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Epilepsy Research 72 (2006) 1824

A single dose of sulthiame induces a selective increase in resting motor threshold in human motor cortex: A transcranial magnetic stimulation study
Michael Siniatchkin a, , Sergey Groppa a , Hartwig Siebner b , Ulrich Stephani a
a b

Neuropediatric Department, Christian-Albrechts-University, Kiel, Germany Department of Neurology, Christian-Albrechts-University, Kiel, Germany

Received 28 March 2006; received in revised form 3 June 2006; accepted 4 July 2006 Available online 22 August 2006

Abstract Sulthiame is a carbonic anhydrase inhibitor that is widely used to treat partial and myoclonic seizures. In 11 healthy adults, we applied transcranial magnetic stimulation (TMS) to the primary motor cortex. Using a cross-over study design, we found that a single oral dose of sulthiame (5 mg/kg) produced a signicant increase of resting motor threshold relative to placebo. No other TMS measure of corticomotor excitability was altered after a single dose of sulthiame. The selective increase in motor threshold suggests that sulthiame produces its antiepileptic effect by reducing the axonal excitability of cortical neurons. 2006 Published by Elsevier B.V.
Keywords: Sulthiame; Transcranial magnetic stimulation; Cortical excitability; Ion channels

1. Introduction Sulthiame (STM) has been used since 1960 for treatment of benign focal epilepsies in childhood (Bast et al., 2003; Rating et al., 2000), West syndrome (Debus and Kurlemann, 2004), myoclonic seizures (GrossSelbeck, 1995), and as add-on therapy for children with refractory epilepsies (Brockmeier, 2003). The anticonvulsant effect of this sulfonamide derivative has been reproduced in several in vitro and animal models of epileptic activity. It has been demonstrated that sulthiame inhibits the enzyme carbonic anhydrase in glial cells, increases the carbon dioxide concentration

Abbreviations: AED, antiepileptic drugs; APB, abductor policis brevis; CSP, cortical silent period; EMG, electromyography; ICI, intracortical inhibition; ICF, intracortical facilitation; MEP, motor evoked potential; RMT, resting motor threshold; TMS, transcranial magnetic stimulation Corresponding author at: Pediatric Neurology, Schwanenweg 20, D-24105 Kiel, Germany. Tel.: +49 431 597 1771; fax: +49 431 5497 1659. E-mail address: m.siniatchkin@pedneuro.uni-kiel.de (M. Siniatchkin). 0920-1211/$ see front matter 2006 Published by Elsevier B.V. doi:10.1016/j.eplepsyres.2006.07.001

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and leads to an acidication of the extracellular uid (Leniger et al., 2002). This results in a reduction of the inward currents operated by NMDA receptors and calcium currents, causing a depression of intrinsic neuronal excitability (Iijima et al., 1986; Tang et al., 1990). Sulthiame has also been found to alter voltage-operated sodium currents (Madeja et al., 2001) and to reduce the concentration of the excitatory neurotransmitter glutamate (Patsalos and Lascelles, 1981) in the hippocampus of rats and guinea pigs, as well as the concentration of the inhibitory neurotransmitter -aminobutyric acid (GABA) in cerebral hemispheres of mice (Saad, 1976). However, it is still unclear which effect accounts for the anticonvulsant properties of sulthiame in humans. Transcranial magnetic stimulation (TMS) of the intact human motor cortex offers an array of measures, which can be used to investigate distinct aspects of cortical excitability. For instance, the threshold intensity that is necessary to induce a motor response (motor threshold) depends on the axonal excitability of the cortical neuronal elements that are primarily activated by the transcranial magnetic stimulus, while other TMS measures allow to assess distinct forms of inhibitory and excitatory synaptic excitability (Ziemann et al., 2004). This array of TMS measures has been successfully used to characterize the mode of action of antiepileptic drugs (AEDs) in vivo (Ziemann, 2004). Several TMS studies have consistently shown that drugs which block voltage-gated sodium channels such as carbamazepine (Ziemann et al., 1996; Schulze-Bonhage et al., 1996), phenytoin (Mavroudakis et al., 1994; Chen et al., 1997), lamotrigine (Ziemann et al., 1996a; Boroojerdi et al., 2001; Tergau et al., 2003), and levitiracetam (Reis et al., 2004) primarily increase the motor threshold without producing consistent effects on paired-pulse inhibitory and excitatory synaptic excitability. Conversely, AEDs with GABA-ergic and glutamate-antagonistic properties such as topiramate (Reis et al., 2002), vigabatrin (Mavroudakis et al., 1997) and diazepam (Inghilleri et al., 1996) have no effect on the motor threshold but modify measures of intracortical synaptic excitability such as short-latency intracortical inhibition (SICI) or intracortical facilitation (ICF). Additionally, some GABA-ergic compounds such as lorazepam (Ziemann et al., 1996b) and tiagabin (Werhahn et al., 1999) increase the duration of the cortical silent period (CSP), which is thought to depend on synaptic

