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Transcranial Magnetic Stimulation and Transcranial DirectCurrent Stimulation (Supplements to Clinical Neurophysiology, Vol. 56)

Editors: W. Paulus, F. Tergau, M.A. Nitsche, I.e. Rothwell, U. Ziemann, M. Hallett© 2003 Elsevier Science B.V. All rights reserved

Chapter 41

Can epilepsies be improved by repetitive transcranial magneticstimulation? - interim analysis of a controlled study

Frithjof Tergau-", Daniela Neumann", Felix Rosenow', Michael A. Nitsche",Walter Paulus" and Bernhard Steinhoff"

a Department of Clinical Neurophysiology, University of Gottingen, D-37075 Gbttingen (Germany)b Epilepsy Center Kork; Kehl-Kork (Germany)

C Interdisciplinary Epilepsy Center, Department of Neurology, University of Marburg, Marburg (Germany)

1. Introduction

Since the early decades of the last century, a varietyof brain stimulation techniques have been - and stillare - evaluated for their therapeutical potential inthe treatment of epilepsies that cannot be sufficientlyimproved by pharmacological and surgical strategies.Besides deep brain stimulation of various brain nucleiand other targets as well as vagal nerve stimula-tion (for review, see Benabid et al., 2000, 2003;Loddenkemper et al., 2001; Weinstein, 2001; Labarand Dean, 2002; Murphy and Patil, 2003), repetitivetranscranial magnetic stimulation (rTMS) has gainedincreasing interest in the investigation of antiepilepticefficacy.

Independently of the investigation of therapeuticalperspectives of rTMS as a technique to induce long-lasting modifications of the excitability of neuronal

* Correspondence to: Dr. Frithjof Tergau, MD,Department of Clinical Neurophysiology, University ofGottingen, Robert-Koch-Strasse 40, D-37075 Gottingen,Germany.Tel: +49-551-39 6650; Fax: +49-551-39 8126;E-mail: f.tergau@med.uni-goettingen.de

network (see below), transcrainal magnetic stimula-tion (TMS) with single and double pulses wasintroduced to explore cortical excitability. Althoughthe studies on several epilepsy syndromes were notalways easy to interpret, it is well accepted thatimpairment of the excitatory as well as the inhibitoryproperties at least in some parts of the epileptic braincan be confirmed by TMS (for review, see Ziemannet al., 1998; Macdonell et al., 2002; Tassinari, 2003).TMS can also be used to study the effect of centralactive drugs - most antiepileptic drugs are shown toreduce cortical excitability (Ziemann et al., 1999;Macdonell et al., 2002; Tassinari, 2003).

In the early days of transcranial magnetic stimu-lation (TMS) research, apprehension existed that thistype of stimulation bears the risk of inducing seizures.However, from numerous studies (cf. Pascual-Leoneet al., 1993; Wassermann et al., 1996; Chen et al.,1997b; Jabanshahi et al., 1997; Ziemann et al., 1998)and a consensus conference (Wassermann, 1998) itwas concluded that single and double pulse TMS aswell as, within certain limits, rTMS cannot be seenas pro-epileptic (for details, see also Tergau andSteinhoff, in press). Moreover, it was demonstratedthat TMS series with slow repetition rates of I Hz or

below (so-called low-frequency rTMS) can reducecortical excitability (Chen et al., 1997a; Muellbacheret aI., 2000). Nevertheless, rTMS with frequenciesabove 1 Hz (so-called high-frequency rTMS) hasbeen shown to increase cortical excitability (pascual-Leone et al., 1994; Berardelli et al., 1998) and withincreasing frequency, stimulus intensity and/or trainduration, the risk of inducing seizures increases.

Based on the findings that the effects of rTMS lastbeyond the period of stimulation itself, therapeuticalantiepileptic potential of low-frequency rTMS washypothesized. Here we present interim analysis of anongoing placebo-controlled trial. The results arediscussed on the bases of the existing rTMS literatureregarding the treatment of epilepsies in humans.

2. Methods

A multicenter cross-over placebo-controlled threearm trial is currently performed by three Germanepilepsy centers. Patients with any type of medicallyintractable focal or generalized epilepsy with at leaston average two seizures per week over a 3 monthbaseline period can be included. The study wasapproved by the local ethics committee and allpatients included gave written informed consent.

