a, Antonio Valentin b,c, and Reetta Ka¨lvia¨inen d
Purpose of review The aim is to critically review recent advances emerging from the application of transcranial magnetic stimulation (TMS) as a research and clinical tool in the field of epilepsy. Recent findings A number of TMS–electromyography (EMG) and TMS–electroencephalography (EEG) studies have identified distinct changes of cortical excitability associated with specific epilepsy syndromes and in asymptomatic siblings of patients with epilepsy. Pharmaco-TMS studies have shed additional light on the effects of traditional and recently introduced antiepileptic drugs on excitatory and inhibitory brain microcircuits as well as cortical plasticity mechanisms. In addition, stronger evidence has emerged that TMS may serve as a biomarker with prognostic (i.e. predicting response to pharmacologic or surgical interventions) and diagnostic potential (for instance aiding in the noninvasive localization of the epileptogenic zone). Finally, the role of repetitive TMS in the therapeutic management of drug-resistant epilepsies and refractory status epilepticus has been further defined and is expected to become more prominent by the optimization of the stimulation parameters. Summary TMS has provided important insight into the pathophysiological substrate of human epilepsies and emerges as a valuable tool with diagnostic, prognostic and therapeutic potential. The recent advent of TMS–EEG can be reasonably expected to contribute further significant advances to the field of epilepsy. Keywords antiepileptic drugs, epilepsy, repetitive TMS, TMS-electroencephalography, transcranial magnetic stimulation
INTRODUCTION Transcranial magnetic stimulation (TMS) was discovered in the mid-1980s and rapidly evolved from a simple technique for studying motor pathways to a cutting-edge technology in the field of neurosciences with diverse research, diagnostic and therapeutic applications. With regard to epilepsy, the applications of TMS can be broadly classified into the following groups: noninvasive investigation of cortical excitability; determination of the effects of antiepileptic drugs (AEDs); noninvasive localization of the epileptogenic zone; and therapeutic management of drug-resistant epilepsies. Recent advances in these research areas are briefly outlined below following a brief methodological introduction. www.co-neurology.com
TRANSCRANIAL MAGNETIC STIMULATION: BASIC CONCEPTS TMS is based on the extracranial application of timevarying magnetic fields, which penetrate the skull in a Laboratory of Clinical Neurophysiology, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece, bDepartment of Clinical Neuroscience, King’s College London, Institute of Psychiatry, cDepartment of Clinical Neurophysiology, King’s College Hospital, London, UK and dDepartment of Neurology, Kuopio Epilepsy Center, Kuopio University Hospital and Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland
Correspondence to Vasilios K. Kimiskidis, MD, PhD, Associate Professor of Neurology and Clinical Neurophysiology, Laboratory of Clinical Neurophysiology, AHEPA Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece. Tel: +30 2310 994667; e-mail: [email protected] Curr Opin Neurol 2014, 27:236–241 DOI:10.1097/WCO.0000000000000071 Volume 27 Number 2 April 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Transcranial magnetic stimulation in epilepsy Kimiskidis et al.
KEY POINTS Patients with focal and generalized epilepsies as well as their asymptomatic siblings exhibit syndrome-specific alterations in cortical excitability. TMS–EMG and TMS–EEG hold great potential as diagnostic and prognostic biomarkers in epilepsy. The therapeutic potential of rTMS in drug-resistant focal epilepsies and refractory status epilepticus warrants further investigation. TMS–EEG is an emerging and highly promising technique for the investigation and modulation of abnormal brain connectivity in epilepsy.
a painless manner and result not only in the trans-synaptic excitation but also inhibition of the principal output neurons of the human cortex, that is the pyramidal neurons. In the original version of the technique [TMS– electromyography (EMG)], stimulation is usually performed over the primary motor area (M1) and the ensuing responses, termed motor evoked potentials (MEPs), are recorded from corresponding muscles. There is a large array of TMS measures that can be used to assess motor cortex excitability including corticomotor threshold (CMT), silent period, and intracortical inhibition (ICI) and facilitation (ICF) [1 ]. CMT is the most frequently used parameter in cross-sectional or longitudinal TMS studies and can be simply defined as the minimal intensity of a magnetic stimulus required to produce an MEP. CMT should not be inferred to represent a general excitability measure of cortical areas other than M1. For instance, CMT values do not correlate with phosphene threshold, which indexes the excitability of the visual cortex [1 ]. CMT reflects axonal excitability that depends primarily on ion channel conductivity [2 ,3]. There are various methods for estimating CMT, including the relative frequency method, the two-threshold method of Mills and Nithi and adaptive methods based on thresholdtracking algorithms [1 ,4], which vary considerably in terms of precision and applicability. The phenomenon of silent period refers to a transient decrease in EMG activity evoked during sustained muscle contraction by transcranial magnetic stimuli. The late part of silent period (>75 ms) is ascribed to cortical inhibitory mechanisms probably related to gamma-aminobutyric acid-B (GABAB) receptor activation [1 ]. ICF and ICI are investigated in the context of paired-pulse TMS studies [5]. In this paradigm, the &&
