Transcranial magnetic stimulation (TMS) can be used for
research in epileptic patients, as a safe and painless method of motor
cortex stimulation. TMS has been used to determine the cortical TMS thresholds
in different epileptic syndromes, the effects of anticonvulsant medications
on cortical TMS thresholds, and the localization of seizure foci.
It has been showed that in different epileptic syndromes,
the cortical TMS threshold is lower, the latencies of motor evoked potentials
(MEP) are shorter and the amplitudes are higher than that of normal controls.
These values are reversed in epileptic patients under anticonvulsant medication,
that is, the TMS thresholds are higher, the latencies are longer and the
amplitudes are lower than in normal groups [1-5]. Hufnagel et al.
stated that the duration of epilepsy, localization of epileptic focus
and seizure type did not affect the MEP and also noted that this conclusion
is concordant with the concept of a global cortical disturbance in the
excitation/inhibition balance in many forms of epilepsy [1, 2].
Silent period (SP) following TMS is mainly due to cortical
inhibitory mechanisms [6-10]. It is generally agreed that the first 50
milliseconds of the cortical SP are due to peripheral factors, whereas
the later part involves a cortical inhibitory mechanism . There are
a few studies of SP in epileptic patients [6, 11-13].
In this study, we aimed to differentiate the effect of
antiepileptic drugs on cortical inhibitory mechanisms in different groups
of epileptic patients. In order to evaluate this, cortical SP values in
epileptic patients under medication but with uncontrolled seizures despite
sufficient serum drug levels were compared with cortical SP in unmedicated
epileptic patients, in epileptic patients with controlled seizures under
medication and in normal subjects.
Subjects and method
Sixteen female and 9 male epileptic patients, aged between
11-42 years (mean 23 ± 10) were included in the study. All of the
patients had been followed-up in Bakirköy State Hospital for Psychiatric
and Neurological Diseases, Epilepsy Outpatient Clinic between February
1998 and July 1998. The control group consisted of 14 normal subjects
(9 female and 5 male), aged between 22-38 years (mean 28 ± 5), who
were normal on neurological examination and who had no epileptic seizure
history or neurological disease. Epileptic patients were divided into
Epileptic patients with controlled seizures under medication
(T+; S). When the seizure frequency before the medication had decreased
by at least 50% or more within 3 months of starting medication, seizures
were regarded as controlled. Five female and 4 male (a total of 9 patients),
aged between 14-42 years (mean 25 ± 11) were included in this group.
Epileptic patients with uncontrolled seizures under medication
(T+S+). When the seizure frequency before the medication had decreased
by less than 50%, remained unchanged or increased within the 3 months
after starting medication, seizures were regarded as uncontrolled. There
were 4 female, 2 male (a total of 6 patients), aged between 18-36 years
(mean 28 ± 8) in this group.
Unmedicated epileptic patients with seizures (TS+).
Recently diagnosed epileptic patients having seizures and who had never
received medicated or who had abandoned therapy for at least one year
were regarded as unmedicated. There were 7 female, 3 male (a total of
10 patients), aged between 11-28 years (mean 19 ± 7) in this group.
The seizure types consisted of
simple partial, complex partial, absence, myoclonic, generalized tonic-clonic
seizures and their combinations. These seizure types were distributed
randomly among the three subgroups of epileptic patients.
Carbamazepine was the antiepileptic medication given in
8 patients, valproic acid in 3, carbamazepine + lamotrigine in 1, carbamazepine
+ clonazepam in 1, carbamazepine + phenobarbital in 1 and phenytoin +
phenobarbital in 1.
In medicated patients, antiepileptic drug (AED) plasma
levels were detected before TMS. Having an AED level within therapeutic
range was one of the inclusion criteria for medicated patients.
Cranial magnetic resonance imaging was performed in 14
patients and computerized brain tomography in 5. Imaging results were
abnormal in 5 patients. These involved right mesial temporal sclerosis
in 2 patients, right caudate nucleus ischemic lesion in 1, bilateral pachygyria-polymicrogyria
in 1 and left parietal focal cortical atrophy in 1.