By April 2003, 28 patients were enrolled, of whichfive patients to date have yet to complete and sixpatients dropped the study due to pregnancy (one),low baseline seizure frequency (one), change ofresidence (one), changed medication (two) or withoutany reason (one). The data of 17 patients, mean age29 ± 10 years, 11 male, are presented here. Patientshad the diagnosis of focal neocortical (11), focalmesial temporal (two), multifocal (two), generalized(two) epilepsy. Duration of epilepsy was 21 ± 12years. Medication was kept constant throughout thestudy. The study course for each patient includedthree treatment periods in randomized order: twodifferent real stimulation types were randomly inter-mixed with placebo stimulation. We used a MagProMagnetic Stimulator, Dantec Medtronic, Dusseldorf,Germany with a round coil (outer diameter 9 cm)placed over the vertex. Placebo stimulation wasapplied by using a specially designed coil with a

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magnetic field intensity reduced to 10% but producingthe 'click' and the cutaneous skin sensations unterthe coil similar to the real coil. The three stimulationtypes differ in frequency: 1 Hz and 0.333 Hz for realstimulation and 0.666 Hz for placebo stimulationrespectively - while all other stimulation parameterswere the identical to the methods previously used(Tergau et aI., 1999). Stimulation on 5 consecutivedays with 1000 pulses (500 monopolar pulses withclockwise current direction followed directly by 500pulses in anti-clockwise direction) each day, stimulusintensity for both coil orientations slightly belowmotor threshold, thus motor or sensory phenomenaother than the acoustic and the cutaneous sensationsunder the coil were prevented. Treatment periodswere preceded and followed by at least 4 weeksobservation phases, and treatment periods wereseparated by at least 8 weeks. A diary record waskept by the patients, by counting all seizure orseizure-like events.

3. Results

All patients tolerated the stimulation without signifi-cant side effects, none of the patients had a majorincrease in seizure frequency after any of the realstimulation types.

Baseline seizure frequency during the 4 weeksprior to each of the treatment periods was relativleyconstant with 6.25 (median, range 2.5-320.5) seizuresper week (SPW) for placebo stimulation, 5.0(1.75- 272.25) spw for 0.333 Hz stimulation and6.75 (1.25-350) spw for 1.0 Hz stimulation (notethat one patient had frequent sensory seizures withup to 50 seizures per day, which enlarged rangeand standard deviation of seizure frequency of thegroup). For further analysis, SPW after stimulation,was individually normalized to the appropriate base-line and expressed in percent. As shown in Fig. I,values over the 4 baseline weeks separately variedon average within the range of 80--120%.SPW duringand after treatment also stayed within this range withtwo exceptions: (i) during 0.333 Hz stimulationseizure frequency was significantly reduced to lessthan 60% (p =0.0004) and stayed below 80% for

Placebo 1.0 Hz

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140

f 120

11 100

j~ 80

]::.. 60

1 40l!lz 20

O+----,.---r-----.-..........-..,.----"""T""-,.-"""'T'"-~_I~ 4 ~ ~ ~ 0 234 5

Weekpre/post rTMS

p=0.0012160

140

i 120

II 100

j! 80

C/l'! 60

I~ 40

20...ClZ

00.333Hz

p=O.58 p=O.52

Fig. 1. The course of mean seizure frequency over aperiod of 9 weeks (4 weeks prior rTMS (-4 to -1), rTMStreatment week (0), 4 weeks post rTMS (1-4» for the threestimulation modes separately. Values represent averageseizure frequency for every week separately individuallynormaIized to their mean seizure frequency during 4 weeksprior to rTMS treatment and are given in percent. Note thaterror bars indicate standard error of mean. Filled symbolindicates significant difference to 4-week baseline period.

another2 weeks; (ii) three to four weeksafter placebostimulation, seizure frequency increased insignifi-cantly (p = 0.37; P = 0.27) up to 120-130%. Noneof the weekly values of the real stimulation modesshowed a statistically significant difference toplacebo. For further analysis, we averagedthe valuesof treatment and 2-weeks post-stimulation periods(cf. Theodore et al, 2002). As depicted in Fig. 2,only for 0.333 Hz stimulation was there a significantreduction in seizure frequency compared to baseline,however, the difference to placebofailed significanceslightly.