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first, conditioning stimulus is given at subthreshold intensities, whereas the second, test stimulus is applied at supratheshold levels after varied interstimulus intervals (ISIs). If the ISI is between 1 and 6 ms, then the test stimulus is suppressed because of a GABA-A receptor-related phenomenon termed short-interval ICI (SICI). If the ISI is between 8 and 30 ms, then ICF occurs with enhancement of the test stimulus because, in part, of N-methyl-Daspartate receptor activation. Finally, if two supratheshold stimuli are applied with an ISI of 50–200 ms, then the test stimulus is suppressed because of longinterval ICI. The above-mentioned TMS measures have been extensively investigated in numerous studies over the last few years [6,7], providing valuable insight into the pathophysiological substrate, the diagnosis and prognosis of epilepsy. However, there are limitations to the type of information that can be obtained from these studies because they employ the method of TMS–EMG in which responses are recorded exclusively from muscles, rather than the cerebral cortex, and stimulation is usually performed over the motor strip. It is conceivable that recordings from the cerebral cortex per se and stimulation over the entire cortical mantle would be far more informative for the investigation of a disease primarily operating at the cortical level, such as epilepsy. Recent technological advances enabled the coupling of high-density electroencephalography (EEG) with TMS (TMS–EEG) [8,9 ]. This novel method opens new avenues for the investigation of epilepsy because it allows, for the first time in a noninvasive manner, the recording and mapping of neuronal responses induced by TMS at the cortical level (EEG reactivity) as well as the investigation and modulation of functional connectivity between brain areas (EEG connectivity). In addition, this novel method permits the detection of epileptiform discharges during repetitive TMS (rTMS), enabling the modification of stimulation parameters or even the termination of a session. Thereby, the safety of therapeutic applications of TMS for drugresistant epilepsy may be significantly improved [10–12]. &
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INVESTIGATION OF CORTICAL EXCITABILITY Converging lines of evidence suggest that epilepsies are in general characterized by cortical hyperexcitability in a syndrome-specific manner. Recently, this concept has been extended to include asymptomatic siblings of patients with epilepsy as well. Badawy et al. [13 ] reported that cortical excitability is higher in asymptomatic siblings of patients
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with focal and particularly generalized epilepsy. The pattern of cortical hyperexcitability, essentially reflecting defective ICI mechanisms, was similar in siblings of patients with various epilepsy syndromes, raising the possibility that genetic factors predispose to both generalized and focal epilepsies and a complex genetic/environmental interaction determines the ultimate clinical phenotype. In idiopathic generalized epilepsy (IGE), a study of 30 drug-naı¨ve patients [10 patients with juvenile myoclonus epilepsy (JME), eight with juvenile absence epilepsy and 12 with generalized tonic– clonic seizures only] concluded that cortical excitability was significantly enhanced in all epilepsy syndromes as evidenced by reduced CMT values and decreased ICI at short and particularly at long ISIs [14]. Patients with JME demonstrated significantly higher levels of cortical excitability compared with the other two groups of patients, thereby differentiating JME from other IGE syndromes. This view is also supported by a meta-analysis of 14 trials involving 265 drug-naı¨ve IGE patients and 424 control subjects, which concluded that only patients with JME had reduced CMT values compared with controls [15]. These observations are in line with the recently proposed construct of ‘system epilepsies’ [16] and set JME as an archetype within this conceptual scheme. However, Puri et al. [17] did not detect reduced CMT in 30 drug-naı¨ve JME patients. These inconsistent results in well characterized IGE cohorts and in the absence of confounding factors, such as AED intake, are probably related to the small magnitude of the threshold decrease and the precision of threshold measurements. Indeed, according to the Internation Federation of Clinical Neurophysiology guidelines [1 ], adaptive methods based on threshold-tracking algorithms provide the most accurate CMT estimation and are probably the optimal method for reliably detecting subtle threshold changes in patients with epilepsy. In certain IGE syndromes, hyperexcitability occurs in other areas of the cortical mantle, beyond the motor strip. Brigo et al. [18] investigated corticomotor and phosphene threshold in 33 patients with IGE, a subset of which displayed photosensitivity. The authors observed decreased phosphene threshold in patients with photosensitivity implying regional hyperexcitability of the primary visual cortex. This observation provides additional evidence in favor of the construct of system epilepsies and suggests that the primary visual cortex is a ‘hub’ of pathophysiological importance in the ‘photosensitivity system’. With regard to progressive myoclonic epilepsies, a unique study by Danner et al. [19 ] investigated 70 genetically verified EPM type 1 patients and &&
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40 controls correlating structural and electrophysiological findings. The authors observed significant elevations of CMT, which were ascribed to medication effects and the increased scalp-to-cortex distance in the context of disease-related cortical atrophy. In addition, they reported significantly prolonged silent period durations, which were interpreted as a cortical inhibitory mechanism reactive to the underlying pathology of EPM1. In the first TMS–EEG study of EPM1 patients, Julkunen et al. [20] reported increased amplitude of the early P30 waveform, suggesting enhanced cortico-cortical excitability and reduced amplitude of the later N100–P180 complex indicating impaired cortical inhibition. In addition, the authors investigated the event-related spectral perturbation, and observed reduced power of alpha, beta and gamma band oscillations and decreased inter-trial coherence following the magnetic stimulus in EPM1 patients, indicating malfunctioning circuits at cortical and subcortical levels. With regard to focal epilepsy, a study by Badawy et al. [21] in 10 drug-naive patients with new-onset temporal lobe epilepsy (TLE) disclosed an interhemispheric imbalance with hyperexcitability in the hemisphere containing the epileptogenic zone and normal excitability of the unaffected hemisphere. In addition, Wright et al. [22] investigated 18 patients with TLE during the preictal state and described changes in cortical excitability in the form of a compound index of intracortical inhibition/ facilitation that was able to predict in the short term the occurrence of epileptic seizures. In 18 adult patients with Lennox–Gastaut syndrome, Badawy et al. [23] reported a hypoexcitability reflected in increased CMT and ICI and decreased ICF. This finding stands in sharp contrast with the persistent hyperexcitability characterizing other refractory epileptic syndromes. It is unclear whether this hypoexcitable state is pertinent to Lennox–Gastaut syndrome only or whether it characterizes other generalized epileptic encephalopathies as well.
