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Surgical resection of incidental diffuse gliomas involving eloquent brain areas. Rationale, functional, epileptological and oncological outcomes
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Original article
Surgical resection of incidental diffuse gliomas involving eloquent brain areas. Rationale, functional, epileptological and oncological outcomes G.L.O. Lima a,b,c , E. Dezamis b,c , R. Corns d , O. Rigaux-Viode b,c , S. Moritz-Gasser g , A. Roux b,c , H. Duffau e,f,g,1 , J. Pallud b,c,e,∗,1 a
Department of Neurosurgery, Onofre Lopes University Hospital, Rio Grande do Norte Federal University, Natal, RN, Brazil Department of Neurosurgery, Sainte-Anne Hospital, 1, rue Cabanis, 75674 Paris cedex 14, France c Paris Descartes University, Sorbonne Paris Cité, Paris, France d Department of Neurosurgery, Leeds General Infirmary, Leeds, United Kingdom e Réseau d’étude des gliomes (REG), Groland, France f Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center, Montpellier, France g Inserm U1051, Institute for Neuroscience of Montpellier, Montpellier, France b
a r t i c l e
i n f o
Article history: Received 7 May 2016 Received in revised form 22 July 2016 Accepted 22 August 2016 Available online xxx Keywords: Awake craniotomy Diffuse low-grade glioma Incidental Outcomes Surgery
a b s t r a c t Objective. – Incidentally discovered diffuse low-grade gliomas progress in a fashion similar to their symptomatic counterparts. Their early detection allows more effective pre-emptive and individualized oncological treatment. We assessed the safety and efficacy of maximal safe resection according to functional boundaries for incidental diffuse low-grade gliomas in eloquent areas. Material and methods. – Two-centre retrospective series of adult patients with incidental diffuse lowgrade gliomas located within/close to eloquent areas in the dominant hemisphere, treated with maximal surgical resection according to functional boundaries under intraoperative functional cortico-subcortical monitoring under awake conditions, and with a minimal follow-up of 24 months. Results. – The series included 19 patients (8 men, 11 women) with no preoperative neurological deficit but with a radiologically enlarged glioma. No intraoperative seizure, postoperative infection, haematoma or wound-healing problem was observed. In the immediate postsurgical period, a transient neurological worsening occurred in 10 patients. The resection (mean rate 96.4%; range, 82.4–100) was supratotal in 5 cases, total in 5 cases, subtotal in 7 cases, and partial in 2 cases. Six months after surgery, all patients recovered after functional rehabilitation, with no permanent neurological deficit, Karnofsky Performance Status was 100 (except for one patient who received early postoperative radiotherapy) and no seizures were observed. The survival without progression requiring oncological treatment was significantly longer in patients with a total/supratotal resection than in patients with a partial/subtotal resection. Conclusions. – These results suggest the reproducibility, safety, and effectiveness of an early maximal functionally based resection within cortico-subcortical functional boundaries for incidental diffuse lowgrade gliomas in adults in centres hyperspecialized in surgical neuro-oncology. © 2016 Elsevier Masson SAS. All rights reserved.
1. Introduction World Health Organization (WHO) grade II glioma (diffuse lowgrade glioma [DLGG]) is a heterogeneous group of brain tumours
∗ Corresponding author. Department of Neurosurgery, Sainte-Anne Hospital, 1, rue Cabanis, 75674 Paris cedex 14, France. E-mail address: [email protected] (J. Pallud). 1 These authors participated equally in this work.
characterized by slow and continuous growth [1–3], with a preferential migration along white matter tracts [4,5] and by an evolution towards a higher grade of malignancy [3,6]. Due to their constant evolution, an active therapeutic attitude is now recommended, with early surgery as the first therapy [6–8]. Intraoperative mapping, with maximal safe resection according to functional boundaries, is associated with a longer overall survival while minimizing morbidity and maintaining quality of life [6,9–12]. The management of DLGG is switching towards a personalized and long-term multistage approach. Each case is individually
http://dx.doi.org/10.1016/j.neuchi.2016.08.007 0028-3770/© 2016 Elsevier Masson SAS. All rights reserved.
