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CLINICAL STUDIES

Awake Mapping Optimizes the Extent of Resection for Low-Grade Gliomas in Eloquent Areas
Alessandro De Benedictis, MD
Department of Surgical Sciences, Neurosurgical Unit, University of Insubria, Varese, Italy

Sylvie Moritz-Gasser, ST
Department of Neurosurgery, Hpital Gui de Chauliac, CHU Montpellier, Montpellier, France

Hugues Duffau, MD, PhD


Department of Neurosurgery, Hpital Gui de Chauliac, and Institut of Neuroscience of Montpellier, INSERM U583, Plasticity of Central Nervous System, Human Stem Cells and Glial Tumors, Hpital Saint Eloi, CHU Montpellier, Montpellier, France Reprint requests: Hugues Duffau, MD, PhD, Department of Neurosurgery, Hpital Gui de Chauliac, CHU Montpellier, 80 Av Augustin Fliche, 34295 Montpellier, France. E-mail: h-duffau@chu-montpellier.fr Received, March 4, 2009. Accepted, November 30, 2009. Copyright 2010 by the Congress of Neurological Surgeons

BACKGROUND: Awake craniotomy with intraoperative electrical mapping is a reliable method to minimize the risk of permanent deficit during surgery for low-grade glioma located within eloquent areas classically considered inoperable. However, it could be argued that preservation of functional sites might lead to a lesser degree of tumor removal. To the best of our knowledge, the extent of resection has never been directly compared between traditional and awake procedures. OBJECTIVE: We report for the first time a series of patients who underwent 2 consecutive surgeries without and with awake mapping. METHODS: Nine patients underwent surgery for a low-grade glioma in functional sites under general anesthesia in other institutions. The resection was subtotal in 3 cases and partial in 6 cases. There was a postoperative worsening in 3 cases. We performed a second surgery in the awake condition with intraoperative electrostimulation. The resection was performed according to functional boundaries at both the cortical and subcortical levels. RESULTS: Postoperative magnetic resonance imaging showed that the resection was complete in 5 cases and subtotal in 4 cases (no partial removal) and that it was improved in all cases compared with the first surgery (P = .04). There was no permanent neurological worsening. Three patients improved compared with the presurgical status. All patients returned to normal professional and social lives. CONCLUSION: Our results demonstrate that awake surgery, known to preserve the quality of life in patients with low-grade glioma, is also able to significantly improve the extent of resection for lesions located in functional regions.
KEY WORDS: Awake surgery, Direct electrical stimulation, Functional brain mapping, Low-grade glioma
Neurosurgery 66:1074-1084, 2010
DOI: 10.1227/01.NEU.0000369514.74284.78

www.neurosurgery-online.com

ecent studies have demonstrated that awake craniotomy with intraoperative electrical brain mapping represents a reliable method to minimize the risk of permanent deficit during surgery for tumors located within eloquent areas.1-10 This method enabled the extent of indications of surgery in regions classically considered inoperable while preserving the quality of life, especially for infiltrative tumors such as lowgrade glioma.11 However, it could be argued that preservation of functional sites might lead to a lesser degree of tumor removal. To the best of our knowledge, the extent of resection was never directly compared between traditional and awake procedures except in 2 previous reports: one by Reithmeier et al12 and one by our team.11
ABBREVIATIONS: FLAIR, fluid-attentuated inversion recovery; WHO, World Health Organization

Even though both observed a better extent of resection with intraoperative mapping, the comparison was made with a control group and not in the same patients. Here, we report for the first time a surgical series of 9 patients who underwent 2 consecutive surgeries for the same tumor in eloquent areas, the first one without and then the second one with awake mapping. We show the statistically significant contribution of the awake procedure to optimize the extent of resection of lowgrade glioma located within eloquent regions.