4. Discussion

Antiepileptic effects of TMS pulses at first were dis-covered by chance when Hufnagel and Elger (1991)tried to activate the epilepticfocus in 48 patientswithintractable epilepsies. By using singlepulseTMStheyfound enhancement as well as suppression of epilep-tiform potentials in seven patients with continuously

Fig. 2. Average seizure frequency is displayed for aperiod of 2 weeks after each of the three modes of rTMStreatment (0.333 Hz, Placebo, 1.0 Hz). Values are mean ±standard deviation of 17 subjects and are expressed aspercentage of seizure frequency during 4 weeks prior torTMS. p values of the student's t test for comparisonto baseline are given at the top of the figure, bold numbersindicate statistical significance (p < 0.05); number inbrackets indicate the p value for the comparison between0.333 Hz and placebo stimulation which slightly failed

significance.

spiking epileptic foci. Additionally, they describedtemporary interruption of epileptiform paroxysms for1-3 s in nine cases and found persistent suppressionof spontaneous spikes in one patient raising evidencethat TMS pulses may inhibit epileptiform activity.When applyingsingle TMS pulses repetitively everythree to ten seconds (0.3 to 0.1 Hz) - before theterm 'repetitive TMS' was coined due to technicallimitation of the stimulation devices- Steinhoffet a1.noticed a decrease in spike frequency for at least5 min after stimulation, most prominently bilaterallywhen TMS was applied contralateral to the epilepticfocus in seven patients with medically intractablecomplex-partial seizures of mesiobasal limbic onset(Steinhoffet al., 1992; Steinhoffet al., 1993). In 1997,preliminary data on three patientswith corticalactionmyoclonus were presented showing that 1 Hz rTMSover 30 min was able to reduce action myoclonus.Although appliedover severaldays, the effect alwaysvanished 2 h after rTMS (Wedegaertner et al., 1997).

The results presented here are interim analyses ofthe first cross-over placebo-controlled investigationon the antiepileptic efficacy of low-frequency rTMS.The data from 17 patients suggest a seizure reduc-tion on average by 30-40% over 2 weeks after rTMStreatment with 0.333 Hz whereas, after placebo aswell as after 1.0 Hz treatment there was nodiscernible effect on seizure frequency. Although asignificant difference to placebo could not be demon-strated in this patient group, the data seems to be inline with the results of the first open pilot study onnine patients who showed reduction in seizurefrequency within a similar range over a 4 week period(Tergau et aI., 1999). Our results were confirminglysupplemented by a case report on a patient with focaldysplasia by another group (Menkes and Gruenthal,2000): biweekly treatment with 100 stimuli at 0.5 Hzand 95% motor threshold intensity using an unfocalcoil placed over the area of dysplasia reduced seizurefrequency by 70% over a 4 weeks period of treat-ment.

In contrast, results of another placebo-controlledstudy - the first being done in this field - were notthat encouraging (Theodore et al., 2002): 12 patientswith focal epilepsies receiving 1 Hz stimulation on7 days, twice daily over 15 min were compared to12 matched patients receiving placebo stimulation.They found only 16 ± 18% seizure reduction over2 weeks after real stimulation, while placebo stimu-lation yielded reduction by 1 ± 24%. This differencefailed significance (p =0.11).

Some methodical aspects should be discussed thatmay have masked better effects in the studies.

First, sample sizes were relatively small. To obtainvalid information on the antiepileptic efficacy, morepatients should be treated. For comparison, in thestudies on vagal nerve stimulation in the tretment ofepilepsy that led to FDA approval of this treatmentstrategy, over hundred patients were studied forsignificant seizure reduction, on average by 24.5%(The Vagus Nerve Stimulation Study Group, 1995).

