Neurol Sci (2004) 25:83–90
DOI 10.1007/s10072-004-0234-3
ORIGINAL
M. Turazzini • P. Manganotti • R. Del Colle • M. Silvestri • A. Fiaschi
Serum levels of carbamazepine and cortical excitability
by magnetic brain stimulation
Received: 19 December 2003 / Accepted in revised form: 22 February 2004
Abstract We investigated the correlation between serum lev-
els of carbamazepine (CBZ) and motor excitability studied by
different parameters of transcranial magnetic stimulation
(TMS) in patients at the beginning of antiepileptic treatment. A
total of 10 patients with complex partial seizures following
stroke were treated with loading doses of CBZ. Motor evoked
potential (MEP) was recorded from the thenar eminence (TE)
muscles of the unaffected arm. In all patients, we studied rest
and active motor threshold (rMT, aMT), MEP amplitude and
cortical silent period (CSP). In three patients, intracortical inhi-
bition (ICI) and intracortical facilitation (ICF) were measured
using paired TMS at short interstimulus intervals (1–25 ms).
The recording sessions were performed before treatment and
after 7, 15 and 60 days (SD=16 days). Serum level of CBZ
were monitored at each recording session. We observed a pro-
gressive increase in rMT and aMT until the serum levels of
CBZ reached a steady state condition. No significant changes
were observed in MEP amplitude, CSP, ICI and ICF. This
study documents the increase of both motor threshold and drug
serum levels in patients treated with loading doses of CBZ,
suggesting a relationship between drug metabolism and the
effect on motor cortical excitability.
Key words Transcranial magnetic stimulation
Carbamazepine • Epilepsy • Stroke
M. Turazzini () • R. Del Colle • M. Silvestri
Department of Neurology
Mater Salutis Hospital of Legnago
Via Gianella 1, I-37045 Legnago (VR), Italy
e-mail: mturazzini@katamail.com
P. Manganotti • A. Fiaschi
Department of Neurological Sciences and Vision
Neurological Rehabilitation Section
University of Verona
Verona, Italy
Introduction
Transcranial magnetic stimulation (TMS) of the brain is used
to evaluate the pharmacological effects of antiepileptic drugs
on the excitability of corticospinal motor pathways in humans
[1–5]. Differently from other neurophysiological techniques
such as electroencephalography, TMS allows a more com-
plete evaluation of cortical excitability through the study of
several parameters representing specific measures of this
excitability, such as motor threshold (MT), motor evoked
potential (MEP) amplitude, cortical silent period (CSP), intra-
cortical inhibition (ICI) and intracortical facilitation (ICF).
It is currently thought that MT mainly reflects the excitabil-
ity of neuronal membranes since voltage-gated sodium- or cal-
cium-channel blockers increase motor thresholds (6–8). MEP
amplitude is related to the number of corticospinal neurons that
are activated at a given stimulus intensity [6]. The CSP evoked
by TMS is related to long-lasting inhibitory GABA-ergic mech-
anisms at cortical level of the motor cortex [9] and is modified
by GABA-ergic and dopaminergic drugs [10–14]. Intracortical
inhibition and facilitation reflect, respectively, the decrement
and the potentiation of MEP amplitude observed at determined
interstimulus intervals (ISIs) in paired TMS [15]. This proce-
• dure allows the measurement of intracortical inhibition and
intracortical facilitation that many reports suggest are the reflec-
tion of the excitability of short inhibitory and facilitatory
interneuronal circuits within the motor cortex [6, 16–18]. In nor-
mal subjects, single oral doses of several GABAergic drugs
(e.g. benzodiazepines, baclofen, ethanol) enhanced ICI [6, 16,
17]. In contrast, ICF seems to be dependent on mechanisms
related to glutamate. In fact, in normal subjects the administra-