PATIENTS AND METHODS


Nine right-handed patients (3 male and 6 female) ranging in age from 19 to 69 years (median, 39 years), underwent 2 consecutive surgical resections of a supratentorial low-grade

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glioma located within eloquent (language and/or sensory-motor) areas. The first operation was performed between 1997 and 2006 in 9 other institutions by 9 surgeons specialized in removing brain gliomas, even if they did not use intraoperative functional mapping. The second surgery was systematically performed between 2006 and 2008 by the same neurosurgeon (H.D.) using intraoperative electrical mapping in awake patients. For the second operation, the same protocol was administrated to all patients as previously reported.5,11,13 Preoperatively, in addition to neurological examination, language was tested by the same speech therapist (S.M.G.) using the Boston Diagnostic Aphasia Examination.14 Hemispheric dominance was assessed with a standardized questionnaire (Edinburgh inventory).15 The topography and the volume of the tumor recurrence were accurately analyzed on a preoperative magnetic resonance image (MRI; T1-weighted and spoiledgradient images obtained before and after gadolinium enhancement in the 3 orthogonal planes, T2-weighted axial coronal images, and fluid-attentuated inversion recovery [FLAIR]weighted axial images). All patients underwent awake surgery under local anesthesia so that functional, especially language, cortical, and subcortical mapping could be carried out with direct electrical stimulation.4,5,11,13,1623 A bipolar electrode with 5-mm-spaced tips delivering a biphasic current (pulse frequency, 60 Hz; single pulse phase duration, 1 ms; amplitude, 2-8 mA) (Nimbus, Hemodia, Labge, France) was applied to the brain of awake patients. In the first stage, cortical mapping was performed after tumor and sulci/gyri identification with ultrasonography and before resection. Sensory-motor mapping was performed first, with the goal of obtaining a positive response. Under local anesthesia, the current intensity adapted to each patient was determined by progressively increasing the amplitude in 1-mA increments, from a baseline of 2 mA, until a sensory-motor response was elicited (ie, an involuntary movement and/or a perception of dysesthesia was reproducibly described by the patient), with 8 mA as the upper limit, with the goal of avoiding the generation of seizures. Then, the patient was asked to perform counting and picture naming24 (preceded by a short sentence to read, namely the French translation of this is a, to check that there were no seizures generating complete speech arrest if the patient was not able to name) to identify the essential cortical language sites known to be inhibited by stimulation. The patient was never informed when the brain was stimulated. The duration of each stimulation was 4 seconds. At least 1 picture presentation without stimulation separated each stimulation, and no site was stimulated twice in succession to avoid seizures. Each cortical site (size, 55 mm because of the spatial resolution of the probe) of the entire cortex exposed by the bone flap was tested 3 times. It is currently accepted, since the seminal publication of Ojemann et al,25 that 3 trials are sufficient to ensure whether a cortical site is essential for language, eg, generating disturbances during its 3 stimulations, with normalization of language as soon as the stimulation is stopped. The type of language disturbances was detailed by a speech therapist (S.M.G.), who was always present in the operative room during the functional mapping, using a classification previously detailed.5,19 Each eloquent area was marked with a sterile number tag on the brain

surface, and its location was correlated to the anatomic landmarks (sulci/gyri/tumor boundaries) previously identified by ultrasonography. A photograph of the cortical map was systematically made before resection. During the second surgical stage, the glioma was removed by alternating resection and subcortical stimulations. The functional pathways were followed progressively from the cortical eloquent sites already mapped to the depth of the resection. The patient had to continue to name when the resection became close to the subcortical crucial structures, which were also identified by functional inhibition during stimulation at the cortical level. Again, the type of disturbance was detailed by a speech therapist throughout the resection. To perform the best possible tumor removal with preservation of the functional areas, all resections were pursued until eloquent pathways were encountered around the surgical cavity, ie, according to functional boundaries. Thus, there was no margin left around the cortico-subcortical eloquent areas. Postoperative functional outcome was assessed with the same protocol as before surgery, during the immediate postoperative stage, at 3 months, and then every 6 months after surgery. A control MRI was performed in all cases immediately, at 3 months, and then every 6 months after surgery. This imaging enabled us to evaluate the extent of glioma removal, interpreted by 2 observers (A.D.B. and H.D.) according to the classification method reported by Berger et al26: total resection if no residual signal abnormality on FLAIR-weighted MRI, subtotal resection if <10 mL residue, and partial resection if >10 mL residue. Postoperative tumor volume evaluated on the MRI 3 months after the first surgery was compared with the postoperative tumor volume evaluated on the MRI 3 months after the second surgery with a Fisher exact test (a significance level of 5% [P < .05] was accepted).

