ORIGINAL ARTICLES
Intraoperative Risk of Seizures Associated With
Transient Direct Cortical Stimulation in Patients With
Symptomatic Epilepsy
Andrea Szelényi, Boban Joksimovič, Volker Seifert
Summary: Direct cortical stimulation— either with the 60-Hz stim-
ulation or the train-of-five technique—is commonly agreed on being
the gold standard for intraoperative mapping of the motor cortex and
the motor pathways but may result in an intraoperative seizure. The
occurrence of intraoperative stimulation associated seizures with
respect to symptomatic epilepsy was evaluated in a group of 129
patients undergoing tumor resection within the central region. Data
were reviewed with respect to the frequency of seizures with both
stimulation techniques and symptomatic epilepsy. Direct stimulation
of the motor cortex was performed with a train of five consecutive
pulses, an interstimulus interval of 4 ms, an individual pulse width
of 0.5 ms, and 40 mA stimulation intensity at maximum. In 1 of 63
patients (1.6%) presenting with symptomatic epilepsy, a stimula-
tion-associated seizure occurred, and 1 of the other 66 patients
(1.5%) had a seizure (n.s., not significant). In the literature, stimu-
lation associated seizures are reported in 1.2% with the train-of-five
technique and significantly more frequently in 9.5% with the 60-Hz
technique (P ⬍ 0.001). In summary, there is no increased risk of the
occurrence of stimulation-associated seizures during surgery for
patients with symptomatic epilepsy compared with those patients
without.
Key Words: Direct cortical stimulation, Motor evoked potential,
Stimulation-associated seizures, Symptomatic epilepsy.
(J Clin Neurophysiol 2007;24: 39–43)
D uring neurosurgical tumor resection within the vicinity
of the central region, direct cortical stimulation of the
adjacent motor cortex is crucial and essential alike for local-
ization and preservation of the motor function. Being the gold
standard for intraoperative localization of the motor cortex,
two mapping techniques have evolved. The 60-Hz technique
applies stimuli with a 50- or 60-Hz frequency over a period
of 1 to 3 seconds in duration and has been described by
Penfield in the 1930s (Penfield and Boldrey, 1937). This
technique has been proposed as the gold standard for intra-
Klinik für Neurochirurgie, Johann Wolfgang Goethe Universität, Frankfurt,
Germany.
Address correspondence and reprint requests to Andrea Szelényi, MD,
University of Frankfurt, Haus 95–AM Schleusenweg 2–16, Frankfurt/
Main, D-60528, Germany; e-mail: A.Szelenyi@em.uni-frankfurt.de
Copyright © 2007 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/07/2401-0039
Journal of Clinical Neurophysiology • Volume 24, Number 1, February 2007
operative mapping of the motor cortex. The incidence of
stimulation-associated seizures is reported in up to 24%
(Sartorius and Wright, 1997; Yingling et al., 1999).
Taniguchi et al. 1993 introduced a technique applying a
high-frequency (256 to 512 Hz) train of five to seven stimuli
to the cortex and allows the recording of muscle motor
evoked potentials (mMEP). This technique—further referred
to as train-of-five technique—not only allows for mapping of
the motor cortex, it also allows for continuous assessment of
the motor function throughout the tumor resection. Com-
monly, this high-frequency–short-train technique is being
less frequently associated with intraoperative seizures. How-
ever, data reviewing both techniques are lacking.
In adults, first-time seizures (i.e., acute symptomatic