excitability of GABA-B ergic circuits (Siebner et al., 1998). In the present study, we used an array of well-dened TMS measures to characterize the acute effects of sulthiame on motor cortex excitability in healthy adults. We reasoned that the prole of acute excitability changes would provide important insights into the anticonvulsant mode of action of sulthiame.

2. Subjects and methods 2.1. Subjects Eleven healthy, right-handed volunteers (seven man and four women, mean age 28.7 7.9, range 2242 years) were recruited from the hospital staff. All subjects fullled the following criteria: no metallic implants or electrical devices, no previous history of any neurological or psychiatric disorder, drug abuse, or alcoholism. Participants were interviewed about their state of health and were not taking any medication on the days of experiment. None of the subjects had any experience with AEDs and TMS. All gave written informed consent. The study was conducted according to the Declaration of Helsinki and was approved by the institutional review board. 2.2. Measures of motor cortex excitability TMS measurements were performed according to the procedures that have been used in previous neuropharmacological TMS studies (Reis et al., 2002, 2004; Tergau et al., 2003; Ziemann et al., 1996a, b). TMS was given to the right primary motor hand area using a standard gure-of-eight-shaped coil and a Magstim 200 magnetic stimulator (Magstim, Whitland, Dyfed, UK, peak magnetic eld 2.2 T). The magnetic stimulus had a nearly monophasic pulse conguration with a rise time of approximately 100 s, decaying back to zero over approximately 0.8 ms. The coil current during the rising phase of the magnetic eld owed toward the handle. The coil was placed tangentially to the scalp with the handle pointing antero-medially at a 45 angle from the midline. The monophasic stimulus induced a current in the brain owing from posterior to anterior, approximately perpendicular to the central sulcus. We determined the optimal position for

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stimulation by moving the coil in 0.5 cm steps around the presumed primary motor hand area. The coil was placed over the site where slightly suprathreshold stimuli evoked a maximal EMG response in the relaxed left APB muscle (referred to as motor hot spot). The motor hot spot was marked with a pen by drawing a semilunar line following the anterior bifurcation of the coil and a straight line indicating the orientation of the coil handle. This enabled us to maintain a constant coil position throughout the experiment. Motor-evoked potentials (MEP) were recorded with Ag/AgCl surface EMG electrodes (9 mm diameter) from the left abductor policis brevis (APB) muscle using a belly-tendon montage. The EMG raw signal was amplied (EMG device Neuropack 2, Nihon Kodhen, Shinjukuku, Tokyo, Japan), bandpass-ltered (1 Hz10 kHz), digitized at a frequency of 5 kHz, and stored on a PC (CED 1622 Micro and Signal 3.0 software, Cambridge Electronic Design, Cambridge, UK). The absence of any voluntary activity in the APB muscle was continuously monitored to ensure complete relaxation throughout the TMS measurements. First, we measured the resting motor threshold (RMT), which has been used in previous neuropharmacological studies to probe drug induced changes in cortical axonal excitability (Ziemann et al., 2004). The RMT was dened as the minimum stimulation intensity necessary to induce a MEP in ve out of 10 consecutive trials (Rossini et al., 1999). During measurements of RMT, we rst used a suprathreshold intensity, which was gradually reduced in 1% steps of maximal stimulator output until this criterion was met. We did not perform additional measurements of the motor threshold during tonic pre-activation of the target muscle because in previous neuropharmacological TMS studies, drug effects always produced analogous changes in motor threshold at rest and during tonic pre-activation (Ziemann et al., 1996a; Manganotti et al., 1999; Reis et al., 2004). To estimate the relationship between stimulus intensity and the MEP amplitude, we applied single-pulse stimuli at 110%, 130% and 150% of individual RMT. At any stimulus intensity, we recorded 10 consecutive MEPs in the relaxed APB muscle. For any stimulus intensity, the mean MEP amplitude was calculated to estimate the stimulusresponse curve. The same TMS protocol was repeated while participants performed a moderate tonic contraction of the left APB muscle at