RESULTS
Clinical, radiological, and surgical results for the 9 patients before and after both surgeries are summarized in Tables 1 through 3. First Surgery The presenting symptoms were seizures in all patients (3 generalized, 6 partial). The preoperative neurological evaluation showed mild memory disturbances in only 1 patient (Table 1). The preoperative MRI demonstrated in all patients a T1-weighted hypointense and T2-weighted hyperintense lesion without enhancement after gadolinium injection (Figures 1A and 2A). In 8 patients, the tumor was located in the left dominant hemisphere: 5 within the left frontal region, 1 within the left superior temporal gyrus, and 2 within the left parietal lobe. In 1 patient, the lesion was located in the right parietooccipital junction, with an anterior tumoral involvement coming very close to the primary somatosensory area. The 9 patients underwent surgery under general anesthesia in other institutions. No permanent postsurgical neurological worsening was induced at standard examination except 2 mild dysphasias. However, no extensive functional assessment was performed after the first surgery, especially concerning language. Postoperative MRI revealed

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FIGURE 1. A, axial fluid-attentuated inversion

recovery (FLAIR)weighted (left), sagittal (middle), and coronal (right) enhanced T1-weighted magnetic resonance imagining (MRI) showing a low-grade glioma involving the left inferior frontal gyrus. B, axial FLAIR-weighted (left), axial (middle,) and coronal (right) enhanced T1-weighted MRI after surgery performed under general anesthesia showing a partial resection of the lesion (20% of preoperative volume, ie, 84 cm3). C, axial T2weighted (left), sagittal (middle,) and coronal (right) enhanced T1-weighted MRI showing the residual tumor before the second surgery, with a growth estimated from 83 to 89 cm3 in 6 months. D, intraoperative photographs before (left) and after (right) resection of the lesion performed under local anesthesia. The letters correspond to the limits of the tumor identified with intraoperative ultrasonography. The eloquent cortical sites were marked by numbers as follows: 25, 27, and 26, ventral premotor cortex inducing articulatory disturbances; and 23 and 24, dorsal premotor cortex inducing semantic paraphasias when stimulated. The left inferior frontal gyrus was removed because no functional troubles were elicited by stimulation in this region. The resection was extended deeply until the arcuate fasciculus, where the stimulation evoked phonemic paraphasias (50); the head of the caudate nucleus superiorly, generating perseverations when stimulated (49); and the descending fibers from the ventral premotor cortex, where stimulation generated articulatory disturbances (45). E, Postoperative axial T2-weighted (left), sagittal (middle), and coronal (right) enhanced T1-weighted MRI showing an almost total tumor resection (4 cm3 residue). The patient returned to a normal socioprofessional life, with an improvement in quality of life compared with the preoperative status.

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TABLE 1. Clinical, Radiological, and Pathological Characteristics Concerning the First Surgerya Patient/ Sex/Age, y 1/F/19 2/M/48 3/F/41 4/F/21 5/M/69 6/F/43 7/F/39 8/M/39 9/F/35 Presenting Symptoms Partial seizures Partial seizures Partial seizures with speech Partial seizures Partial seizures Generalized seizures Generalized seizures Generalized seizures Partial seizures Clinical Examination Memory disturbances Normal Normal Normal Normal Normal Normal Normal Normal Location Left superior temporal gyrus Right parietooccipital Left inferior frontal gyrus Left premotor frontal Left frontal Left frontal Left parietal Left frontal Left Retrocentral gyrus Year 2006 1999 2006 2002 2000 2006 2005 2003 1997 Extent of Resection Subtotal Partial Partial Subtotal Partial Partial Partial Subtotal Partial Pathology (WHO) Ganglioglioma WHO II glioma WHO II glioma WHO II glioma WHO II glioma WHO II glioma WHO II glioma WHO II glioma WHO II glioma no RT/CT (temozolomide) No No CT (temozolomide) CT (temozolomide) CT (temozolomide) No No Adjuvant Therapy

