ORIGINAL ARTICLE

Impact of Intraoperative Neurophysiological Monitoring on
Surgery of High-Grade Gliomas
Theodoros Kombos, Thomas Picht, Athanasios Derdilopoulos, and Olaf Suess
Introduction: Controversy exists on the application of intraoperative mon-
itoring (IOM) procedures during malignant glioma surgery. Because resec-
tion rate correlates with the survival rate, it is of paramount importance to
determine these values. This study evaluates the impact of IOM on the
resection rates, the survival rate, the quality of life, and the functional
outcome of malignant gliomas.
Methods: Forty patients with a glioma were included in the study. They
were divided into two groups: group 1, patients with a glioma not adjacent
to motor cortical areas operated without the use of IOM, and group 2,
patients with a glioma adjacent to the central region operated under IOM.
The further treatment was the same in both groups. The following parameters
were analyzed: tumor resection rate, survival rate, preoperative and postop-
erative Karnowsky Performance Score, and preoperative and postoperative
motor function.
Results: There were no statistically significant differences in the type of
surgery performed or in the resection grade in both groups. No statistically
significant difference was found in the median survival of the two groups in
the Kaplan-Meier analysis with mean survival time 48.8 and 48.2 weeks. The
mean Karnowsky Performance Score preoperative was 82.5 and 81.5, and
81.1 and 82.7 after 6 months, for groups 1 and 2, respectively.
Conclusion: The data presented here demonstrate that tumor resection is not
negatively influenced by IOM. Accordingly, gliomas that are found to be
otherwise resectable should not be excluded from aggressive management
simply because of their vicinity to the motor cortex. Surgery should be
performed under IOM.
Key Words: Intraoperative monitoring, Glioma.
(J Clin Neurophysiol 2009;26: 422–425)
T
he development of imaging procedures have led to marked
advances in anatomic orientation during the past 2 decades. This
has paved the way for microsurgical techniques aiming to preserve
function during brain surgery. The more aggressive the approach,
the better the survival and the quality of life (Ammirati et al., 1987;
Ciric et al., 1987; Hirakawa et al., 1984; Laws et al., 1984). The
aggressiveness is often limited by the proximity of functionally
eloquent areas. Although magnetic resonance imaging (MRI) en-
ables exact localization of lesions in relation to the central sulcus
(Yousry et al., 1996), these morphologic data do not correlate with
function. Therefore, intraoperative functional mapping and monitor-
ing techniques are of paramount importance in localizing function-
ally relevant areas and allowing maximal resection with minimal
morbidity.
Although the clinical relevance of intraoperative mapping and
intraoperative monitoring (IOM) has been demonstrated in various
publications (Berger et al., 1989, 1990a; Cedzich et al., 1996;
Ebeling et al., 1990; Ebeling and Reulen, 1992; LeRoux et al., 1991;
Ojemann et al., 1989; Skirboll et al., 1996; Yigling et al., 1999),
controversy exists on its application during malignant glioma sur-
gery. A major critic point is that there is no data on the influence of
mapping and monitoring procedures on the resection rate of gliomas.
Because resection rate correlates with the survival rate (Ammirati et
al., 1987; Ciric et al., 1987; Hirakawa et al., 1984; Laws et al.,
1984), it is of paramount importance to determine these values. This
study was designed to evaluate the impact of intraoperative mapping
and IOM procedures on the resection rates of malignant gliomas and
therefore on the survival rate, the quality of life, and the functional
outcome.
We realize that such a study should ideally compare two
groups of patients with gliomas in the central region: one with
monitoring and the other without. However, as IOM has been
proven to be clinical relevant for reducing the surgery-dependent
morbidity, operating on patients in the central region without it
would be ethically questionable. For this reason, this study is based
on the comparison of two groups with gliomas: one in the vicinity of
the central region and the other in the frontal lobe. We are aware of
the inhomogenity of the two groups, but the questions to be an-
swered are (a) does IOM have a negative impact on the aggressive-
ness of tumor reduction and (b) does IOM have a negative influence
on the survival rate? In other words, do we trade off survival rate for
a better functional outcome by applying IOM?