DETERMINATION OF THE EFFECTS OF ANTIEPILEPTIC DRUGS A large body of pharmaco-TMS studies has established that voltage-dependent Naþ and Ca2þ channel blockers elevate CMT, whereas GABAergic AEDs increase ICI and reduce ICF [2 ]. Recent studies have shed additional light on the effects of AEDs on human brain function. Lang et al. [24] explored the acute effects of lacosamide and carbamazepine on various measures of cortical excitability in 15 healthy subjects. Both drugs &&
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Transcranial magnetic stimulation in epilepsy Kimiskidis et al.
increased CMT significantly but did not affect silent period or any parameters of intracortical synaptic excitability, thereby confirming the view that lacosamide and carbamazepine act predominantly as modulators of neuronal membrane excitability. An elegant study by Delvendahl et al. [25] investigated the effects of lamotrigine on motor cortical plasticity induced by paired associative stimulation (PAS25), a protocol that induces cortical plasticity resembling long-term potentiation (LTP). Study participants exhibited an intrinsically defined propensity for expressing either LTP or long-term depression (LTD)-like plasticity in the context of PAS25. Lamotrigine differentially modulated this phenomenon by decreasing the LTP-like MEP increase in the LTP-responders and reducing the LTD-like MEP decrease in the LTD-responders. These observations suggest that the antiepileptic and mood-stabilizing properties of lamotrigine may occur, in part, through down-regulation of LTP and LTD, respectively. A question of particular clinical importance relates to whether AED-induced changes in TMS indices of cortical excitability can predict response to pharmacological interventions in the long term. Badawy et al. [26] addressed this issue in a longitudinal study of 77 patients with IGE or focal epilepsy repeatedly evaluated over a 3-year period. At study onset, all patient groups had increased cortical excitability. The introduction of an effective AED reversed cortical hyperexcitability in those patients that subsequently remained seizure free. In contrast, hyperexcitabiliy persisted or even progressively increased (for instance involving the initially unaffected hemisphere of patients with focal epilepsy) in the group of pharmacoresistant epilepsy. These population-level data are interesting because they imply that TMS may be used as a biomarker of pharmacoresistant epilepsy. However, they are not yet applicable at the level of the individual patient because they lack sufficient diagnostic accuracy. The further optimization of a TMS-based biomarker predicting response to treatment with AEDs is certainly warranted and may prove of great value in two particular settings [27]. At the individual level, this biomarker may reflect the adequacy of AED treatment and dictate appropriate changes in drug regimen before the occurrence of clinical events. This would be a clear advance over the current situation, in which the administration of AEDs is performed on a purely empirical basis, that is drug regimens are modified after seizures and/or toxicity occurs. At the clinical trial level, this biomarker may prove to be of value during the preliminary evaluation of new potential AEDs at the end of
phase I studies, before pivotal efficacy trials are undertaken. In this setting, a TMS-based protocol might serve as a standardized biomarker predicting efficacy of potential AEDs and providing critical help in the decision to enter the costly process of clinical development.
LOCALIZATION OF THE EPILEPTOGENIC ZONE The interest in this application of TMS has been rather limited up to now [28] primarily because of the inability to record reliably EEG signals concurrently with brain stimulation. However, the recent advent of TMS–EEG is expected to increase significantly the clinical and research interest in this field. Valentin et al. [29] investigated 15 patients with focal epilepsies and a group of normal controls by delivering TMS stimuli at standard positions of the 10–20 system. The authors recorded early EEG responses, which corresponded to the normal N100 waveform, and late responses, which resembled the typical interictal discharges or took the form of repetitive rhythmic activity. Interestingly, the late TMS– EEG responses were never observed in the control group but were present in 11 out of 15 epileptic patients. On the basis of these data, the authors concluded that TMS–EEG can reliably identify the epileptogenic zone and may significantly improve the diagnostic approach to epilepsy.
THERAPEUTIC ASPECTS The antiepileptic effects of rTMS have been explored in case reports, open-label as well as randomized, sham-controlled clinical trials [11]. The overall conclusion from these studies is that rTMS exerts a modest but statistically significant antiepileptic effect that critically depends on various methodological parameters including the accessibility of the epileptogenic zone to TMS. In a recent controlled study, Sun et al. [30] investigated 60 patients with partial epilepsy, the majority of which had epileptogenic zones in centroparietal and frontal lobes and therefore accessible to direct stimulation by TMS. The authors concluded that low frequency stimulation of the epileptogenic zone reduces seizure frequency and epileptiform discharges and improves the psychological state of these patients. The vast majority of the therapeutic TMS studies in epilepsy have focused on the interictal state. However, TMS can be also applied in the ictal state in an effort to suppress clinical and electrographic seizures. Liu et al. [31 ] applied low-frequency rTMS to two patients with focal status epilepticus refractory to multiple AEDs and anesthetics. The TMS
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procedure was uneventful and resulted in decreased seizure frequency. In addition, the study allayed concerns about the use of rTMS in the ICU setting by demonstrating the absence of any significant interference with the electronic equipment at site. In a similar vein, Thordstein et al. [32 ] reported the beneficial effects of low-frequency rTMS in a patient with super-refractory status epilepticus. TMS was delivered over the epileptogenic focus in eight daily 1-h sessions and resulted in EEG and clinical improvement. Finally, Kimiskidis et al. [33 ] recently explored the acute effects of TMS on epileptiform discharges in partial epilepsy and provided evidence that repetitive TMS can reduce the duration of epileptiform discharges in patients with superficial epileptogenic foci. In an effort to interpret these findings, the authors investigated the modulatory effects of TMS stimuli on brain connectivity patterns and observed that during electrographic seizures, partial directed coherence, a linear measure of effective connectivity, increases significantly in the area surrounding the epileptogenic zone. This pathological phenomenon is reversed, to a large extent, by the application of TMS stimuli in a node-specific manner. &
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CONCLUSION The last year has witnessed the publication of significant TMS studies in the field of epilepsy. These studies contributed to the further elucidation of the pathophysiology of human epilepsies and the deeper understanding of the mechanism of action of AEDs, and helped to better define the therapeutic role of TMS. Finally, accumulating evidence suggested that TMS and the recently introduced technique of TMS–EEG hold great potential for becoming diagnostic and prognostic biomarkers with multiple implementation possibilities. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Groppa S, Oliviero A, Eisen A, et al. A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2012; 123:858–882. This is an excellent and clinically oriented report on the basic concepts, methodological issues and clinical applications of TMS.