seizures) are frequently the index sign of a brain tumor, and
symptomatic epilepsy is common in patients with brain tu-
mors. This might increase the risk of stimulation associated
intraoperative seizures.
In this study, the incidence of stimulation-associated
intraoperative seizures was evaluated in patients undergoing
tumor surgery in the vicinity of the central region with regard
to symptomatic epilepsy. The data were reviewed with pub-
lished data to assess the incidence of stimulation-associated
seizures with either method.
PATIENTS AND METHODS
In this study, 129 patients (48.4 ⫾ 15.1 years; 58
female, 71 male) were prospectively analyzed. Table 1 lists
patient diagnosis and histologic findings; Table 2 lists the
tumor location.
All surgeries were performed with a total intravenous
anesthesia regimen containing 4 to 7 mg/kg per hour propofol
and 0.2 to 0.5 ␮g/kg per minute remifentanil or 0.3 to 0.5
mg/kg per hour sufentanil. Short-acting muscle relaxants
(rocuronium) were administered for intubation purposes only.
Intraoperative monitoring consisted of somatosensory
evoked potentials (SSEP), mMEPs elicited as well by trans-
cranial electrical stimulation (TES) as by direct cortical
stimulation (DCS).
Muscle motor evoked potentials were elicited with a train
of five pulses consisting of constant current anodal, monopolar,
square-wave pulses of 0.5 ms width and an interstimulus interval
of 4 ms (Osiris, Inomed Co., Teningen, Germany). The maxi-
mum current for DCS was in general limited to 25 mA, but in
39
Szelényi et al. Journal of Clinical Neurophysiology • Volume 24, Number 1, February 2007
TABLE 1. Histological Diagnosis in 129 Patients
Histological Diagnosis No of Patients [n]
Astrocytoma 40
Glioblastoma 44
Oligoastrocytoma 6 Before surgery, 63 of 129 (48.8%) patients presented
Metastasis 9 with seizures, whereas 66 (51.2%) patients presented with
Meningeoma 20
Ependymoma 2 During surgery, in one patient of those 63 (1.6%)
Others 8 patients with symptomatic epilepsy, a stimulation-associated
Total 129
TABLE 2. Tumor Location in 129 Patients
Tumor Location No of Patients [n]
Precentral and central 60
Frontal 31
Insular 8 nately, the serum level was not taken within the perioperative
Parietal 18
Temporal invading basal ganglia or 12
internal capsule
Total 129
some cases the stimulation intensity for mapping only was
increased to 40 mA. Pairs of needle electrodes were used for
recording of mMEPs from the following muscles contralateral to
the side of stimulation: abductor pollicis brevis, biceps brachii,
extensor digitorum communis, and tibial anterior muscles. In
case of parasagittal located lesions, mMEPs were also recorded
from abductor hallucis muscles and in case of lateral located
lesions, from the abductor digiti minimi and genioglossus mus-
cles. For recording of mMEPs either the EWACS or the ISIS
system (Inomed Co., Teningen, Germany) were used.
After dura opening, the technique of phase reversal was
used to determine the central sulcus by placing a four-contact
strip electrode (individual electrode diameter, 0.4 cm; Inomed
Co., Teningen, Germany) tangentially over the central sulcus.
Thereafter, the strip electrode was placed as parallel as
possible over the motor cortex. The contact with the lowest
stimulation threshold was used for continuous DCS to elicit
mMEPs. Additionally, functional cortical and subcortical
mapping for the localization of the motor cortex and for the
determination of the corticospinal tract was performed. For
this, a monopolar stimulation probe (0.15 cm diameter,