20% of maximum force level. We recorded 10 consecutive EMG traces (400 ms) which were triggered by single-pulse TMS at 110%, 130% and 150% of individual RMT. The duration of the cortical silent period (CSP) was measured in each trial and dened as the period between the rst turning point of the MEP and the rst reoccurrence of voluntary EMG activity. The mean duration of the CSP was calculated for any intensity of stimulation. The paired-pulse technique described by Kujirai et al. (1993) was employed to probe intracortical excitability of the right motor cortex Paired magnetic pulses were generated by two high power Magstim 200 stimulators connected by a Bistim module and delivered to the motor hot spot through the same gure-ofeight coil that was used for single-pulse TMS (Magstim Company, Whitland, Dyfed, UK). The intensity of the conditioning stimulus was adjusted to 70% of individual RMT, while the intensity of the test stimulus was set at 120% of individual RMT. Paired-pulse TMS used interstimulus intervals (ISIs) of 2 or 15 ms. An ISI of 2 ms was chosen to assess intracortical inhibition (ICI), and an ISI of 15 ms was used to probe intracortical facilitation (ICF). In addition, we applied single pulses at 120% of RMT without a conditioning stimulus (i.e. test stimulus alone). Stimulation conditions were pseudorandomly intermingled and 15 MEPs were recorded for each stimulation condition. The inter-trial interval was randomly jittered between 7 and 15 s. To measure the relative strength of ICI and ICF, the amplitudes of the conditioned MEPs were measured from peak to peak (mV) and averaged for each condition. Mean peak-topeak amplitude of the conditioned MEP responses were expressed as a percentage of the unconditioned MEP response (=100%). 2.3. Experimental procedures and statistics Using a placebo-controlled, cross-over study design, we measured corticomotor excitability immediately before and 2 h after a single oral dose of 5 mg/kg sulthiame or placebo. Each subject participated in two measurements (verum versus placebo), which were performed in a counterbalanced order at least 1 week apart. The dosage of sulthiame as well as the timing of TMS was based on the known pharmacokinetics and pharmacodynamics of sulthiame. The commonly prescribed single oral dosage is 5 mg/kg, and the

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maximal dose of sulthiame is 10 mg/kg a day divided into two single dosages (Bast et al., 2003; Debus and Kurlemann, 2004; Gross-Selbeck, 1995; Rating et al., 2000). TMS measurements were performed 2 h after a single oral dose of sulthiame or placebo, because peak concentrations and the maximal effect is reached approximately 2 h after drug intake (May et al., 1991). Though blinded assessment of cortical excitability would have been desirable, this was not possible in the present study because almost all subjects exhibited obvious side effects after taking sulthiame but not after placebo medication. These side effects included mild hyperventilation, paraesthesia, nausea, restlessness but none of the participants reported signicant sedation. However, since the within-subject testretest reliability of TMS measures has shown to be high (Maeda et al., 2002; Wassermann, 2002; Malcolm et al., 2006), unblinded assessment of corticospinal excitability was still reliable. It should also be noted that we had no a priori prediction regarding the pattern of excitability changes caused by sulthiame, which might have biased the experimenter towards a specic change in excitability. Because the data were normally distributed and characterized by homogenous variances (KolmogorovSmirnoff test), ve separate repeatedmeasures analyses of variance (ANOVA) were performed using the RMT, stimulusresponse curve, CSP, ICI and ICF as dependent variables. The ANOVA model was two-factorial with the within-subject factors time of measurement (before medication versus 2 h after medication) and drug (sulthiame versus placebo). For the stimulusresponse curve and the CSP measurements, the intensity of TMS

was included as additional factor in the ANOVA model. Signicance level was corrected for multiple comparisons using the Bonferroni method and was accepted at p < 0.010.

3. Results and discussion Table 1 summarizes the mean data for each experimental condition. Using the RMT as dependent variable, ANOVA revealed no main effect of time of measurement or drug for any measure of corticomotor excitability (p > 0.2). There was, however, an interaction between time of measurement and drug [F (1, 11) = 13.57; p = 0.004]. Fig. 1 illustrates individual changes in RMT after a single dose of sulthiame and placebo. Sulthiame led to an increase in the motor threshold in nine out of 11 participants, whereas placebo had no consistent effect on the RMT. For the other measures of corticomotor excitability, ANOVA showed no main effects time of measurement and drug as well as no interaction between time of measurement and drug (p > 0.2) indicating that sulthiame specically increased the RMT without modifying the stimulusresponse curve, ICI, ICF or CSP compared with placebo. The main effect intensity of TMS was signicant for both the CSP duration [F (2, 22) = 67.12, p < 0.001] and MEP amplitudes within the stimulusresponse curve [F (2, 22) = 18.74; p < 0.001]. This effect underlines the validity of TMS data demonstrating a signicant increase of the CSP duration and MEP amplitude with increasing TMS intensity. There were no signicant interaction between intensity of TMS and other factors.