tion of single doses of riluzole (a glutamate antagonist [18]) and
of dextromethorphan (a non-competitive N-methyl-D aspartate
antagonist [17]), suppressed ICF. Moreover, antiepileptic drugs
increased motor threshold in treated patients [1, 2, 19, 20].
Single oral doses of phenytoin, carbamazepine (CBZ), lamot-
rigine and losigamone in normal subjects significantly increased
motor threshold within a few hours, followed by a rapid return
to baseline values [5, 21–23], without effect on ICI and ICF [5,
84
21]. Nevertheless, few studies have monitored the long-term
effects on motor excitability in normal subjects and in epileptic
patients during loading doses of anticonvulsive medication and
the possible relation with the serum concentration of the drug.
Only one study using TMS has reported changes in brain
excitability related to drug plasma levels in a small number
of normal subjects after a single dose of phenytoin [22],
while no information exists for patients at the onset of
antiepileptic treatment. The effects of loading doses of lam-
otrigine on motor excitability using TMS have been docu-
mented in epileptic patients in our previous study, but drug
serum levels were not available [8].
The aim of this study was to monitor motor excitability
measured by different parameters of TMS during loading
doses of CBZ in epileptic patients at the beginning of treat-
ment and to study the correlation with drug plasma levels.
We studied a group of patients suffering from complex par-
tial seizures following cerebrovascular accidents and treated
for the first time with carbamazepine.
Patients and methods
The study enrolled 10 patients (mean age, 60.8 years; SD=12.9
range, 40–74; 6 men) in a chronic condition after hemispheric
stroke (time since stroke ranged from 5 to 9 months). The study and
the tests were performed according to the Helsinki declaration.
Two of the 10 patients presented visual and coordination problems.
Eight patients at the time of the stroke had suffered severe hemi-
paresis with complete loss of hand function. By the time TMS
recording was performed, four of them showed a good recovery
with either completely normal hand function or only minor resid-
ual coordination problems. The remaining patients presented
incomplete recovery with a significant reduction of hand function.
All patients gave informed consent to participate in the study, and
the study was approved by the hospital’s ethics committee.
The patients were given CBZ as anticonvulsant treatment for
epileptic seizures that followed the cerebrovascular accident.
Complex partial seizures occurred in a range between 5 and 9
months after the stroke. Two patients had already been treated with
CBZ but, because a low compliance, therapy was suspended and
reinstated after a second seizure occurred. None of the subjects
complained of seizures before the stroke. For blood work-up and
CBZ measurement the EMIT method on serum with “ACA IV”
Dupont instrument was used.
CBZ treatment was initiated at 400 mg in two doses on the first
two days, followed by 600 mg in three doses for the next 2 days
and 800 mg in three doses thereafter. The daily maintenance regi-
men was 800 mg in three doses.
TMS was performed in four sessions: before drug administra-
tion as baseline, after 7 and 15 days of treatment, and after a peri-
od ranging from one to three months of treatment (mean, 60 days;
SD=16 days). Drug serum levels were tested in all sessions. Blood
samples were taken 30 minutes before each TMS recording.
Electroencephalography (EEG) was performed at the first and last
TMS recording sessions in all patients. TMS recording sessions
were performed with methods in conformity with our previous
paper [8]. The TMS recording sessions lasted for a mean of 30 min