Inomed Co., Teningen, Germany) with a needle electrode
serving as reference at Fz or Fpz was used.
In case of an intraoperative seizure, cold Ringer’s
lactate solution was administered directly onto the cortex,
according to the description by Sartorius and Berger (1998).
The administration of bolus doses of propofol, diazepam, or
barbiturates was not favored because it changes the cortical
excitability and might jeopardize further monitoring.
For statistical analysis, the Fisher exact test was used
(Feldman and Klinger, 1963).
40
RESULTS
In all patients, TES-mMEPs were present. After dura
opening, DCS was performed in all patients. DCS-mMEPs
were obtained in 124 of 129 patients (96%). The lowest
stimulation threshold to evoke muscle responses was 4 mA.
other symptoms than seizures.
seizure occurred. The seizure occurred while the motor cortex
was mapped with up to 25 mA. In this patient, the anaplastic
oligoastrocytoma (WHO grade III) was located precentral.
The seizure was focal, did not generalize, and was terminated
with cold Ringer’s lactate solution. After surgery, there were
no neurologic deficit and no seizures. The patient was receiv-
ing antiepileptic medication (carbamazepine) for 3 months
before surgery reportedly stopping the seizures. Unfortu-
course. There was also one patient who had a seizure of the
66 (1.5%) patients without a symptomatic epilepsy. In this
patient with precentral cavernoma, stimulation intensities for
mapping ranged from 12 to 18 mA. The seizure occurred
while the motor threshold was determined for the contralat-
eral hand and arm muscles (see Fig. 1). There was no
significant difference (P ⫽ 1) between both groups. Revisit-
ing the literature including this study, 4 of 200 (2%) patients
with symptomatic epilepsy had an intraoperative seizure and
1 of 142 (0.7%) patients without symptomatic epilepsy had
an intraoperative seizure (P ⫽ 0.41, n.s., Table 3).
There are only two reports from which the incidence of
intraoperative stimulation associated seizures in patients with
a symptomatic epilepsy can be drawn: In 1 of 18 patients
(5.6%) with symptomatic epilepsy, a seizure during surgery
occurred, whereas none of the other 24 patients had a seizure
(P ⫽ 1, n.s.) ( Berger et al., 1989; King and Schell, 1987).
There is also no significant difference in the occurrence of
stimulation associated seizures between the train-of-five tech-
nique (4 of 200 patients) and the 60-Hz technique (1 of 18
patients, P ⫽ 0.35) in patients with a symptomatic epilepsy
and those without (Table 3).
Revisiting the overall occurrence of intraoperative sei-
zures associated with the train-of-five technique, the inci-
dence is 5 of 421 (1.2%) patients (Kombos et al., 2001;
Neuloh et al., 2004; Sala and Lanteri, 2003; Taniguchi et al.,
1993) and 26 of 272 (9.5%) patients (Berger et al., 1989;
Duffau et al., 1999; Ebeling et al., 1989; King and Schell,
1987; Romstock et al., 2002; Sartorius and Wright, 1997;
Yingling et al., 1999) with the 60-Hz technique, which is
significantly higher (P ⬍ 0.000) (Table 3).
DISCUSSION
Seizures as a presenting symptom in 49% of our pa-
tients appear to be a little lower in frequency compared with
figures reported by other groups. Within a comparable group
of patients presenting with tumors of the central region,
Duffau et al. (1999) reported an incidence of 61% (37 of 60),
Copyright © 2007 by the American Clinical Neurophysiology Society
Journal of Clinical Neurophysiology • Volume 24, Number 1, February 2007 Seizure Risk Epileptic Patients