PATIENTS AND METHODS
Patients
Forty consecutive patients with a glioma were included in the
study. The patients were divided into two groups, 20 in each group.
The first group consisted of patients with a glioma in the nondomi-
nant temporal or parietal lobe not adjacent to motor cortical areas,
and the second group consisted of patients with a glioma adjacent to
the central region. Only patients with a tumor in the central region
of the nondominant hemisphere were included in the study. The
central region was defined as the precentral gyrus and the frontal
gyrus directly rostral to it. The anatomic location of the tumor was
evaluated preoperatively by means of an MRI and intraoperative by
somatosensory-evoked potential phase reversal (SEP-PR). Patients
with gliomas in the parietal or nondominant temporal lobe were
chosen as the control group, so the influence of the secondary motor
areas and the supplementary motor cortex could be excluded.
In the first group, surgery was performed conventionally
without the use of intraoperative neurophysiological techniques. In
the second group, intraoperative localization of the central sulcus
and the central region was performed by a combination of SEP-PR
From the Department of Neurosurgery, Charite´ - Universita¨tsmedizin Berlin,
Campus Benjamin Franklin, Berlin, Germany.
Address correspondence and reprint requests to Theodoros Kombos, M.D., De-
partment of Neurosurgery, Charite´ - Universita¨tsmedizin Berlin, Campus
Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany; e-mail:
theodoros.kombos@charite.de.
Copyright © 2009 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/09/2606-0422
Journal of Clinical Neurophysiology • Volume 26, Number 6, December 2009 422
and direct monopolar anodal high-frequency electrical stimulation
of the cortex (Kombos et al., 2000).
The inclusion criteria were as follows: a histologically proven
glioma WHO fourth degree or third degree, a preoperative Kar-
nowsky Performance Score (KPS) of 70 or above, no recurrent or
multifocal malignant glioma, and muscle strength Ն4, according to
the BMRC grading. The local ethic commission approved the study
and patients were included consecutively in a prospective way.
Intraoperative Monitoring
After the functional mapping of the motor cortex, a repetitive
electrical stimulation was performed. A special stimulation electrode
of 0.8 cm diameter was positioned over the motor cortex. A short
train (7–10 pulses) of monopolar, anodal, rectangular pulses was
applied to the cortex at a frequency of 400 to 500 Hz. The cathode
was located ipsilaterally on either Fp1 or Fp2, according to the
10–20 system. An intensity of 5 to 20 mA was applied with impulse
duration of 0.1 to 0.7 milliseconds. Stimulation intensity was grad-
ually increased until action potentials were elicited in the target
muscles. A constant voltage stimulator was used, and the maximum
stimulation intensity was set at 25 mA. Action potentials were
recorded from the forearm flexor, thenar, and quadriceps muscles
contralateral to the stimulation. A pair of subdermal needle elec-
trodes was used for recording. If the tumor was near the midline, ie,
in the leg area, additional muscles such as the anterior tibial and
extensor hallucis longus muscle were recorded.
Throughout surgery, the recorded motor-evoked potentials
were analyzed regarding their latency, width, and amplitude. Based
on previous publications, warning criteria were defined as amplitude
change of more than 80% and latency alterations of more than 30%,
always compared with the initial recordings (Kombos et al., 2001;
Suess et al., 2006). Surgical maneuvers performed before observed
changes in the parameters were noted. Monitoring was ended on
closure of the dura. All operations were performed under total
intravenous anesthesia. Muscle relaxants were administered only for
intubation, not during surgery. Anesthesia was induced by propofol
(1–2 mg/kg) and fentanyl (5–10 ␮g/kg). Propofol (75–125 ␮g/kg/h)
was continuously applied during surgery. Analgesia was achieved
by alfentanyl, sulfentanyl, or fentanyl.
Data Analysis
Patients were examined preoperatively and postoperatively
according to a standardized protocol. Muscle strength was eval-
uated according to the British Medical Research Council Scale
(Haerer, 1992).