WHO, World Health Organization; RT, radiotherapy; CT, chemotherapy.

no complete resections, 3 subtotal resections (residue <10 cm3), and 6 partial resections (>10 cm3 residue) (Figures 1B, 2B, 3A and 4A). The mean volume of residual tumor was 29 cm3 (range, 6-84 cm3). Histological examination revealed a World Health Organization (WHO) grade II glioma in 8 patients and a WHO grade I glioma in 1 patient (ganglioglioma). Three patients did not return to their professional activity after the operation because of a mild dysphasia in 2 and a depressive syndrome in 1. During follow-up, 4 patients received chemotherapy (temozolomide) as adjuvant treatment, which was combined with radiotherapy in 1 patient. Second Surgery When referred to our department, 7 patients presented with seizures (6 partial, 1 generalized), which were medically intractable in 3 patients. One patient also had an anxious-depressive syndrome. One patient was without any symptoms (Table 2). The preoperative clinical evaluation and Boston Diagnostic Aphasia Examination revealed neurological disturbances in 7 patients: speech, memory, writing, and concentration disorders in 4 patients with a left frontal glioma tumor and in the patient with a left temporal tumor; a quadrantanopsia for the patient harboring the right occipitoparietal lesion; and a right somatosensory deficit with ataxia for the patient with a left parietal tumor. Two patients had a normal examination. In the 9 patients, the preoperative MRI showed a volumetric increase in the residual glioma compared with the MRI performed

after the first surgery (Figures 1C, 2C, 3B and 4B). The mean tumor volume was 45 cm3 (range, 13-90 cm3). In 3 patients (1 with right parietooccipital and 2 with left frontal lesions), an enhancement was visible after gadolinium injection. The mean delay between the first and second surgeries was 57 months (range, 8-120 months). The 9 surgeries were performed under local anesthesia (Figures 1D, 2D, 3C and 4C). All patients tolerated the awake phase of the surgery well. Eloquent sites were identified in all patients through the use of intraoperative electrical stimulation with no negative mapping. The resection was pursued until both cortical and subcortical functional structures were encountered to optimize the extent of tumor removal. The median time of surgery was 4 hours. The clinical evaluation in the immediate postoperative period noted a transient worsening in language performance in 4 patients. The patient with the right parietooccipital tumor presented transitory finger dysesthesia. Moreover, in 1 patient, a mild deficit of accurate movements of the left fingers was observed over 5 days. Three patients had a normal examination immediately following the second operation. The median length of hospital stay was 1 week, and 5 patients underwent language rehabilitation at home. All patients improved their neurological status relative to their immediate postoperative condition within weeks after surgery; they recovered to their preoperative condition, particularly overcoming speech disturbances. The 2 patients who interrupted their professional activity because

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FIGURE 2. A, axial T2-weighted (left), coronal

(middle), and sagittal (right) T1-weighted magnetic resonance imaging (MRI) before the first surgery performed under general anesthesia showing a left frontal low-grade glioma. B, postoperative axial fluid-attentuated inversion recovery (FLAIR) weighted (left, middle) and coronal T1-weighted MRI (right) control, showing a partial resection of the tumor. C, axial (left), coronal (middle), and sagittal (right) enhanced T1-weighted MRI 8 years after the first surgery showing the volumetric increase in lesion residue (from 12-25 cm3) with the occurrence of an enhancement. D, Photographs showing intraoperative view before (left) and after (right) the resection performed under local anesthesia. The letters correspond to the limits of the tumor identified using intraoperative ultrasonography. Cortical mapping allowed identification of the eloquent sites as follows: 1, ventral premotor cortex eliciting anarthria during stimulation; 5 and 3, pars opercularis of left inferior frontal gyrus inducing phonemic paraphasias when stimulated; and 4, semantic paraphasia elicited by stimulation of the dorsolateral prefrontal cortex. The resection was performed according to functional boundaries, with identification of the subcortical pathways as follows: 43, anterior part of the inferior fronto-occipital fasciculus inducing semantic paraphasias when stimulated; 45, descending fibers from the ventral premotor cortex inducing articulatory disturbances when stimulated; and 50, superior fibers of the inferior fronto-occipital fasciculus coming in contact with the dorsolateral prefrontal cortex and eliciting semantic paraphasias during stimulation. E, postoperative axial (left), coronal (middle), and sagittal (right) enhanced T1-weighted MRI demonstrating complete resection of the tumor. The patient returned to a normal socioprofessional life with no deficit.