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tailored based on clinical, radiological, and histomolecular factors, thus supporting personalized, functional, and preventive neurooncology [8]. The natural history of DLGG development can be summarized in four stages [13–15]: • the biological birth without any symptom and below the detection limit of routine MRI; this is the occult stage; • at some point, the glioma becomes visible on MRI, yet the patient remains asymptomatic; this is the clinically silent stage; • the glioma elicits clinical symptoms, most commonly epileptic seizures; this is the symptomatic stage; • at some point in time, the glioma progresses from its rather indolent behaviour to that of a higher grade glioma, ultimately killing the patient due to brain invasion and spread; this is the malignant transformation. The “clinically silent” period has recently been estimated to last approximately 14 years [14]. When symptomatic, DLGG are usually revealed by inaugural seizures in young adults with no or mild neurological and neuropsychological deficits [7,16]. However, the long period of evolution while asymptomatic but detectable on MRI explains why DLGG can be incidentally discovered on MRI in up to 0.3% of the healthy population [17–19]. This corresponds to 3% of diagnosed primary brain tumours in clinical practice [20]. This early detection represents an opportunity to apply preventive oncological treatment with a maximal chance of efficacy [8,17]. This type of approach has to be supported by evidence of radiological progression of the incidentally discovered DLGG. Previous studies have shown that incidental DLGG are progressive tumours with: • • • •
a constant rate of growth similar to that of symptomatic DLGG; insidious but objective neuropsychological impairments [21]; a natural tendency towards becoming a symptomatic DLGG; histopathological and molecular findings similar to those of symptomatic DLGG; • a risk of malignant transformation [17,22–27].
In addition, the glioma can be discovered late in its natural history, as either a secondary anaplastic glioma or a secondary glioblastoma, after the malignant but silent transformation of the DLGG [28]. All these observations support the benefits of early intervention for incidental DLGG. However, the management of incidental DLGG involving eloquent brain areas is ill defined and requires further investigation [26,29]. Here we report a two-centre study aiming at assessing the safety and efficacy of early and preventive intervention for incidental DLGG with maximal surgical resection according to functional boundaries under intraoperative functional cortico-subcortical monitoring under awake conditions. Specifically, we assessed the postoperative outcomes, the oncological control, and functional status (including epileptic seizure control, neuropsychological assessments, ability to work).
within or near eloquent brain areas. All surgery was performed by the same neurosurgeons at each institution. Inclusion criteria were: • adult patients older than 18 at the time of radiological diagnosis; • incidental DLGG defined as a previously undetected and incidental tumour at the time of imaging diagnosis that was an unexpected discovery and unrelated to the purpose of the MRI examination [17]; • glioma location within or close to eloquent areas in the dominant hemisphere [30]; • maximal surgical resection according to functional boundaries under intraoperative functional cortico-subcortical monitoring under awake conditions using the asleep-awake-asleep protocol previously described [31–33]; • minimum postoperative follow-up of 24 months. 2.2. Evaluation methods Data on the following parameters were collected: gender, age at radiological diagnosis, reason for initial investigation, tumour location, time interval between radiological diagnosis and surgery, preoperative tumour volume and surgically resected volume (evaluated on pre- and postoperative MRI using Fluid Attenuated Inversion Recovery [FLAIR] sequence), histopathological diagnosis according to the WHO classification version 2007 [34], postoperative oncological treatment, duration of follow-up, malignant transformation, and survival. In addition, the patients’ neurological status and language functions were evaluated pre- and postoperatively at six months after surgery. Handedness was assessed using the standardized Edinburgh inventory. Language evaluation was performed using the Boston Diagnostic Aphasia Examination and a test of picture naming (DO80 test). Finally, the patients’ functional status was evaluated by means of the Karnofsky Performance Status (KPS) [16] before and after the surgery. 2.3. Magnetic resonance imaging evaluation The tumour volume was calculated using region of interest measurements of abnormal signal on FLAIR or T2-weighted sequences, as previously described [35]. Postoperatively, the volume of the residual tumour (if any) was calculated using the same method on an MRI obtained at 3 months after surgery. In all cases, at least two MRIs at a 3-month interval were performed before surgery, to estimate the rate of radiological growth, using the method described above [35]. The extent of resection was defined as “total” when no residual abnormal signal was present on FLAIR or T2-weighted sequence, as “supratotal” when a margin of parenchyma was removed around the preoperative FLAIR or T2-weighted sequence signal abnormality, with a larger volume of surgical cavity as compared with the presurgical tumour volume, as previously described [33], and as “subtotal” when the postoperative residual signal was less than 10 cm3 [36]. All other cases were considered a partial resection.
