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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
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)
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: email@example.com
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.
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
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.
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
11 100j~ 80]::.. 60
1 40l!lz 20
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i 120II 100j! 80C/l'! 60
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.
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
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