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TABLE 2. Clinical, Radiological and Pathological Characteristics Concerning the Second Surgerya Presenting Symptoms Partial seizures, depressive syndrome Partial seizures Intractable partial seizures Clinical Examination Memory, writing disturbances Quadrantanopsia Working memory and attentional disturbances, paraphasias Speech disturbances Normal Attention and memory disturbances Right somatosensory deficit, right ataxia Speech and memory disturbances Normal Delay Since the First Surgery, mo 8 Extent of Resection Total Postoperative Examination Normal Adjuvant Therapy No Rehabilitation Yes

Patient 1

Pathology (WHO) Ganglio glioma

2 3

84 6

Subtotal Subtotal

Finger dysesthesia (5 d) Speech slowness, attentional disorders (7 d) Speech recovery (3 d) Normal Transitory speech disturbances (5 d) Slight right superior limb ataxia (5 d) Speech recovery (6 d) Normal

WHO II glioma with anaplastic foci WHO II glioma

CT No

No Yes

4 5 6

Intractable partial seizures Normal Normal

70 91 25

Subtotal Total Total

WHO II glioma WHO III glioma WHO II glioma

No RT No

Yes No No

Intractable partial seizures Generalized seizures Intractable partial seizures

42

Subtotal

64

Total

120

Subtotal

WHO II glioma with anaplastic foci WHO II glioma with anaplastic foci WHO II glioma

No

Yes

CT

Yes

No

No

WHO, World Health Organization; RT, radiotherapy; CT, chemotherapy.

of language disorders after the first surgery returned to work. The patient who experienced a depressive syndrome after the first operation returned to a normal social life, finished her studies, and started to work. Thus, there was no morbidity resulting from the second surgery. The quality of life improved in these 3 patients relative to their preoperative condition. Pathological examinations confirmed a WHO grade I glioma (ganglioglioma) in 1 patient and a WHO grade II glioma in 5 patients. In the 3 patients with a contrast enhancement on the preoperative MRI, anaplastic foci were identified. Postoperative MRI showed complete resection in 4 patients, subtotal removal in 5 patients (<10 cm3 of residue), and no partial resections (Figures 1E, 2E, 3D and 4D). The extent of resection was improved in all patients compared with the first surgery. The mean volume of residual tumor was 1.6 cm3 (range, 0-5 cm3) (P = .04; Table 3). With a mean follow-up of 13 months, 7 patients had postoperative relief of seizures. One patient received adjuvant radiotherapy, and 2 patients underwent chemotherapy (temozolomide) because of an increase of the rate of partial seizures (beginning of anaplastic transformation on pathological examination in the 3 patients).

DISCUSSION
Surgical management of low-grade gliomas changed dramatically in the past decade, especially concerning those involving brain crucial regions.27-40 Advances in methods of intraoperative functional mapping in awake patients have been demonstrated to significantly increase indications of surgical resection while minimizing the risk of permanent deficit for low-grade gliomas located within the so-called eloquent areas, classically considered inoperable.2,11,41-50 Here, we reviewed the recent literature from 2003 on surgery for gliomas in functional regions (Table 4). It shows that the use of intraoperative electrical mapping has decreased the incidence of permanent neurological deficit to 4.1% (analysis of 1460 surgical resections for glioma, including 522 low-grade gliomas). Interestingly, in a previous article, we performed a similar review from 1994 to 2003 (analysis of 834 gliomas, including 358 low-grade gliomas) and found an almost similar rate of sequelae of 4.2% against a mean of 19% of definitive deficit in series in which intraoperative electrical mapping was not used.11 Such data support the reliability of awake mapping to preserve the quality of life of patients operated on for a low-grade glioma and the increased use of an intrasurgical method of functional mapping in

