This study evaluates the impact of intraoperative monitoring (IOM) on the resection rates, the survival rate, the quality of life, and the functional outcome of malignant gliomas. The data presented here demonstrate that tumor resection is not negatively influenced by IOM.
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Impact of intraoperative neurophysiological monitoring on surgery of high-grade gliomas.pdf
This study evaluates the impact of intraoperative monitoring (IOM) on the resection rates, the survival rate, the quality of life, and the functional outcome of malignant gliomas. The data presented here demonstrate that tumor resection is not negatively influenced by IOM.
This study evaluates the impact of intraoperative monitoring (IOM) on the resection rates, the survival rate, the quality of life, and the functional outcome of malignant gliomas. The data presented here demonstrate that tumor resection is not negatively influenced by IOM.
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 signicant differences in the type of surgery performed or in the resection grade in both groups. No statistically signicant 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 inuenced 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: 422425) 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 inuence 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 inuence 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 rst 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 dened 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 inuence of the secondary motor areas and the supplementary motor cortex could be excluded. In the rst 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 - Universitatsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany. Address correspondence and reprint requests to Theodoros Kombos, M.D., De- partment of Neurosurgery, Charite - Universitatsmedizin 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 4, 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 (710 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 1020 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 exor, 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 dened 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 (12 mg/kg) and fentanyl (510 g/kg). Propofol (75125 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, dened radiographically as the absence of contrast-enhancing tissue on T1-weighted images, was classied as a subtotal resection. RESULTS The study population included 28 men and 12 women with a mean age of 51 (range, 3169) 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 ve patients of groups 1 and 2, respectively. There was no statistical signicant difference (P 0.666) in the resection grade between the groups. In group 1, SEP-PR conrmed the distance to the central sulcus in 15 cases. In ve 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 rst 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 signicant 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 signicantly 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 inltrating 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, ve 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 signicant 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% condence 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 signicant 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 ve cases and remained unchanged in 15 (Table 2). DISCUSSION The prediction of function through classic anatomic criteria is insufcient 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 inltrating 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 rst reliable data on the prognostic signicance 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 specically 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 (40 years) is a favor- able prognostic factor; however, the association of frontal-only tumors compared with other locations remains to be conrmed. 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 denition 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 rst 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; Luders et al., 1983; Nuwer et al., 1991; Wood et al., 1988; Woolsey et al., 1979). In 1993, Taniguchi et al. (1993) described a modication of monopolar cortical stimulation. A high-frequency (400500 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 rst 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 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 inuenced 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 inuence of IOM on the resection or survival rate was found. Even though these inltrating 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 patients quality of life, without any negative effect on the survival rate. 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