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2. Ziemann U. Pharmaco-transcranial magnetic stimulation studies of motor excitability. Handb Clinl Neurol 2013; 116:387–397. This is a comprehensive, up-to-date and critical overview of the field of pharmacoTMS studies. 3. Paulus W, Classen J, Cohen LG, et al. State of the art: pharmacologic effects on cortical excitability measures tested by transcranial magnetic stimulation. Brain Stimul 2008; 1:151–163. 4. Silbert BI, Patterson HI, Pevcic DD, et al. A comparison of relative-frequency and threshold-hunting methods to determine stimulus intensity in transcranial magnetic stimulation. Clin Neurophysiol 2013; 124:708–712. 5. Chen R, Cros D, Curra A, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008; 119:504–532. 6. Macdonell RA, Curatolo JM, Berkovic SF. Transcranial magnetic stimulation and epilepsy. J Clin Neurophysiol 2002; 19:294–306. 7. Tassinari CA, Cincotta M, Zaccara G, et al. Transcranial magnetic stimulation and epilepsy. Clin Neurophysiol 2003; 114:777–798. 8. Ilmoniemi RJ, Kicic´ D. Methodology for combined TMS and EEG. Brain Topogr 2010; 22:233–248. 9. Daskalakis ZJ, Farzan F, Radhu N, et al. Combined transcranial magnetic & stimulation and electroencephalography: its past, present and future. Brain Res 2012; 1463:93–100. This is a detailed review article containing practical information on how to obtain and interpret TMS–EEG data. 10. Rotenberg A. Prospects for clinical applications of transcranial magnetic stimulation and real-time EEG in epilepsy. Brain Topogr 2010; 22:257– 266. 11. Kimiskidis VK. Transcranial magnetic stimulation for drug-resistant epilepsies: rationale and clinical experience. Eur Neurol 2010; 63:205– 210. 12. Vernet M, Walker L, Yoo WK, et al. EEG onset of a seizure during TMS from a focus independent of the stimulation site. Clin Neurophysiol 2012; 123: 2106–2108. 13. Badawy RA, Vogrin SJ, Lai A, et al. Capturing the epileptic trait: cortical & excitability measures in patients and their unaffected siblings. Brain 2013; 136:1177–1191. The authors describe abnormal cortical excitability profiles in asymptomatic siblings of patients with focal and generalized epilepsy, thereby providing support for the existence of a familial seizure propensity the ultimate expression of which depends on complex genetic/environmental interactions. 14. Badawy RA, Vogrin SJ, Lai A, et al. Patterns of cortical hyperexcitability in adolescent/adult-onset generalized epilepsies. Epilepsia 2013; 54:871– 878. 15. Brigo F, Storti M, Benedetti MD, et al. Resting motor threshold in idiopathic generalized epilepsies: a systematic review with meta-analysis. Epilepsy Res 2012; 101:3–13. 16. Avanzini G, Manganotti P, Meletti S, et al. The system epilepsies: a pathophysiological hypothesis. Epilepsia 2012; 53:771–778. 17. Puri V, Sajan PM, Chowdhury V, et al. Cortical excitability in drug naive juvenile myoclonic epilepsy. Seizure 2013; 22:662–669. 18. Brigo F, Bongiovanni LG, Nardone R, et al. Visual cortex hyperexcitability in idiopathic generalized epilepsies with photosensitivity: a TMS pilot study. Epilepsy Behav 2013; 27:301–306. 19. Danner N, Julkunen P, Hyppo¨nen J, et al. Alterations of motor cortical & excitability and anatomy in Unverricht-Lundborg disease. Mov Disord 2013; 28:1860–1867. This is a combined neurophysiological and neuroradiological study providing novel insight into the pathophysiological substrate of Unverricht-Lundborg disease. 20. Julkunen P, Sa¨isa¨nen L, Ko¨no¨nen M, et al. TMS-EEG reveals impaired intracortical interactions and coherence in Unverricht-Lundborg type progressive myoclonus epilepsy (EPM1). Epilepsy Res 2013; 106:103– 112. 21. Badawy RA, Vogrin SJ, Lai A, et al. The cortical excitability profile of temporal lobe epilepsy. Epilepsia 2013; 54:1942–1949. 22. Wright MA, Orth M, Patsalos PN, et al. Cortical excitability predicts seizures in acutely drug-reduced temporal lobe epilepsy patients. Neurology 2006; 67:1646–1651. 23. Badawy RA, Macdonell RA, Vogrin SJ, et al. Cortical excitability decreases in Lennox-Gastaut syndrome. Epilepsia 2012; 53:1546–1553. 24. Lang N, Rothkegel H, Peckolt H, et al. Effects of lacosamide and carbamazepine on human motor cortex excitability: a double-blind, placebo-controlled transcranial magnetic stimulation study. Seizure 2013; 22:726–730. 25. Delvendahl I, Lindemann H, Heidegger T, et al. Effects of lamotrigine on human motor cortex plasticity. Clin Neurophysiol 2013; 124:148– 153. 26. Badawy RA, Jackson GD, Berkovic SF, et al. Cortical excitability and refractory epilepsy: a three-year longitudinal transcranial magnetic stimulation study. Int J Neural Syst 2013; 23:1250030. 27. Engel J Jr. Progress in epilepsy: reducing the treatment gap and the promise of biomarkers. Curr Opin Neurol 2008; 21:150–154. 28. Schu¨ler P, Claus D, Stefan H. Hyperventilation and transcranial magnetic stimulation: two methods of activation of epileptiform EEG activity in comparison. J Clin Neurophysiol 1993; 10:111–115.
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Transcranial magnetic stimulation in epilepsy Kimiskidis et al. 29. Valentin A, Arunachalam R, Mesquita-Rodrigues A, et al. Late EEG responses triggered by transcranial magnetic stimulation (TMS) in the evaluation of focal epilepsy. Epilepsia 2008; 49:470–480. 30. Sun W, Mao W, Meng X, et al. Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: a controlled clinical study. Epilepsia 2012; 53:1782–1789. 31. Liu A, Pang T, Herman S, et al. Transcranial magnetic stimulation for refractory & focal status epilepticus in the intensive care unit. Seizure 2013; 22:893– 896. Building on their previous experience, the authors report that rTMS in the ICU is feasible and may contribute to the resolution of drug-resistant focal status epilepticus.