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A
FIGURE 3. A, axial fluid-attentuated inversion recovery (FLAIR)weighted (left), coronal T2-weighted (middle), and sagittal enhanced T1-weighted (right) magnetic resonance imagine (MRI) showing partial resection of a left parietal low-grade glioma after surgery performed under general anesthesia. B, axial FLAIR-weighted (left), coronal enhanced T1-weighted (middle,) and sagittal T2-weighted MRI (right) showing the lesion growth after 3 years, with a volumetric increase from 65 to 90 cm3. C, intraoperative photographs during a second surgery performed under local anesthesia showing the cortical landmarks. Intraoperative photographs before (left) and after (right) resection of the lesion performed under local anesthesia. The letters correspond to the limits of the tumor identified with intraoperative ultrasonography. The eloquent cortical sites were marked by numbers as followed: 47, left ventral premotor cortex inducing anarthria during stimulation; 2, primary motor cortex of the face; 50, primary motor cortex of the hand; within the retrocentral gyrus, primary somatosensory cortex of the face (4), fingers (48, 6, 5, 7), and forearm (8). The resection was performed according to functional boundaries, with identification, at the level of the subcortical white matter, of the somatosensory thalamocortical fibers inducing dysesthesias in the upper (39) and lower (46) limb, and of the arcuate fasciculus (38), eliciting phonemic paraphasias during stimulation. D, immediate postoperative FLAIR axial (left), coronal (middle), and sagittal (right) enhanced T1weighted MRI showing a subtotal glioma removal with a residue (3 cm3) in the anterior part of the surgical cavity, where somatosensory fibers represented the anterior limit of resection. The patient returned to a normal socioprofessional life with no deficit.

recent years (522 operations in the last 5 years instead of 358 operations in the previous 9 years). In the present study, we confirm the improvement in functional results owing to intraoperative awake mapping, especially concerning language performance, seizure control, and thus optimization of socioprofessional quality of life. After the first surgery performed under general anes-

thesia, 3 patients did not return to their professional activity, in 2 cases because of mild dysphasia. After the second operation, performed under awake conditions and with postsurgical speech therapy, all patients returned to work. However, neurosurgeons have to keep in mind that the first goal of surgery for low-grade glioma is to maximize the extent of

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TABLE 3. Comparison of Residual Volume of Glioma After the First and Second Surgeriesa First Surgery Patient Postop- Extent erative of Volume, Resection cm3 12 41 84 6 13 10 65 8 20 ST P P ST P P P ST P Second Surgery Preop- Postop- Extent Followup, mo erative erative of Volume, Volume, Reseccm3 cm3 tion 12 43 89 25 25 13 90 65 0 2 4 5 0 0 3 0 0 T ST ST ST T T ST T T 27 27 20 13 8 8 7 4 3

1 2 3 4 5 6 7 8 9
a

ST, subtotal; T, total; P, partial.

TABLE 4. Permanent Neurological Deficit Reported in the Literature From 2003 After Surgery of Gliomas Performed With Intraoperative Electrical Mappinga Gliomas (WHO II Gliomas When Available), n 294 21 (9) 7
41

Authors (Year)

Severe Permanent Postoperative Deficits, n patients (%) 14 (4.8) 0 0 0 2 (2.3) 0 14 (10) 1 13 8 (3.2) 6 (3.9) 1 (14.2) 2 (1.7) 61 (4.1)

Keles et al (2004)32 Otani et al (2005)7 Bello et al (2006)2 Benzagmout et al (2007) Bello et al (2007)2 Sakurada et al (2007)49 Carrabba et al (2007)43 Low et al (2007)46 Serletis et al (2007)10 Sanai et al (2008)8 Ilmberger et al (2008)6 Amorim (2008) Total
a

7 (7) 88 (44) 3 (2) 146 13 (7) 367 (137) 250 (124) 142 (74) 7 (3) 115 (115) 1460 (522)