The surgery was performed in all cases by the same two
surgeons who are familiar with IOM and its interpretation. A
questionnaire based on the following points: (a) “was the operative
strategy changed due to the IOM result?” and (b) “was the resection
changed by the IOM results?” was answered. The further treatment
was the same in both groups. All patients received radiation therapy
postoperatively.
The groups were comparable for age, sex, and their preoper-
ative KPS. The following parameters were analyzed: extent of tumor
resection, preoperative and postoperative KPS, preoperative and
postoperative motor function, and outcome. Outcome was estimated
as overall survival and progression-free survival. Statistical analysis
was performed using the Wilcoxon test, and the survival rate was
performed by a Kaplan-Meier analysis. The results are presented as
Kaplan-Meier graphs.
The extent of resection was determined by comparing MRI
scans obtained before surgery with those obtained within 48 hours
after surgery. Anything less than gross total resection, defined
radiographically as the absence of contrast-enhancing tissue on
T1-weighted images, was classified as a subtotal resection.
RESULTS
The study population included 28 men and 12 women with a
mean age of 51 (range, 31–69) years. All patients underwent
primary craniotomy. Postoperative MRI showed gross total tumor
removal in 14 cases of group 1 and in 15 cases of group 2 (Table 1).
Therefore, subtotal resection was performed in six and five patients
of groups 1 and 2, respectively. There was no statistical significant
difference (P 0.666) in the resection grade between the groups.
In group 1, SEP-PR confirmed the distance to the central
sulcus in 15 cases. In five patients with frontopolar tumors, SEP-PR
was not performed. In group 2, SEP-PR was recordable in 18
patients. In two cases, this was not the case; however, mapping was
possible by direct electrical stimulation. The anatomic relation
between tumor and central sulcus was different from the one
estimated based on radiographical examinations in seven cases.
In group 2, the first question of the questionnaire “was the
operative strategy changed due to the IOM result?” was answered
with “yes” in two cases. The question “was the resection changed by
the IOM results?” was answered with “yes” in six cases. In two
patients, the effect was “reduced resection.” In one case of glioblas-
toma within the precentral gyrus, a significant reduction in the
compound muscle action potentials (CMAPs) was recorded during
tumor removal, so the procedure was interrupted. In another case of
glioblastoma in the frontal gyrus directly adjacent to the precentral
gyrus, CMAPs were significantly reduced during tumor preparation
in the depth, so tumor removal from the dorsal border was not
performed. In four cases, the effect was “increased resection.”
Overall, in two cases CMAPs remained unchanged and in further
two CMAPs improved during tumor resection. Therefore, the resec-
tion was continued, despite the macroscopical proximity to the
subcortical motor pathways. In group 1, in one case, a right temporal
GBM was infiltrating the basal ganglia, so only a subtotal reduction
was performed. In two other cases of parietal anaplastic astrocy-
toma, the callosum was invaded by the tumor, so again only a
subtotal removal was performed.
Postoperative clinical deterioration occurred in three cases of
group 2 despite unaltered intraoperative CMAPs. Postoperative
computed tomography/MRI scans revealed massive edema in all
cases. Clinical deterioration was noticed within the initial postoper-
ative hours. Antiedematous treatment restored motor function to the
preoperative level in all cases. In further three patients, muscle
strength improved directly postoperatively. There was no permanent
postoperative clinical deterioration (Fig. 1).
Further complications of surgery, such as mood disturbances,
headaches, postoperative hemorrhage, seizure, or wound infections,
were minimal between both groups, precluding a detailed statistical
analysis. All patients received adjuvant radiation therapy.
In group 1, five patients underwent an additional surgery more
than 3 months after the initial operation. In group 2, three patients had
surgery for a recurrent tumor. There was no statistically significant
difference in the median survival of the two groups in the Kaplan-Meier
analysis (P 0.884). The mean survival time was 48.8 weeks in group 1
and 48.2 weeks in group 2, with the 95% confidence interval being
42.58 to 55.01 and 42.65 to 53.74 weeks, respectively (Fig. 2).