32. Thordstein M, Constantinescu R. Possibly lifesaving, noninvasive, EEGguided neuromodulation in anesthesia-refractory partial status epilepticus. Epilepsy Behav 2012; 25:468–472. This is a case report detailing the beneficial outcome of neuromodulation with rTMS in super refractory status epilepticus. 33. Kimiskidis VK, Kugiumtzis D, Papagiannopoulos S, et al. Transcranial mag& netic stimulation (TMS) modulates epileptiform discharges in patients with frontal lobe epilepsy: a preliminary EEG-TMS study. Int J Neural Syst 2013; 23:1250035. This is a TMS–EEG study investigating the acute effects of rTMS on focal epileptiform discharges and describing changes in underlying brain connectivity patterns. &
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Transcranial magnetic stimulation for the diagnosis and treatment of epilepsy Vasilios K. Kimiskidis a, Antonio Valentin b,c, and Reetta Ka¨lvia¨inen d
Purpose of review The aim is to critically review recent advances emerging from the application of transcranial magnetic stimulation (TMS) as a research and clinical tool in the field of epilepsy. Recent findings A number of TMS–electromyography (EMG) and TMS–electroencephalography (EEG) studies have identified distinct changes of cortical excitability associated with specific epilepsy syndromes and in asymptomatic siblings of patients with epilepsy. Pharmaco-TMS studies have shed additional light on the effects of traditional and recently introduced antiepileptic drugs on excitatory and inhibitory brain microcircuits as well as cortical plasticity mechanisms. In addition, stronger evidence has emerged that TMS may serve as a biomarker with prognostic (i.e. predicting response to pharmacologic or surgical interventions) and diagnostic potential (for instance aiding in the noninvasive localization of the epileptogenic zone). Finally, the role of repetitive TMS in the therapeutic management of drug-resistant epilepsies and refractory status epilepticus has been further defined and is expected to become more prominent by the optimization of the stimulation parameters. Summary TMS has provided important insight into the pathophysiological substrate of human epilepsies and emerges as a valuable tool with diagnostic, prognostic and therapeutic potential. The recent advent of TMS–EEG can be reasonably expected to contribute further significant advances to the field of epilepsy. Keywords antiepileptic drugs, epilepsy, repetitive TMS, TMS-electroencephalography, transcranial magnetic stimulation
INTRODUCTION Transcranial magnetic stimulation (TMS) was discovered in the mid-1980s and rapidly evolved from a simple technique for studying motor pathways to a cutting-edge technology in the field of neurosciences with diverse research, diagnostic and therapeutic applications. With regard to epilepsy, the applications of TMS can be broadly classified into the following groups: noninvasive investigation of cortical excitability; determination of the effects of antiepileptic drugs (AEDs); noninvasive localization of the epileptogenic zone; and therapeutic management of drug-resistant epilepsies. Recent advances in these research areas are briefly outlined below following a brief methodological introduction. www.co-neurology.com
TRANSCRANIAL MAGNETIC STIMULATION: BASIC CONCEPTS TMS is based on the extracranial application of timevarying magnetic fields, which penetrate the skull in a Laboratory of Clinical Neurophysiology, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece, bDepartment of Clinical Neuroscience, King’s College London, Institute of Psychiatry, cDepartment of Clinical Neurophysiology, King’s College Hospital, London, UK and dDepartment of Neurology, Kuopio Epilepsy Center, Kuopio University Hospital and Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland
Correspondence to Vasilios K. Kimiskidis, MD, PhD, Associate Professor of Neurology and Clinical Neurophysiology, Laboratory of Clinical Neurophysiology, AHEPA Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece. Tel: +30 2310 994667; e-mail: [email protected] Curr Opin Neurol 2014, 27:236–241 DOI:10.1097/WCO.0000000000000071 Volume 27 Number 2 April 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Transcranial magnetic stimulation in epilepsy Kimiskidis et al.
KEY POINTS Patients with focal and generalized epilepsies as well as their asymptomatic siblings exhibit syndrome-specific alterations in cortical excitability. TMS–EMG and TMS–EEG hold great potential as diagnostic and prognostic biomarkers in epilepsy. The therapeutic potential of rTMS in drug-resistant focal epilepsies and refractory status epilepticus warrants further investigation. TMS–EEG is an emerging and highly promising technique for the investigation and modulation of abnormal brain connectivity in epilepsy.
a painless manner and result not only in the trans-synaptic excitation but also inhibition of the principal output neurons of the human cortex, that is the pyramidal neurons. In the original version of the technique [TMS– electromyography (EMG)], stimulation is usually performed over the primary motor area (M1) and the ensuing responses, termed motor evoked potentials (MEPs), are recorded from corresponding muscles. There is a large array of TMS measures that can be used to assess motor cortex excitability including corticomotor threshold (CMT), silent period, and intracortical inhibition (ICI) and facilitation (ICF) [1 ]. CMT is the most frequently used parameter in cross-sectional or longitudinal TMS studies and can be simply defined as the minimal intensity of a magnetic stimulus required to produce an MEP. CMT should not be inferred to represent a general excitability measure of cortical areas other than M1. For instance, CMT values do not correlate with phosphene threshold, which indexes the excitability of the visual cortex [1 ]. CMT reflects axonal excitability that depends primarily on ion channel conductivity [2 ,3]. There are various methods for estimating CMT, including the relative frequency method, the two-threshold method of Mills and Nithi and adaptive methods based on thresholdtracking algorithms [1 ,4], which vary considerably in terms of precision and applicability. The phenomenon of silent period refers to a transient decrease in EMG activity evoked during sustained muscle contraction by transcranial magnetic stimuli. The late part of silent period (>75 ms) is ascribed to cortical inhibitory mechanisms probably related to gamma-aminobutyric acid-B (GABAB) receptor activation [1 ]. ICF and ICI are investigated in the context of paired-pulse TMS studies [5]. In this paradigm, the &&