45

Duffau et al (2008)5

WHO, World Health Organization.

resection. Despite the lack of phase III studies, there is growing evidence that more extensive tumor removal may be associated with a more favorable life expectancy for patients with low-grade gliomas by delaying the anaplastic transformation.10,18,28,51-58 Therefore, it could be argued that the use of intraoperative mapping with preservation of eloquent cortical and subcortical structures might

lead to a smaller degree of resection. To the best of our knowledge, the extent of glioma removal was never directly compared between traditional and awake procedures, except in 2 previous studies by Reithmeier et al12 and by our team.11 Nonetheless, even though both reported an improved extent of resection with intraoperative mapping, the comparison was made with a control group and not in the same patients. The present study is, to the best of our knowledge, the first that evaluates the 2 surgical modalities in the same patients. As a consequence, the fact that both surgeries were performed consecutively for low-grade gliomas located in the same eloquent regions enabled us to objectively compare the extent of resection without and then with the use of awake mapping. In the first surgery, performed under general anesthesia, the choice of surgical limits resulted from the macroscopic evidence of the visible pathological tissue. However, it is well known that low-grade glioma is an invasive, poorly circumscribed lesion. As a consequence, on the basis of purely anatomic criterion, when the tumor is located in presumably eloquent areas, the extent of resection is decreased to avoid permanent deficit. In the present study, there was no complete resection, only 3 subtotal resections and 6 partial resections, with a high mean volume of residue 29 cm3. In addition, despite these precautions, 2 patients had a moderate but objective language worsening, preventing them from working. On the contrary, during second surgery, direct cerebral stimulation enabled the surgeon to define a map specific for each patient and to take into account the interindividual anatomofunctional variability to tailor the resection according to functional boundaries at both the cortical and subcortical levels.5,21 As a consequence, the glioma removal was pursued until eloquent structures were encountered, not before.11 Interestingly, this methodology allowed us to take a margin around the tumor, eg, in patients 2 and 4. Such strategy based on intrasurgical awake mapping enabled the maximization of the extent of glioma resection beyond the visible limits of the tumor-because it is now known that tumor cells invade brain tissue far away from the boundaries of the tumor image-but without inducing permanent deficit. Even within crucial areas, thanks to mechanisms of brain plasticity extensively described in cases of slow-growing lesions such as low-grade gliomas,18,20,41 intraoperative awake mapping allows opening the door to an increased extent of resection than that based on purely anatomic criterion. In the present study, there was no partial resection after the second surgery, with a mean volume of residual tumor of only 1.6 cm3, significantly reduced compared with the mean residue left after the first operation. These results can be explained by the fact that it was possible to remove parts of tumor located in regions classically considered crucial for function because of functional reshaping shown by intraoperative mapping but that these portions of glioma were judged a priori as inaccessible during the first intervention. Interestingly, despite optimization of lesion removal because no margin was left around the eloquent structures detected by electrostimulation,5 it is worth noting that the brain function and quality of life of patients were preserved and

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A
FIGURE 4. A, Axial fluid-attentuated

inversion recovery (FLAIR)weighted (left), sagittal T1-weighted (middle), and coronal T2-weighted (right) magnetic resonance imagine (MRI) showing a partial resection of a right parietooccipital low-grade glioma after a surgery performed under general anesthesia. B, axial (left), sagittal (middle), and coronal (right) enhanced T1-weighted MRI showing the growth of the residual tumor, with a very slow volumetric increase (from 41 to 43 cm 3 in 84 months, after radiotherapy and chemotherapy) but with the occurrence of an enhancement in the posterior part. C, intraoperative photographs before (left) and after (right) resection of the lesion performed under local anesthesia. The letters correspond to the limits of the tumor identified with intraoperative ultrasonography. The eloquent cortical sites were marked by numbers as followed: 1, primary motor cortex of the hand; 5, primary somatosensory cortex of the forearm; and 2, 4, 9, and 5, primary somatosensory cortex of the fingers. The resection was performed according to functional boundaries, with identification, at the level of the subcortical white matter and of the somatosensory thalamocortical fibers inducing dysesthesias in the upper (10) and lower (11) limb when stimulated. D, postoperative FLAIR-weighted axial (left), sagittal (middle), and coronal (right) T1-weighted MRI showing a subtotal glioma removal (2 cm 3 of residue in the depth). The patient returned to a normal socioprofessional life with no deficit.