The functional outcome was assessed with the KPS (24). There
was no statistically significant difference between the two groups in the
TABLE 1. Resection Grade as Assessed Intraoperative and
Proven on Postoperative Imaging
Resection Group 1 Group 2 P
Intraoperative 17 18 0.666
Imaging 14 15
Journal of Clinical Neurophysiology • Volume 26, Number 6, December 2009 Intraoperative Monitoring and Glioma
Copyright © 2009 by the American Clinical Neurophysiology Society 423
KPS 6 months after surgery. The mean KPS preoperative was 82.5 and
81.5 in groups 1 and 2, respectively, and 81.1 and 82.7 after 6 months.
Motor function improved in seven patients in group 2 and was un-
changed 1 week postoperatively in the remaining 13. Correspondingly,
the KPS improved in these seven cases. In group 2, the KPS improved
in five cases and remained unchanged in 15 (Table 2).
DISCUSSION
The prediction of function through classic anatomic criteria is
insufficient because of the variability of cortical organization (Her-
holz et al., 1996; Ojemann, 1979; Ojemann and Whitaker, 1978;
Ojemann et al., 1989), distortion of the cerebral topography as a
result of the mass effect of the tumor, and functional reorganization
because of plasticity (Ojemann et al., 1996; Seitz et al., 1995;
Wunderlich et al., 1998). Because of the infiltrating nature of brain
tumors such as gliomas, it is common for a portion of the mass to
occupy tissue involved in the motor function, even if the patient has
no paresis.
Surgical treatment of high-grade gliomas in eloquent cortical
areas has been a controversial issue (Nazzaro and Neuwelt, 1990;
Quigley and Maroon, 1991). A conservative or limited resection has
been the favored treatment, even though there is no evidence-based
data to support this strategy. The first reliable data on the prognostic
significance of tumor location were published in the mid-1990s by
the Radiation Therapy Oncology Group (Curran et al., 1993; Kaplan,
1993). These data were assessed from patients with intracranial metas-
tasis. It demonstrated that patients’ age and KPS score are the major
prognostic factors, whereas tumor location had no prognostic value.
Although these studies refer specifically to metastasis rather than to
primary gliomas, they represent the most extensively valid evidenced-
based data available; they indicate that the location of tumors is not a
primary factor in determining disease prognosis. Lamborn et al. (2004)
showed that frontal location in young patients (Ͻ40 years) is a favor-
able prognostic factor; however, the association of frontal-only tumors
compared with other locations remains to be confirmed.
For the treatment of gliomas, recent investigations considered
tumor location among other prognostic factors, and in most studies,
it was found to be of no prognostic value (Barker et al., 1998; Bindal
et al., 1995; Huang et al., 2001; Lacroix et al., 2001; Obwegeser et
al., 1995; Tortosa et al., 2003). A recent publication based on an
analysis of the Glioma Outcomes Project database demonstrated that
the laterality of high-grade gliomas is not an independent prognostic
factor for predicting survival or functional outcome. This study was
not limited to the motor cortex, and the definition “eloquent cortex”
varies widely (Polin et al., 2005). Although major advances in the
treatment of gliomas have been achieved in recent years, the surgical
treatment of gliomas located in motor cortical areas remains con-
troversial and is based on the “feeling” and experience of the
treating surgeon.
In recent years, several studies (Amassian and Cracco, 1987;
Barker et al., 1985; Berger et al., 1989, 1990b) have substantiated
the need for intraoperative functional mapping and monitoring
during surgery in and around the motor cortex. The method of phase
reversal of somatosensory-evoked potentials was first described by
Goldring (1978) and Goldring and Gregorie (1984) for intraopera-
tive localization of the central sulcus during epilepsy surgery.