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first, conditioning stimulus is given at subthreshold intensities, whereas the second, test stimulus is applied at supratheshold levels after varied interstimulus intervals (ISIs). If the ISI is between 1 and 6 ms, then the test stimulus is suppressed because of a GABA-A receptor-related phenomenon termed short-interval ICI (SICI). If the ISI is between 8 and 30 ms, then ICF occurs with enhancement of the test stimulus because, in part, of N-methyl-Daspartate receptor activation. Finally, if two supratheshold stimuli are applied with an ISI of 50–200 ms, then the test stimulus is suppressed because of longinterval ICI. The above-mentioned TMS measures have been extensively investigated in numerous studies over the last few years [6,7], providing valuable insight into the pathophysiological substrate, the diagnosis and prognosis of epilepsy. However, there are limitations to the type of information that can be obtained from these studies because they employ the method of TMS–EMG in which responses are recorded exclusively from muscles, rather than the cerebral cortex, and stimulation is usually performed over the motor strip. It is conceivable that recordings from the cerebral cortex per se and stimulation over the entire cortical mantle would be far more informative for the investigation of a disease primarily operating at the cortical level, such as epilepsy. Recent technological advances enabled the coupling of high-density electroencephalography (EEG) with TMS (TMS–EEG) [8,9 ]. This novel method opens new avenues for the investigation of epilepsy because it allows, for the first time in a noninvasive manner, the recording and mapping of neuronal responses induced by TMS at the cortical level (EEG reactivity) as well as the investigation and modulation of functional connectivity between brain areas (EEG connectivity). In addition, this novel method permits the detection of epileptiform discharges during repetitive TMS (rTMS), enabling the modification of stimulation parameters or even the termination of a session. Thereby, the safety of therapeutic applications of TMS for drugresistant epilepsy may be significantly improved [10–12]. &
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INVESTIGATION OF CORTICAL EXCITABILITY Converging lines of evidence suggest that epilepsies are in general characterized by cortical hyperexcitability in a syndrome-specific manner. Recently, this concept has been extended to include asymptomatic siblings of patients with epilepsy as well. Badawy et al. [13 ] reported that cortical excitability is higher in asymptomatic siblings of patients
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with focal and particularly generalized epilepsy. The pattern of cortical hyperexcitability, essentially reflecting defective ICI mechanisms, was similar in siblings of patients with various epilepsy syndromes, raising the possibility that genetic factors predispose to both generalized and focal epilepsies and a complex genetic/environmental interaction determines the ultimate clinical phenotype. In idiopathic generalized epilepsy (IGE), a study of 30 drug-naı¨ve patients [10 patients with juvenile myoclonus epilepsy (JME), eight with juvenile absence epilepsy and 12 with generalized tonic– clonic seizures only] concluded that cortical excitability was significantly enhanced in all epilepsy syndromes as evidenced by reduced CMT values and decreased ICI at short and particularly at long ISIs [14]. Patients with JME demonstrated significantly higher levels of cortical excitability compared with the other two groups of patients, thereby differentiating JME from other IGE syndromes. This view is also supported by a meta-analysis of 14 trials involving 265 drug-naı¨ve IGE patients and 424 control subjects, which concluded that only patients with JME had reduced CMT values compared with controls [15]. These observations are in line with the recently proposed construct of ‘system epilepsies’ [16] and set JME as an archetype within this conceptual scheme. However, Puri et al. [17] did not detect reduced CMT in 30 drug-naı¨ve JME patients. These inconsistent results in well characterized IGE cohorts and in the absence of confounding factors, such as AED intake, are probably related to the small magnitude of the threshold decrease and the precision of threshold measurements. Indeed, according to the Internation Federation of Clinical Neurophysiology guidelines [1 ], adaptive methods based on threshold-tracking algorithms provide the most accurate CMT estimation and are probably the optimal method for reliably detecting subtle threshold changes in patients with epilepsy. In certain IGE syndromes, hyperexcitability occurs in other areas of the cortical mantle, beyond the motor strip. Brigo et al. [18] investigated corticomotor and phosphene threshold in 33 patients with IGE, a subset of which displayed photosensitivity. The authors observed decreased phosphene threshold in patients with photosensitivity implying regional hyperexcitability of the primary visual cortex. This observation provides additional evidence in favor of the construct of system epilepsies and suggests that the primary visual cortex is a ‘hub’ of pathophysiological importance in the ‘photosensitivity system’. With regard to progressive myoclonic epilepsies, a unique study by Danner et al. [19 ] investigated 70 genetically verified EPM type 1 patients and &&
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40 controls correlating structural and electrophysiological findings. The authors observed significant elevations of CMT, which were ascribed to medication effects and the increased scalp-to-cortex distance in the context of disease-related cortical atrophy. In addition, they reported significantly prolonged silent period durations, which were interpreted as a cortical inhibitory mechanism reactive to the underlying pathology of EPM1. In the first TMS–EEG study of EPM1 patients, Julkunen et al. [20] reported increased amplitude of the early P30 waveform, suggesting enhanced cortico-cortical excitability and reduced amplitude of the later N100–P180 complex indicating impaired cortical inhibition. In addition, the authors investigated the event-related spectral perturbation, and observed reduced power of alpha, beta and gamma band oscillations and decreased inter-trial coherence following the magnetic stimulus in EPM1 patients, indicating malfunctioning circuits at cortical and subcortical levels. With regard to focal epilepsy, a study by Badawy et al. [21] in 10 drug-naive patients with new-onset temporal lobe epilepsy (TLE) disclosed an interhemispheric imbalance with hyperexcitability in the hemisphere containing the epileptogenic zone and normal excitability of the unaffected hemisphere. In addition, Wright et al. [22] investigated 18 patients with TLE during the preictal state and described changes in cortical excitability in the form of a compound index of intracortical inhibition/ facilitation that was able to predict in the short term the occurrence of epileptic seizures. In 18 adult patients with Lennox–Gastaut syndrome, Badawy et al. [23] reported a hypoexcitability reflected in increased CMT and ICI and decreased ICF. This finding stands in sharp contrast with the persistent hyperexcitability characterizing other refractory epileptic syndromes. It is unclear whether this hypoexcitable state is pertinent to Lennox–Gastaut syndrome only or whether it characterizes other generalized epileptic encephalopathies as well.