Second, in the study by Theodore et aI. (2002) afocal stimulation protocol was used, while in ourstudies stimulation was applied unfocally. It is knownthat focal stimulation. at threshold intensities only

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activates a small area of cortex lying some 3 embeneath the skull. It may be assumed that in somepatients the epileptic focus cannot be reached prop-erly. This could be an explanation for not being ableto produce better results in the study by Theodore etal, (2002) when taken into account that 10 of the 24patients had an temporo-mesial epileptic focus; sub-group analysis showed that neocortical epilepsiesresponded much better (24 ± 22% seizure reduction)than mesial epilepsies (-11 ± 28%), this difference,however, was not significant, most likely due to thesmall sample size. Until now, it is not known, whetherthe focal stimulation technique attempting to inacti-vate the epileptic focus is superior or whether aconcept of unfocal stimulation trying to downregulatethe excitability of the cortical network responsible forseizure propagation (comparable to "unfocal" effectsof antiepileptic drugs or vagal nerve stimulation?) asused in our study has more advantages. Support to thelatter concept can be found by neurophysiological andbrain imaging studies with observations that brainareas remote from the TMS stimulation site can bemodified (Paus et aI., 1997; Gerschlager et aI., 2001).

Third, the stimulation frequency could be of crucialimportance. In our study, significant seizure reduc-tion compared to baseline was only seen after0.333 Hz stimulation while 1.0 Hz stimulation wasquite similar to placebo. Until now, the meaning ofthis observation can only be speculative. 1.0 Hz is afrequency mainly inducing inhibition. This seems tobe confirmed by a PET study, showing that high-frequency led to an increase of regional cerebralblood flow (rCBF) in the stimulated brain areas,whereas, under low-frequency the rCBF decreased(Post et al., 1999; Speer et aI., 2000). From theexisting literature we do not know where the border-line frequency between induction of facilitation andinhibition really is. Since the mechanisms behind thisphenomenon are not really understood, it is, hence,not known whether the separation between those twoobviously contradictory modifications of corticalexcitability, facilitation and inhibition, are fixed at thesame frequency for all patients. Indeed, a couple ofstudies demonstrated a possibly large interindividualvariability in the susceptibility to inhibitory and

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excitatory rTMS, (Maeda et al., 2000). Moreover, itis not clear whether the results on the motor cortex(Chen et al., 1997a; Chen and Seitz, 2001) or on thevisual cortex (Boroojerdi et al., 2000) can be seen asgenerally valid for all brain regions. Nevertheless, itis well accepted in general that activation is morelikely induced when higher frequencies are used andinhibition is yielded by low frequencies. Taking thisinto account, it may be speculated that in somepatients induced inhibition by 1.0 Hz was not strongenough. Although subgroup analysis on our dataremains to be carried out, it has to be considered thatinterindividual differences exist in the susceptibilityto inhibitory and excitatory rTMS (cf. Maeda et al.,2000).

Major criticism to the studies on rTMS in epilep-sies could be that the amount of reduction in seizurefrequency is not sufficient at all. However, one hasto consider that techniques of brain stimulation otherthan rTMS failed to show superior effects so far,especially in placebo-controlled trials. This is prob-ably due to the fact that in all studies on newtreatment, the included patients suffered from verysevere epilepsy syndromes and were resistant toseveral antiepileptic drugs. It seems unlikely that atherapeutic strategy can be developed that improvesall kind of epilepsies to an extent greater than it wasseen for new-developed drugs (e.g. for levetiracetam,Betts et at, 2000). As stated earlier, it should be notedthat the effects of vagus nerve stimulation were at asimilar range (The Vagus Nerve Stimulation StudyGroup, 1995). Magic effects should not be expectedfrom rTMS.

However, many questions in this field are still tobe answered. The mechanisms underlying the effectsof rTMS on cortical excitability are still yet to bediscovered (cf. Lisanby and Belmaker, 2000; Mulleret at, 2000). The stimulation parameters such asfrequency, intensity, focality, duration and repetitionrate of the trains require further detailed studies.For this, rTMS has the advantages of being easy toapplicate and to be non-invasive, thus, there is norisk from surgical procedures. Probably, individuallyoptimised stimulation parameters are needed and,furthermore, it may be expected that different

epilepsy syndromes may respond differently torTMS. Also, chronic application of rTMS has to beevaluated to see whether the antiepileptic effects anbe preserved over a suitable period, also possible sideeffects should be investigated further.

In conclusion, it will take time and numerousstudies are needed before decisions can be made asto whether low-frequency rTMS may be an alterna-tive adjunctive antiepileptic treatment in intractableepilepsy. First results are not dispiriting.

Acknowledgement

The work was supported by The DanteclMedtronicCompany, Dusseldorf, Germany

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