even improved compared with the first surgery because all patients are now working. However, we have to acknowledge 3 limitations of our studies. First, there was a significant time interval between surgeries. Interestingly, taking into account this significant time interval between surgeries and the fact that all WHO grade II gliomas are growing tumors, the mean volume of the lesion before the second surgery was greater than the mean volume after the first resection (Table 3). Consequently, it was not obvious that the amount of resection could be greater in the second surgery, especially

because of the location of the gliomas within eloquent areas. Second, in the statistical comparison of residual tumor volumes with and without mapping, there is a bias resulting from poor resection in some first procedures, which had been performed in another institution and which could have been much more extended even without mapping, particularly the portions of those tumors that were not directly adjacent to eloquent areas. Third, the reliability of electrical mapping should be discussed. We have already reported that the reliability of the initial cortical mapping was confirmed by the subcortical mapping, and the congruence between

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these maps (gray and white matter) guarantees the practitioner that the organization of the network (and not only isolated cortical epicenters) has been correctly understood.5 Furthermore, the patient continued to perform tasks throughout the resection, allowing the surgeons to check the anatomofunctional integrity of the eloquent circuits online, in addition to the data provided by the electrical mapping. However, we acknowledge that there is still a risk of false positives with electrostimulation. We have nevertheless demonstrated that awake mapping allows an increase in the extent of resection while preserving brain function despite the fact that the specificity of cortico-subcortical electrical mapping remains a matter of concern.

CONCLUSION
We show not only that the use of intraoperative direct awake brain stimulation during surgery of low-grade gliomas enables the surgeon to perform a resection according to functional boundaries, minimizing postoperative morbidity and even improving quality of life, but also that this technique has a quantitative impact on the extent of resection. The direct comparison between the results obtained after consecutive surgeries without and then with electrical mapping in the same patient demonstrates for the first time and for sequential surgeries better resection with mapping than with traditional surgery under general anesthesia. The paucity of cases discussed in this study in relation to the period considered and the average number of cases of low-grade gliomas treated by the same senior author (250) suggests that a growing number of patients underwent surgery with the help of awake brain mapping because this technique is increasingly safe, achievable, and reproducible. Therefore, the continuation of its spread is desirable, thanks to multidisciplinary and multicenter studies, with a greater standardization of criteria for data collection, which is essential for a more objective comparison of results between different managements. Disclosure
The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.

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Acknowledgment
The authors would like to thank Nicolas Menjot de Champfleur, MD, for his help with the figures.

COMMENTS
his article illustrates well how the use of awake mapping of the brain can optimize the extent and safety of resection of low-grade gliomas. The main concern about the study is that the authors demonstration is based on the comparison with what they consider traditional resection. However, in the 4 provided figures of the postoperative images after initial surgery, the stigmas are those of open biopsies rather traditional (even partial) resections. The quality of the results achieved with the use of awake mapping in their 9 patients constitutes a sufficient argumentation to illustrate the usefulness of the method. From an oncological point of view, it has been reported that the prognosis of the low-grade gliomas depends significantly on the extent of the removal. This is, of course, especially true for astrocytomas. As far as oligodendrogliomas are concerned, one should be circumspect in the appraisal of the oncological value of extremely large resections. It has been well established by pathologists that tumor cells invade brain tissue far away from the boundaries of the tumor, especially through the intrahemispheric and even the interhemispheric fascicles and commissures. In addition, one must not underestimate the limitation and especially the pitfalls of brain cortical stimulation, not only because of false-positive but also because of false-negative responses, the latter caused by refractory phases after stimulation. Plus, white-matter mapping is not very reliable and has not been codified yet. The authors should be acknowledged for their intensive work and energy in promoting awake mapping within the neurosurgical community. Marc Sindou Lyon, France

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