DETERMINATION OF THE EFFECTS OF ANTIEPILEPTIC DRUGS A large body of pharmaco-TMS studies has established that voltage-dependent Naþ and Ca2þ channel blockers elevate CMT, whereas GABAergic AEDs increase ICI and reduce ICF [2 ]. Recent studies have shed additional light on the effects of AEDs on human brain function. Lang et al. [24] explored the acute effects of lacosamide and carbamazepine on various measures of cortical excitability in 15 healthy subjects. Both drugs &&
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increased CMT significantly but did not affect silent period or any parameters of intracortical synaptic excitability, thereby confirming the view that lacosamide and carbamazepine act predominantly as modulators of neuronal membrane excitability. An elegant study by Delvendahl et al. [25] investigated the effects of lamotrigine on motor cortical plasticity induced by paired associative stimulation (PAS25), a protocol that induces cortical plasticity resembling long-term potentiation (LTP). Study participants exhibited an intrinsically defined propensity for expressing either LTP or long-term depression (LTD)-like plasticity in the context of PAS25. Lamotrigine differentially modulated this phenomenon by decreasing the LTP-like MEP increase in the LTP-responders and reducing the LTD-like MEP decrease in the LTD-responders. These observations suggest that the antiepileptic and mood-stabilizing properties of lamotrigine may occur, in part, through down-regulation of LTP and LTD, respectively. A question of particular clinical importance relates to whether AED-induced changes in TMS indices of cortical excitability can predict response to pharmacological interventions in the long term. Badawy et al. [26] addressed this issue in a longitudinal study of 77 patients with IGE or focal epilepsy repeatedly evaluated over a 3-year period. At study onset, all patient groups had increased cortical excitability. The introduction of an effective AED reversed cortical hyperexcitability in those patients that subsequently remained seizure free. In contrast, hyperexcitabiliy persisted or even progressively increased (for instance involving the initially unaffected hemisphere of patients with focal epilepsy) in the group of pharmacoresistant epilepsy. These population-level data are interesting because they imply that TMS may be used as a biomarker of pharmacoresistant epilepsy. However, they are not yet applicable at the level of the individual patient because they lack sufficient diagnostic accuracy. The further optimization of a TMS-based biomarker predicting response to treatment with AEDs is certainly warranted and may prove of great value in two particular settings [27]. At the individual level, this biomarker may reflect the adequacy of AED treatment and dictate appropriate changes in drug regimen before the occurrence of clinical events. This would be a clear advance over the current situation, in which the administration of AEDs is performed on a purely empirical basis, that is drug regimens are modified after seizures and/or toxicity occurs. At the clinical trial level, this biomarker may prove to be of value during the preliminary evaluation of new potential AEDs at the end of
phase I studies, before pivotal efficacy trials are undertaken. In this setting, a TMS-based protocol might serve as a standardized biomarker predicting efficacy of potential AEDs and providing critical help in the decision to enter the costly process of clinical development.
LOCALIZATION OF THE EPILEPTOGENIC ZONE The interest in this application of TMS has been rather limited up to now [28] primarily because of the inability to record reliably EEG signals concurrently with brain stimulation. However, the recent advent of TMS–EEG is expected to increase significantly the clinical and research interest in this field. Valentin et al. [29] investigated 15 patients with focal epilepsies and a group of normal controls by delivering TMS stimuli at standard positions of the 10–20 system. The authors recorded early EEG responses, which corresponded to the normal N100 waveform, and late responses, which resembled the typical interictal discharges or took the form of repetitive rhythmic activity. Interestingly, the late TMS– EEG responses were never observed in the control group but were present in 11 out of 15 epileptic patients. On the basis of these data, the authors concluded that TMS–EEG can reliably identify the epileptogenic zone and may significantly improve the diagnostic approach to epilepsy.
THERAPEUTIC ASPECTS The antiepileptic effects of rTMS have been explored in case reports, open-label as well as randomized, sham-controlled clinical trials [11]. The overall conclusion from these studies is that rTMS exerts a modest but statistically significant antiepileptic effect that critically depends on various methodological parameters including the accessibility of the epileptogenic zone to TMS. In a recent controlled study, Sun et al. [30] investigated 60 patients with partial epilepsy, the majority of which had epileptogenic zones in centroparietal and frontal lobes and therefore accessible to direct stimulation by TMS. The authors concluded that low frequency stimulation of the epileptogenic zone reduces seizure frequency and epileptiform discharges and improves the psychological state of these patients. The vast majority of the therapeutic TMS studies in epilepsy have focused on the interictal state. However, TMS can be also applied in the ictal state in an effort to suppress clinical and electrographic seizures. Liu et al. [31 ] applied low-frequency rTMS to two patients with focal status epilepticus refractory to multiple AEDs and anesthetics. The TMS
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procedure was uneventful and resulted in decreased seizure frequency. In addition, the study allayed concerns about the use of rTMS in the ICU setting by demonstrating the absence of any significant interference with the electronic equipment at site. In a similar vein, Thordstein et al. [32 ] reported the beneficial effects of low-frequency rTMS in a patient with super-refractory status epilepticus. TMS was delivered over the epileptogenic focus in eight daily 1-h sessions and resulted in EEG and clinical improvement. Finally, Kimiskidis et al. [33 ] recently explored the acute effects of TMS on epileptiform discharges in partial epilepsy and provided evidence that repetitive TMS can reduce the duration of epileptiform discharges in patients with superficial epileptogenic foci. In an effort to interpret these findings, the authors investigated the modulatory effects of TMS stimuli on brain connectivity patterns and observed that during electrographic seizures, partial directed coherence, a linear measure of effective connectivity, increases significantly in the area surrounding the epileptogenic zone. This pathological phenomenon is reversed, to a large extent, by the application of TMS stimuli in a node-specific manner. &
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CONCLUSION The last year has witnessed the publication of significant TMS studies in the field of epilepsy. These studies contributed to the further elucidation of the pathophysiology of human epilepsies and the deeper understanding of the mechanism of action of AEDs, and helped to better define the therapeutic role of TMS. Finally, accumulating evidence suggested that TMS and the recently introduced technique of TMS–EEG hold great potential for becoming diagnostic and prognostic biomarkers with multiple implementation possibilities. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Groppa S, Oliviero A, Eisen A, et al. A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2012; 123:858–882. This is an excellent and clinically oriented report on the basic concepts, methodological issues and clinical applications of TMS.