Table 1 Means and SD of TMS measures of corticospinal excitability before and 2 h after a single dose of sulthiame or placebo Sulthiame Before medication RMT (% of stimulator output) MEP at 110% (mV) MEP at 130% (mV) MEP at 150% (mV) CSP at 110% (ms) CSP at 130% (ms) CSP at 150% (ms) ICI (conditioning/test ratio) ICF (conditioning/test ratio) 43.3 0.29 0.86 2.13 73.3 113.1 144.3 0.30 1.35 5.7 0.19 0.47 1.29 35.5 44.4 45.4 0.16 0.25 During medication 45.8 0.37 1.14 2.15 78.2 124.1 145.9 0.41 1.53 5.6 0.13 0.97 1.41 31.7 43.3 49.2 0.24 0.58 Placebo Before medication 42.2 0.33 0.81 1.98 93.3 137.3 163.3 0.46 1.47 5.9 0.16 0.46 1.51 29.2 37.3 40.3 0.31 0.92 During medication 42.1 0.35 1.12 1.99 85.5 139.7 154.8 0.57 1.39 5.8 0.18 0.98 1.83 30.9 43.2 45.9 0.47 0.56

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Fig. 1. Resting motor thresholds before and 2 h after a single oral dose of sulthiame (A) or placebo (B) in 11 healthy subjects.

Our results show that a single dose of sulthiame causes an acute decrease in axonal excitability as indexed by an increase in RMT, but did not modify TMS measures of intracortical synaptic excitability. This prole is identical to the acute cortical effects of anticonvulsive drugs that block voltage-gated sodium channels (Boroojerdi et al., 2001; Chen et al., 1997; Mavroudakis et al., 1997; Reis et al., 2004; SchulzeBonhage et al., 1996; Tergau et al., 2003; Ziemann et al., 1996a). Though we did not assess changes in spinal and peripheral excitability, we propose that sulthiame inuences the excitability of cortico-cortical and cortico-spinal axons because previous studies did not demonstrate any effect of sodium channel blockers on spinal or peripheral excitability (Ziemann et al., 1996; Boroojerdi et al., 2001). It is also unlikely that the increase in RMT was caused by an unspecic sedative effect of sulthiame, because sulthiame produced no or little sedation in our participants. Moreover, other sedative antiepileptic drugs, which inuence the GABAergic system have no effect on the motor threshold but modify the strength of intracortical inhibition or facilitation (Ziemann, 2004). In the present study, hyperventilation was a frequent side effect of sulthiame. This begs the question whether drug induced hyperventilation contribute to the changes in RMT after sultiame intake? Several studies have used TMS to assess the impact of hyperventilation on corticospinal excitability in healthy subjects. These studies reported an increase in MEP amplitude at rest (Kukumberg et al., 1996; Seyal et al., 1998) or a shortening of the CSP (Priori et al., 1995), but found no effects on RMT. Since a single dose of sulthiame

produced no effects on the mean MEP amplitude and the duration of the CSP, the increase in RMT cannot be attributed to hyperventilation. Our results would be compatible with the notion that sulthiame exerts its anticonvulsive effect in humans by reducing the conductivity of voltage-gated sodium channels. In good agreement with this hypothesis, sulthiame has been shown to reduce voltage-operated sodium currents in isolated hippocampal neurons from guinea pig (Madeja et al., 2001). This mechanism blocked the generation of repetitive action potentials in cortico-cortical axonal connections. Leniger et al. (2002) demonstrated that sulthiame induces a modest intracellular acidication of CA3 hippocampal neurons. This acidication was accompanied by a reversible decrease in epileptiform activity, which was related to blocking axonal bursts of action potentials. The shift in intracellular pH value has been shown to produce multiple inhibitory effects on the function of sodium and calcium channels (Traynelis, 1998). Therefore, we propose that the inhibition of carbonic anhydrase activity lowers the intracellular pH and thus, reduces the amount of transmembrane ion currents and increases the threshold for generating action potentials. This mechanism may explain the selective increase in RMT after a single oral dose of sulthiame.

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