FIGURE 1. Monopolar mapping

of the motor cortex with the train-
of-five technique in a precentral
cavernoma. MEPs were recorded
from the left biceps, extensor, ab-
ductor pollicis brevis (APB), and
abductor hallucis muscles. *Indi-
cates seizure, which shows irregular
EMG activity. DCS was immediately
stopped; cold Ringer’s lactate solu-
tion was applied, and the seizure
stopped.

TABLE 3. Seizures Related to Symptomatic Epilepsy and Different Mapping Techniques

Intraoperative seizures in

Total Max Stim. Max. Max. Charge Patients with

Patients Intensity Charge/Phase Density/Phase Sympt. Epilepsy pat. w. Sympt. pat. w/o Sympt.
Author [n] [mA] [␮C/Phase] [␮C/cm2* Phase] [n] Epilepsy [n] Epilepsy [n]

Train-of-five technique
Taniguchi, 1993 9 20 10 13 Not reported 0
Cedzich, 1996* 991 20 8 10 Not reported Not reported
Kombos, 2001 70 25 17.5 182 Not reported 0
Sala, 2003 51 20 10 80 45 (88 %) 2/45 (4.4 %)2 0/6
Neuloh, 2004 162 30 9 12 92 (56 %) 1/92 (1.1 %) 0/70
Szelényi 129 40 20 1130 63 (49 %) 1/63 (1.6 %) 1/66 (1.5 %)
Incidence of seizures in 342* 200* (58.5 %) 4/200 (2 %) 1/142 (0.7 %)
sympt. epilepsy
Overall incidence of 421 5 (1.2 %)
seizures
60-Hz technique
King, 1987 29 10 5 637 10 (at least 5) 0/5 0/19
Berger, 1989 133 16 8 1019 13 (100 %) 1/13 (7.6 %) n/a
Ebeling, 1989* 214 40 4 509 8 (38 %) Not reported
Sartorius, 1997 ⬎605 18 9 1146 Not reported 20 % (i.e. 12/60)
Duffau, 1999 436 16 8 1019 37 (61 %) Not reported (10%, i.e. 4/43;7)
Yingling, 1999 66 8 4 509 Not reported 7/66 (11 %)8
Romstöck, 2002 40 30 1.5 12 Not reported 2/40 (5 %)
Incidence of seizures in 42* 18 1/18 (5.6 %) 0/24
sympt. epilepsy
Overall incidence of 1484,* 10 (6.8 %)
seizures
Overall incidence of 272 26 (9.5 %)
seizures incl.
Duffau and Sartorius
*If intraoperative seizures were not reported as side effects or if the exact numbers were not reported, data were not included for statistical analysis.
1
The train technique was used in 25 patients.
2
The authors reported 4 more patients with intraoperative seizures not being correlated with DCS or TES.
3
Mapping of the motor cortex under general anesthesia was performed in 13 of 16 patients participating in the study.
4
Mapping was performed under partial muscle relaxation.
5
Intraoperative mapping was performed in awake and anesthetized patients.
6
In 43 of 60 studied patients, intraoperative mapping was performed under general anesthesia.
7
Intraoperative seizures occur in approximately 10% of the patients (Duffau, 2006, personal communication).
8
An additional 9 patients were reported with ongoing EMG activity, which was also interpreted as a seizure. This gives a total of 16 of 66 (24%) seizures.