Subsequent studies have also demonstrated its usefulness in tumor
surgery (Cedzich et al., 1996; Desmedt and Chron, 1982; Firsching
et al., 1992; Grundy, 1983; Lesser et al., 1979; Lu¨ders et al., 1983;
Nuwer et al., 1991; Wood et al., 1988; Woolsey et al., 1979). In
1993, Taniguchi et al. (1993) described a modification of monopolar
cortical stimulation. A high-frequency (400–500 Hz) monopolar
train of stimuli elicits motor evoked potentials with a stimulation
intensity that is 50 to 100 times lesser than the intensity required for
bipolar stimulation (Berger et al., 1989, 1990a; Ebeling et al., 1990,
1992; King and Schell, 1987). The first clinical experience with this
new stimulation technique was reported by Cedzich et al. (1996).
Further clinical studies have demonstrated a correlation between
intraoperative CMAP changes and postoperative clinical outcome.
This method allows a quantitative analysis of the recorded potentials
and therefore an IOM of the functional motor system. In terms of
physiology, MCS stimulates the pyramidal cells causing a direct
stimulation of the pyramidal tract. Therefore, the subcortical path-
ways can be monitored with this technique. Although intraoperative
FIGURE 1. Motor strength in group 2 according the
BMRC grading.
FIGURE 2. Kaplan-Meier plot showing overall survival in the
two groups. There is no significant difference (P ϭ 0.884).
TABLE 2. Mean KPS Scores in Patients Surgically Treated
for High-Grade Gliomas
Factor (Mean) Group 1 Group 2 P
KPS preoperative 82.5 81.5 0.755
KPS 6 mo postoperative 81.1 82.7 0.703
Recurrent surgery 5 3
Survival (wk) 48.8 48.2 0.884
KPS, Karnowsky Performance Score.
T. Kombos et al. Journal of Clinical Neurophysiology • Volume 26, Number 6, December 2009
Copyright © 2009 by the American Clinical Neurophysiology Society 424
CMAP monitoring has proven its clinical relevance for surgery in
and around the motor cortex, its impact on glioma surgery has not
yet been established. The main point of criticism is the assumption
that IOM leads to reduced tumor resection.
However, the data presented here demonstrate that tumor resec-
tion is not negatively influenced by IOM. On the contrary, based on
IOM criteria, gross total tumor removal was achieved in most of the
patients of group 2. There was no statistical difference between the two
groups for the parameter “tumor resection.” Because of the IOMresults,
tumor resection was not complete in two cases, but the same percentage
was found in the group without monitoring.
The authors are aware of the fact that both groups are not
similar. The critical comparison would be between two similar
groups of central region glioblastomas with and without IOM.
However, as stated earlier, the authors believe that a randomized
study will be, according to the already published articles on the
impact of IOM on the quality of life, ethically questionable. Al-
though frontal tumors have been reported to have a better prognosis
(Lamborn et al., 2004), this was not an issue in the presented study.
Furthermore, the survival rate was the same in both groups. This
is probably because the extension of tumor removal was comparable.
Although the tumors were located in the vicinity of the central region
(group 2), the postoperative functional outcome was unchanged or
improved in the majority of the patients, even in the two cases where
monitoring resulted in subtotal tumor resection. No permanent postop-
erative neurologic deterioration was observed in group 2.
Intraoperative neurophysiological monitoring during glioma
surgery in the vicinity of the central region has been proven to
increase the safety of the procedure. No influence of IOM on the
resection or survival rate was found. Even though these infiltrating
tumors were in or around the cortical motor areas, no permanent
postoperative clinical deterioration was observed. The ultimate goal
in the treatment of gliomas is to optimize the quality of life and the
survival rate. IOM has been shown to improve patient’s quality of
life, without any negative effect on the survival rate. Accordingly,
gliomas that are found to be otherwise resectable should not be
excluded from aggressive management simply because of their
vicinity to the motor cortex. Surgery should be performed although
under CMAP monitoring. The results presented here demonstrate
that there is no basis for fearing increased postoperative morbidity
and mortality in otherwise resectable tumors of the motor cortex.
ACKNOWLEDGMENT
The authors thank Michael Hanna, Ph.D., for editing the
manuscript.
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Journal of Clinical Neurophysiology • Volume 26, Number 6, December 2009 Intraoperative Monitoring and Glioma
Copyright © 2009 by the American Clinical Neurophysiology Society 425