and at least 100 stimuli were delivered to each patient.
M. Turazzini et al.: Serum carbamazepine and motor excitability
TMS Study
Different TMS parameters were used to measure the excitability of
motor areas:
1. The threshold intensity, expressed as a percentage of stimulator
output, was approached from slightly suprathreshold intensities
by reducing the stimulator intensity of 1% steps and was defined
as the lowest stimulator output intensity capable of inducing
MEPs of at least 50 µV peak-to-peak amplitude in the target mus-
cles in at least half of 10 trials in conformity with several studies
[3, 24, 25]. This was done at rest (rest motor threshold, rMT) and
with the target muscles preactivated at about 5% of maximum
strength (active motor threshold, aMT) [11]. The high gain dis-
play used for motor threshold determination (50 µV) allows iden-
tification of MEPs of 35 µV or higher. It is currently thought that
MT mainly reflects the excitability of neuronal membranes since
voltage-gated sodium- or calcium-channel blockers increase
motor thresholds [5].
2. The recruitment curve of MEP amplitude. MEPs were recorded
at rest with stimulator output intensities of 10%, 20% and 30%
above the motor threshold. A total of 10 stimuli were delivered to
target muscles at each of the three stimulus intensities in each ses-
sion. The MEP peak-to-peak amplitude as elicited by TMS was
expressed as the percentage of compound motor action potential
(cMAP) of the target muscle elicited by peripheral stimulation of
the median nerve at the wrist for thenar eminence (TE) muscles.
This parameter was used in a previous study [26] to avoid errors
in measuring MEP peak-to-peak amplitude due to different place-
ment of the electrodes in multiple recording sessions. MEP
amplitude is related to the number of corticospinal neurons that
are activated at a given stimulus intensity [5].
3. The duration of the cortical silent period (CSP) was deter-
mined at stimulus intensities of 10%, 20%, and 30% above
aMT in the TE muscles contracting at 10%–20% of maximum
strength. CSP was measured in the single trial rectified elec-
tromyography (EMG) recordings from the end of the preced-
ing MEP to the onset of sustained voluntary EMG activity.
Averages of 7 trials were calculated for each stimulus intensi-
ty. CSP is related to long-lasting inhibitory mechanisms at the
cortical level of the motor cortex [9].
4. ICI and ICF were measured in 3 patients by generating a sub-
threshold conditioning stimulus set at 5% of maximum stimu-
lator output below aMT and delivering it through the same
magnetic coil at interstimulus intervals (ISIs) of 1, 2, 3, 4, 5, 6,
7, 10, 15, 20, 25, 30 ms before a suprathreshold test stimulus.
The test stimulus intensity was adjusted to 10%–15% of max-
imum stimulator output above rMT [23–26]. Averages of the
single trial peak-to-peak MEP amplitudes were calculated and
changes in the mean control MEP size produced by the condi-
tioning stimulus were expressed as a percentage of the uncon-
ditioned mean. The early ICI and the ICF were then calculated
by averaging the ratios across ISIs of 1–4 and 7–15 ms respec-
tively [17]. This procedure allows the measurement of intra-
cortical inhibition and intracortical facilitation that many
reports suggest are the reflection of the excitability of short
inhibitory and facilitatory interneuronal circuits within the
motor cortex [5, 15–17].
In order to study the effect of CBZ on motor conduction time,
the latency of MEP was evaluated. Cervical stimulation was per-
formed with the coil centered between spinous processes C5 and
C6. Current coil flowed counterclockwise. Central conduction
time (CCT) was obtained by subtracting cortical and cervical MEP
onset latencies.
M. Turazzini et al.: Serum carbamazepine and motor excitability 85