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2. Ziemann U. Pharmaco-transcranial magnetic stimulation studies of motor excitability. Handb Clinl Neurol 2013; 116:387–397. This is a comprehensive, up-to-date and critical overview of the field of pharmacoTMS studies. 3. Paulus W, Classen J, Cohen LG, et al. State of the art: pharmacologic effects on cortical excitability measures tested by transcranial magnetic stimulation. Brain Stimul 2008; 1:151–163. 4. Silbert BI, Patterson HI, Pevcic DD, et al. A comparison of relative-frequency and threshold-hunting methods to determine stimulus intensity in transcranial magnetic stimulation. Clin Neurophysiol 2013; 124:708–712. 5. Chen R, Cros D, Curra A, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008; 119:504–532. 6. Macdonell RA, Curatolo JM, Berkovic SF. Transcranial magnetic stimulation and epilepsy. J Clin Neurophysiol 2002; 19:294–306. 7. Tassinari CA, Cincotta M, Zaccara G, et al. Transcranial magnetic stimulation and epilepsy. Clin Neurophysiol 2003; 114:777–798. 8. Ilmoniemi RJ, Kicic´ D. Methodology for combined TMS and EEG. Brain Topogr 2010; 22:233–248. 9. Daskalakis ZJ, Farzan F, Radhu N, et al. Combined transcranial magnetic & stimulation and electroencephalography: its past, present and future. Brain Res 2012; 1463:93–100. This is a detailed review article containing practical information on how to obtain and interpret TMS–EEG data. 10. Rotenberg A. Prospects for clinical applications of transcranial magnetic stimulation and real-time EEG in epilepsy. Brain Topogr 2010; 22:257– 266. 11. Kimiskidis VK. Transcranial magnetic stimulation for drug-resistant epilepsies: rationale and clinical experience. Eur Neurol 2010; 63:205– 210. 12. Vernet M, Walker L, Yoo WK, et al. EEG onset of a seizure during TMS from a focus independent of the stimulation site. Clin Neurophysiol 2012; 123: 2106–2108. 13. Badawy RA, Vogrin SJ, Lai A, et al. Capturing the epileptic trait: cortical & excitability measures in patients and their unaffected siblings. Brain 2013; 136:1177–1191. The authors describe abnormal cortical excitability profiles in asymptomatic siblings of patients with focal and generalized epilepsy, thereby providing support for the existence of a familial seizure propensity the ultimate expression of which depends on complex genetic/environmental interactions. 14. Badawy RA, Vogrin SJ, Lai A, et al. Patterns of cortical hyperexcitability in adolescent/adult-onset generalized epilepsies. Epilepsia 2013; 54:871– 878. 15. Brigo F, Storti M, Benedetti MD, et al. Resting motor threshold in idiopathic generalized epilepsies: a systematic review with meta-analysis. Epilepsy Res 2012; 101:3–13. 16. Avanzini G, Manganotti P, Meletti S, et al. The system epilepsies: a pathophysiological hypothesis. Epilepsia 2012; 53:771–778. 17. Puri V, Sajan PM, Chowdhury V, et al. Cortical excitability in drug naive juvenile myoclonic epilepsy. Seizure 2013; 22:662–669. 18. Brigo F, Bongiovanni LG, Nardone R, et al. Visual cortex hyperexcitability in idiopathic generalized epilepsies with photosensitivity: a TMS pilot study. Epilepsy Behav 2013; 27:301–306. 19. Danner N, Julkunen P, Hyppo¨nen J, et al. Alterations of motor cortical & excitability and anatomy in Unverricht-Lundborg disease. Mov Disord 2013; 28:1860–1867. This is a combined neurophysiological and neuroradiological study providing novel insight into the pathophysiological substrate of Unverricht-Lundborg disease. 20. Julkunen P, Sa¨isa¨nen L, Ko¨no¨nen M, et al. TMS-EEG reveals impaired intracortical interactions and coherence in Unverricht-Lundborg type progressive myoclonus epilepsy (EPM1). Epilepsy Res 2013; 106:103– 112. 21. Badawy RA, Vogrin SJ, Lai A, et al. The cortical excitability profile of temporal lobe epilepsy. Epilepsia 2013; 54:1942–1949. 22. Wright MA, Orth M, Patsalos PN, et al. 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Transcranial magnetic stimulation in epilepsy Kimiskidis et al. 29. Valentin A, Arunachalam R, Mesquita-Rodrigues A, et al. Late EEG responses triggered by transcranial magnetic stimulation (TMS) in the evaluation of focal epilepsy. Epilepsia 2008; 49:470–480. 30. Sun W, Mao W, Meng X, et al. Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: a controlled clinical study. Epilepsia 2012; 53:1782–1789. 31. Liu A, Pang T, Herman S, et al. Transcranial magnetic stimulation for refractory & focal status epilepticus in the intensive care unit. Seizure 2013; 22:893– 896. Building on their previous experience, the authors report that rTMS in the ICU is feasible and may contribute to the resolution of drug-resistant focal status epilepticus.
32. Thordstein M, Constantinescu R. Possibly lifesaving, noninvasive, EEGguided neuromodulation in anesthesia-refractory partial status epilepticus. Epilepsy Behav 2012; 25:468–472. This is a case report detailing the beneficial outcome of neuromodulation with rTMS in super refractory status epilepticus. 33. Kimiskidis VK, Kugiumtzis D, Papagiannopoulos S, et al. Transcranial mag& netic stimulation (TMS) modulates epileptiform discharges in patients with frontal lobe epilepsy: a preliminary EEG-TMS study. Int J Neural Syst 2013; 23:1250035. This is a TMS–EEG study investigating the acute effects of rTMS on focal epileptiform discharges and describing changes in underlying brain connectivity patterns. &
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