Copyright © 2007 by the American Clinical Neurophysiology Society 41

Szelényi et al. Journal of Clinical Neurophysiology • Volume 24, Number 1, February 2007
Neuloh et al. (2004) of 56% (92 of 162), and Sala and Lanteri
(2003) of 88% (45 of 51).
Reviewing the literature, the incidence of seizures as-
sociated with direct cortical electrical stimulation using the
train-of-five stimulation technique with 1.2% is low (Table 3)
(Cedzich et al., 1998; Cedzich et al., 1996; Ebeling et al.,
1989; Kombos et al., 2001; Neuloh et al., 2004; Romstock et
al., 2002; Sala and Lanteri, 2003; Taniguchi et al., 1993).
Despite one patient in this study, all other seizures occurred
in patients with a history of tumor-related symptomatic epi-
lepsy. The patient reported by Neuloh et al. (2004) had a low
antiepileptic drug serum level, which was not determined in
our patient. In the patients with symptomatic epilepsy re-
ported by Sala, the seizures were mostly intractable (Sala,
personal communication). Despite the fact that there are only
two reports with low numbers, from which the incidence of
seizures related to symptomatic epilepsy and the 60-Hz tech-
nique can be drawn, there seems to be also no higher
incidence of seizures in patients with symptomatic epilepsy
caused by the 60-Hz technique. Therefore, it has to be
concluded that patients with symptomatic epilepsy are not at
a higher risk of having an intraoperative stimulation associ-
ated seizure than patients without a history of symptomatic
epilepsy.
Data are not sufficient to find predicting factors for
stimulation-associated seizures such as the level of antiepi-
leptic medication, anesthesia regimen, duration of stimulation
(60-Hz technique), the number of pulses (train-of-five tech-
nique), stimulation intensity, or the charge per phase.
As has been noted by other authors (Gordon et al.,
1990; Kombos et al., 2001; MacDonald, 2002; Ojemann,
1979; Ojemann and Whitaker, 1978; Van Buren et al., 1978),
the applied charge/phase was found to exceed the safety
recommendations of 0.4 ␮C/phase and the charge density of
40 ␮C/cm2* phase (Agnew and McCreery, 1987; Pudenz et
al., 1975). The major difference between the stimulation
protocol on which Agnew et al. based their recommendation
and the commonly intraoperatively applied stimulation pro-
tocols is the long-standing duration of stimulation of several
hours over several days in the first case. There are few papers
concerning short-term stimulation. Rowland et al. (1960)
described the safe application of long trains with an accumu-
lated charge of 10 C if the charge/phase did not exceed 20
␮C/phase. With our stimulation parameters, this charge/phase
is only met with the highest stimulation intensity that we use
in case of an inconclusive mapping for a maximum of 5
stimulation sides. An accumulated total charge of 10 C is not
reached. This author furthermore described that stimulation
frequencies above 20 Hz are not associated with substantial
tissue lesioning. Human brain tissue being intermittently
stimulated with a charge/phase of 4 ␮C and charge densities
of 57 ␮C/cm2* phase did not show histopathologically any
lesions typically for damage caused by electrical stimulation
(Gordon et al., 1990). For the train-of-five technique applied
over a short time period, safety data are lacking. As the 60-Hz
train is applied over a 4-second period, the total amount of
charge/stimulus is higher compared with the train-of-five
42
technique, which might contribute to the higher incidence of
seizures.
Electrocorticography (EcoG) might be useful to con-
firm and monitor cortical seizure activity during intraopera-
tive DCS. The observation of increasing after-discharge ac-
tivity might lead to interruption of DCS and prevent a seizure.
Although EcoG is commonly recorded in epilepsy surgery, it
is rarely used in tumor surgery. Pouratian et al. (2004) related
mapping thresholds (60-Hz technique) and afterdischarge
activity and reported that in some patients, mapping thresh-
olds to elicit motor responses exceeded afterdischarge activ-
ity. It was concluded that especially in situations with map-
ping thresholds exceeding afterdischarge activity, mapping
should be performed more cautiously to prevent a seizure.
Recording after-discharge activity caused by the 60-Hz and
the train-of-five technique with EcoG in the same patient
finally would allow for the comparison of seizure incidence
of both techniques. Within the central region, the incidence of
stimulation associated seizures with the 60-Hz technique,
which is a long train, but low-frequency stimulation is 9.5%
(Table 3) (Berger et al., 1989; Duffau et al., 1999; Ebeling et
al., 1992; King and Schell, 1987; Yingling et al., 1999). This
stresses that this method is significantly more ictogenic com-
pared with the train-of-five technique. The occurrence of
seizures ranging between 0% and 24% is a surprising finding
of this data review. One explanation might be a difference in
judging the occurrence of intraoperative seizures. Yingling et
al. (1999) define an intraoperative seizure as movement or
EMG activity continuing after terminating the stimulation. As
EMG recording with the 60-Hz technique is not common,
continuing EMG activity might not always be accompanied
by visible tonic or clonic movement. This might be an
explanation of a lower seizure incidence reported by some
authors.
In none of the patients, intraoperative seizures were
reportedly associated with a postoperative deficit or an in-
crease of seizure frequency. Most of the seizures were focal
and self-terminating or were terminated either by cold
Ringer’s lactate solution or barbiturate administration.
There is no report about persistent seizure activity after
direct cortical stimulation.
In conclusion, the train-stimulation technique has a
significantly lower incidence of stimulation-associated intra-
operative seizures than the 60-Hz technique. There is no
increased risk of the occurrence of stimulation-associated
seizures for patients with a symptomatic epilepsy compared
with those patients without seizures.
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