TMS was performed using a 9 cm diameter magnetic coil connected
to Magstim 200 (Magstim Company LTD, Dyfed, UK). Maximum output was 1.5
Tesla. TMS threshold stimulation was defined as the stimulation which
produces at least 3 MUPs of at least 100 µV in five, single, sequential
stimulation. The initial output level for TMS was 30% of maximum output.
Output was increased in steps of 5% until TMS threshold stimulation was
reached. SP measurements were done at TMS threshold stimulation. Hand
dominancy was determined by the Edinburgh Hand Preferency Test. If the
left hemisphere was dominant then, it was stimulated by using face A of
the magnetic coil (counter-clockwise) facing upwards, and if the right
hemisphere was dominant then, it was stimulated by B facing upwards (clockwise).
EEG electrodes were used for recording the MEPs from the
abductor digiti minimi (ADM) muscle, which is contralateral to the stimulated
hemisphere. Recording was done during maximal contraction of the ADM muscle
for measuring SP. During recording, display sweep time of electromyograph
(Medelec Sapphire, Medelec Ltd, Surrey UK) was 100 millisecond, and display
gain was 100 µV/division. Low cut and high cut filters were set to
3 Hz and 5 kHz, respectively.
The unpaired t-test, Mann-Whitney test, ANOVA and Tukey
HSD tests were used for comparisons and statistical analysis. P values
less than 0.05 were accepted for significance.
SP values of the patient and normal groups are shown in
table 1. SP durations
were longer in the TS+ group compared to the normal control group.
The difference between these two groups was statistically significant
in the unpaired t-test (table
2). Comparing the TS+ group to the T+S+ group, the difference
between the SP values was not significant in the unpaired t-test. Similarly,
there was no statistically significant difference between the SP values
for the TS+ and T+S groups. Neither was any significant difference
found between the T+S+ and T+S groups. Comparing multiple groups
to each other in the ANOVA with the Tukey HSD test, the difference between
SP values for the normal control group and the T+S+ group was significant
(table 2). Excluding the
normal group, when SP values for patient subgroups were compared to each
other in the Tukey HSD test, differences were not significant.
Cortical silent period (SP) following transcranial magnetic
stimulation is mainly due to the cortical and peripheral inhibitory mechanisms
[6, 7]. In a study by Cincotta et al., it was found that SP values
for 8 patients with clonic seizures were longer than in the normal group
and also longer than those of 10 patients with cryptogenic partial epilepsy
without clonic seizures. In this study it was also reported that SP durations
recorded from the healthy hemispheres were longer than those of epileptogenic
hemispheres of these patients . The authors claimed that interictal
inhibitory mechanisms were probably overactive in epileptic patients with
partial motor seizures originating from primary motor cortex. Furthermore,
in order to balance the diseased hemisphere by a kind of compensatory
mechanism, this inhibitory effect might be stronger in the healthy hemisphere
than in the epileptic one . Similarly, in our study, mean SP durations
in epileptic patients were significantly longer than that in the normal
group. In addition, SP differed among the patient subgroups. However,
probably due to the small number of patients included in the subgroups,
this difference was not statistically significant. The difference among
the SP of patient subgroups in our study can be interpreted from the same
point of view as in the study of Cincotta et al. . SP of the
medicated patients with controlled seizures were longer than those in
the normal group but shorter than those in the unmedicated patients with
uncontrolled seizures. Therefore, it can be proposed that the cortical
inhibitory mechanisms in unmedicated patients could be overactive in order
to suppress epileptogenic activity, whereas the condition which forces
inhibitory mechanisms is no longer present in medicated patients with
controlled seizures. In medicated patients with uncontrolled seizures,
SP was the longest, probably due to the overactive cortical inhibitory
conclusion, our findings probably indicate the enhanced interictal inhibitory
mechanisms in epilepsy which is resistant to antiepileptic medication. However,
the differences in SP values among the patient subgroups were not statistically
significant. The reason for this could be that the epileptic seizure types
were not homogeneously distributed among the patient subgroups.