a
Serum carbamazepine, µg/l

Baseline 7 days 15 days 60 days

TMS recording session

b
Rest motor threshold, %

Baseline 7 days 15 days 60 days

TMS recording session

c
Active motor threshold, %

Figure 1a-c Carbamazepine levels in serum and

parameters of motor excitability in 10 patients with
seizures. a Serum carbamazepine. b Rest motor
threshold of unaffected thenar eminence muscle,
expressed as percentage of maximum stimulator out-
put. c Active motor threshold of unaffected thenar
Baseline 7 days 15 days 60 days eminence muscle, expressed as percentage of maxi-
mum stimulator output. Values are expressed at
TMS recording session baseline (prior to treatment), at 7 and 15 days, and at
a mean of 60 days (SD=16 days) of treatment
86
In order to study the effect of CBZ on spinal excitability and on
peripheral nerve conduction, F and M waves were evaluated. F
responses were elicited by supramaximal stimulation of the median
nerve at the wrist at 1-second intervals and recorded from TE muscles
using a bandpass of 100–5000 Hz. For each set of 15 stimuli, we mea-
sured the absolute M-wave latency, the mean F-wave latency and
amplitude, and the F-wave persistence [27]. Skin temperature was
measured over the forearm and hand before each session.
Statistical analysis
Data for rest and active motor thresholds were analyzed using one-
way ANOVA with the recording sessions as main factor, with post-hoc
comparisons to identify significant interactions. The differences were
considered significant if p<0.05. Mean MEP amplitude, cortical silent
period duration, F-wave amplitude and F-wave persistence were com-
pared using Wilcoxon’s signed ranks test. MEP and M-wave and F-
wave latencies were compared using a paired t test.
Results
We used transcranial magnetic stimulation (TMS) to monitor
motor excitability in 10 patietns starting therapy with carba-
mazepine (CBZ) for complex partial seizures that developed
5–9 months after hemispheric stroke.
Serum CBZ levels reached mean values of 6.1 µg/ml
(SD=1.8) after 7 days, 9.8 µg/ml (SD=1.1) after 15 days, and
11 µg/ml (SD=1.5) after 60 days treatment (Fig. 1a). The range
of our laboratory is from 8 to 12 µg/ml in the epileptic patiens
treated with CBZ. No patient complained of seizures after the
beginning of treatment. Only two patients had transient dizzi-
ness during the rapid increase of CBZ from 400 to 800 µg/day.
During recording sessions the analysis of serum levels
revealed significant effects (F2,18=67.2; p<0.001). The subjects
showed a significant increase of serum CBZ levels (mean val-
MEP amplitude, % of cMAP
Baseline 7 days 15 days
M. Turazzini et al.: Serum carbamazepine and motor excitability
ues 6.1 µg/ml) recorded at the first week of treatment in com-
parison to those obtained (mean values 9.8 µg/ml) at the second
week of treatment (p<0.001). No significant differences were
observed in drug serum levels recorded at the second week of
treatment in comparison to those recorded after 1–3 months of
medication.
Rest and active motor thresholds in unaffected TE muscles
progressively increased from baseline to 15 days (Fig. 1b, c).
Analysis of the rest and active motor threshold of unaffected
TE muscles revealed significant effects during recording ses-
sions (rest MT: F3,27=43.8; p<0.001. Active MT F3,27=50.7;
p<0.001). Changes in rest and active MT values between base-
line and the second session (7 days) and between the second
and third sessions (15 days) were significant (p<0.001). No sig-
nificant change in rest or active MT was observed between the
third and the fourth sessions (Fig. 1b, c).
MEP amplitudes of TE muscles, elicited using stimulator
output intensities of stimulation 10%, 20% and 30% above the
rest motor threshold, were not significantly different at the four
recording sessions (Fig. 2). The MEP amplitude recorded from
TE muscle using a stimulator output intensity 10% above the
motor threshold showed a tendency to decrease in the last
recording session. This finding however was not consistent in
all the subjects (Fig. 2).
No significant changes in cortical silent period obtained
with stimulator output intensities of 10%, 10%, 20% and 30%
above aMT were observed across the recording sessions (Fig.
3). Similarly, no significant changes were observed for ICI and
ICF across the recording sessions (Fig. 4).
Absolute latencies of MEP obtained after cortical stimula-
tion did not change, and no significant changes in central con-
duction time were observed (Table 1). Absolute M-wave and
mean F-wave latencies as well as the amplitude and persistence
of F wave did not change during drug treatment.
No paroxymal activity was observed in the EEG recordings
of any patient.
Fig. 2 Motor evoked potential (MEP)
amplitude values recorded from
thenar eminence (TE) muscles and
obtained at 10%, 20% and 30% of
stimulator output intensity. MEP
amplitudes are expressed as percent-
age of peripheral compound motor
action potential (cMAP). Values are
60 days
mean and standard error of 10 sub-
jects treated with carbamazepine
M. Turazzini et al.: Serum carbamazepine and motor excitability 87

CSP, ms
Fig. 3 Cortical silent period (CSP) recorded from TE
muscles and obtained at 10%, 20% and 30% of stim-
ulator output intensity. Values are mean and standard Baseline 7 days 15 days 60 days
error for 10 patients treated with carbamazepine

a b

Fig. 4a,b Intracortical inhi-

bition (a) and intracortical
facilitation (b) averaged
ICI, %

across inhibitory interstim-

ICF, %

ulus intervals of 1–5 ms

and facilitatory intervals of
7–15 ms, respectively.
Values are expressed as the
ratio of conditioned motor
evoked potential (MEP) to
control MEP amplitudes.
Baseline 7 days 15 days 60 days Baseline 7 days 15 days 60 days Values are expressed for 3
Recording session Recording session patients treated with carba-
mazepine

Table 1 Effect of carbamazepine treatment for seizures on spinal excitability and peripheral nerve conduction. Values are mean (SD) for
10 patients. Measurements at the four time periods are not significantly different

Baseline Day 7 Day 15 Day 60a

MEP latency, ms 24.0 (1.5) 24.0 (1.3) 24.0 (1.6) 24.0 (1.4)
CCT, ms 9.3 (0.9) 9.3 (0.7) 9.1 (0.7) 9.3 (0.7)
M-wave latency, ms 4.7 (1.9) 4.3 (1.8) 4.5 (1.3) 4.5 (1.3)
F-wave latency, ms 32.3 (2.9) 31.3 (2.2) 33.3 (1.2) 32.5 (1.5)
F-wave amplitude, µV 100 (10) 100 (20) 100 (15) 100 (15)
F-wave persistence, % 90 (5) 90 (5) 90 (6) 90 (4)
a Mean values (SD=16 days)

MEP, motor evoked potential; CCT, central conduction time

88
Discussion
The present study documents that treatment with CBZ pro-
duced changes in motor cortex excitability in epileptic patients
and that these changes were associated with increased drug
serum levels. Although numerous studies have evaluated the
effects of drugs on the drug effect on motor response evoked
by TMS [1, 19–21, 28], few have evaluated the long-term phar-
macological effects on motor excitability in patients at the
beginning of anticonvulsant treatment.
The patients in this study received anticonvulsant treat-
ment because of seizures after a focal cerebrovascular lesion.
The occurrence of epileptic seizures after a cerebrovascular
accident is well documented [29–33]. Fibrotic processes and
rearrangement of the central nervous system have been pos-
tulated as possible causes [29–33]. In addition, changes in
excitability of the motor areas of both hemispheres have
been documented by TMS studies in patients affected by
stroke during the recovery period [34–36].
The main finding of this study is that the motor threshold
in distal muscles is significantly increased after only one
week of treatment in all subjects. A further increase in motor
threshold was observed in all subjects at the end of the sec-
ond week of treatment, associated with increased serum CBZ
evels. The achievement of a steady state of serum CBZ lev-
els was parallel to that of stable levels of “excitability” as
measured by TMS. A similar trend between MT and serum
CBZ suggests the particular sensitivity of MT to the phar-
macokinetics of the drug, which usually reaches a steady
state level in a short time [37].
The sensitivity of TMS to pharmacological action is due
to the characteristics of the TMS technique which, at low
intensity, activates the corticospinal neurons trans-synapti-
cally [38, 39]. In this study, motor threshold was the most
sensitive parameter to the drug’s effect in comparison to the
other TMS parameters evaluated. Motor threshold is
believed to reflect the excitability of horizontal axonal ele-
ments oriented parallel to the direction of the induced current
and projecting into the motor cortex and the post-synaptic
targets within the motor system [40]. Sodium- and calcium-
channel blockers such as CBZ and lamotrigine (LTG)
increase motor threshold, while drugs with GABAergic
properties without modulatory effects on ion channels (e.g.
vigabatrin) do not affect motor threshold [5, 9]. It is plausi-
ble, therefore, that the motor threshold, as determined by
TMS, primarily depends on mechanisms at the neuronal
membrane that regulate the firing of action potentials.
It is important to note that the long-term effect of CBZ on
brain excitability has been documented only with electrical
stimulation in cats [41] and monkeys [42].
The fact that no seizures were reported during the 1-3
months of treatment in any of the patients examined suggests
a relationship between changes in motor threshold and the
efficacy of treatment. Although most patients complained of
only one seizure before the antiepileptic treatment, two
M. Turazzini et al.: Serum carbamazepine and motor excitability
patients experienced a second seizure when CBZ therapy
was voluntarily stopped.
The MEP amplitude, expressed as a percentage of periph-
eral cMAP, remained unchanged at low- and high-intensity
stimulation throughout the recording sessions. The stable
MEP amplitude obtained at intensities 10%, 20% and 30%
above motor threshold stimulation, despite the motor thresh-
old increase, may be attributed to the adaptation of magnet-
ic stimulation intensity to the individual motor threshold dur-
ing each session.
In contrast to previous studies [5, 29], which reported a
lengthening of the cortical silent period, in our study no con-
sistent changes in cortical silent period were present in any
of the subjects. The silent period, which denotes the inhibi-
tion of sustained muscle contraction observed after TMS, is
mediated by spinal mechanisms during its first part and
probably by supraspinal mechanisms during the second part
[43, 44]. The silent period can be modified by pharmacolog-
ical action: dopamine increases the duration of the silent
period in parkinsonian patients as well as in normal subjects
[45]. GABAergic neuronal pathways are also supposed to
modulate the activity of the motor cortex [46]: benzodi-
azepine significantly shortens the silent period but does not
change the MT [4]. The main mechanism of action of CBZ,
however, is not mediated through GABAergic modulation of
neuronal activity and this may account for the absence of any
modification in silent period duration in our study.
Similar reasoning can be suggested to explain in our
patients the absence of significant effect of CBZ on intracor-
tical inhibition (ICI) and intracortical facilitation (ICF),
which probably underlie GABAergic and glutamaergic
mechanisms [5, 15–18]. Single doses of CBZ did not affect
intracortical inhibition and facilitation [5].
The absence of drug effects on MEP latencies, central
conduction time, on M-wave and F-wave latencies, and F-
wave amplitude and persistence documents that CBZ does
not affect peripheral or central motor conduction and does
not change spinal excitability.
These findings lead us to conclude that CBZ induces a
significant increase in motor thresholds at the cortical level
in the first weeks of treatment in patients with epileptic
seizures. These changes are associated with increased serum
levels of the drug. These observations suggest that TMS may
be an additional tool of research in epilepsy and clinical
pharmacology for monitoring brain excitability during the
early phase of treatment in patients with seizures.
Sommario Scopo di questo studio è stato quello di valutare la
correlazione tra i livelli sierici di carbamazepina (CBZ) e la
eccitabilità corticale motoria, studiata con vari parametri
attraverso la stimolazione magnetica transcranica (SMT), in
pazienti all’inizio del trattamento anticomiziale. Sono stati
valutati 10 pazienti con crisi parziali complesse secondarie ad
ictus cerebrale, che sono stati trattati con dosi crescenti di
M. Turazzini et al.: Serum carbamazepine and motor excitability
CBZ. Sono stati valutati, inoltre, il potenziale evocato motorio
(MEP), registrando dall’eminenza thenar del lato non affetto,
la soglia di eccitabilità corticale sia a riposo (rMT) che con
attivazione (aMT), l’ampiezza del MEP, il periodo silente cor-
ticale (CSP) e, in tre soggetti, anche l’inibizione intracorticale
(ICI) e la facilitazione intracorticale (ICF), usando il doppio
stimolo a brevi intervalli interstimolo (ISI) (1–25 ms); tutte le
registrazioni sono state eseguite a 7, 14 e 60 giorni dall’inizio
del trattamento, così come il dosaggio farmacologico della
CBZ. Si sono evidenziati un progressivo incremento della
soglia di eccitabilità corticale sia a riposo (rMT) che con atti-
vazione (aMT) da quando i livelli plasmatici della CBZ hanno
raggiunto la condizione di “steady state”, mentre non si sono
osservate variazioni significative nell’ampiezza del MEP, nel
CSP, ICI e ICF; questo studio, in conclusione, documenta l’in-
cremento sia della soglia di eccitabilità corticale che dei livel-
li sierici di CBZ in pazienti trattati con dosi crescenti del far-
maco, suggerendo una relazione tra il metabolismo dello stes-
so e l’effetto sulla eccitabilità della corteccia motoria.
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