2. Methods
2.4. Surgical procedure
2.1. Data source
In all cases, intraoperative functional cortical and subcortical direct electrostimulation mapping was performed using the “asleep-awake-asleep” protocol in the two institutions, as previously reported [26,32,37]. Cerebral sulci and gyri were first identified using intraoperative ultrasonography. Functional mapping used a bipolar electrode (5-mm space between tips; Centre 1, Nimbus, Newmedic, Hemodia; Centre 2, Osiris NeuroStimulator, Inomed, Madison WI) delivering a biphasic current (pulse frequency 60 Hz; pulse phase duration 1 ms). The entire exposed
This prospective study examined a consecutive series of 19 patients who underwent maximal functional-based surgical resection at two different neurosurgical institutions (Centre 1: Gui de Chauliac University Hospital of Montpellier, France, between December 1998 and December 2010, France; Centre 2: Sainte-Anne Hospital Center–University Paris Descartes, France, between January 2010 and December 2013) for an incidental DLGG located
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cortex was stimulated and all responsive sites were re-stimulated three times for confirmation; all the other sites were stimulated at least three times. The current intensity used for individual patients was determined by progressively increasing the amplitude in 0.5 to 1 mA increments until a functional response was elicited (baseline 1 mA, maximum 4 mA in Centre 1, 6 mA in Centre 2). In all cases in which the central region was exposed, sensorimotor mapping was first performed to confirm the positive responses (movement and/or paraesthesia). The patient was then asked to perform language tasks: counting (regular rhythm, from 1 to 10, repetitively) and picture naming (DO80) with the goal to identify the essential cortical sites known to be inhibited by stimulation. Before naming each picture, the patient was asked to read a short phrase, namely the French translation of “this is a etc.” to check that there were no seizures generating complete speech arrest if the patient was not able to name the picture. For the picture naming task, DO80 was used pre- and postoperatively. The patient was never informed when the brain was stimulated. The duration of each stimulation was about 4 s. At least 1 picture was presented without stimulation in between each actual stimulation, and in order to avoid seizures, no site was stimulated twice in succession. The types of language disturbances (speech arrest, anomia, phonetic/phonemic/semantic paraphasia, slowness with initiation disturbances and perseverations) were classified by a senior speech therapist (Centre 1: SMG; Centre 2: ORV) using a classification previously described [31]. Each eloquent area was marked with a sterile numbered tag (0.25 cm2 ) on the brain surface and its location was correlated with the anatomical landmarks previously identified by ultrasonography. The glioma was then removed by alternating resection and electrostimulation for subcortical functional mapping. Using the same stimulation parameters, including current intensity, the functional pathways were followed progressively from the cortical eloquent areas already mapped to the depth of the resection. The patient had to continuously perform the naming task and right limb movement throughout the glioma resection, especially when the resection came close to the subcortical eloquent structures, which were also identified by functional inhibition during stimulation as at the cortical level. Thus, we were able to detect the subcortical tracts involved in language and sensorimotor functions in the white matter tracts. To optimize the tumour removal, with function preservation, all resections were pursued until eloquent structures were encountered around the surgical cavity. Thus, resection was performed according to individual functional cortical and subcortical boundaries. This means that there was no margin left around the eloquent areas, both within the grey matter and the white matter [38]. As a consequence, when possible, the resection was extended beyond the tumour limits visible on preoperative MR imaging and on intraoperative ultrasonography [33]. Intraoperative photographs of the functional mapping were routinely performed before and after resection. 2.5. Endpoints Survival without progression requiring oncological was measured from the date of histopathological diagnosis to the date of a new oncological treatment administered for clinical/imaging progression. For surviving patients, these intervals were censored at the date of last follow-up [16]. Univariate analyses were carried out using the Fisher’s exact tests for comparing categorical variables. Unadjusted survival curves for survival before progression requiring an oncological treatment was plotted by the KaplanMeier method and statistical significance was assessed using the log rank test. A P-value of less than 0.05 was considered significant. Analyses were performed using JMP 11.0.0 (SAS Institute Inc., Cary, NC).
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3. Results 3.1. Clinical and imaging findings Patient characteristics are summarized in Table 1. The series consisted of 19 patients (8 men and 11 women) with a mean age of 32.8 years at diagnosis (range, 18–51). Eighteen out of 19 patients were right-handed, all of them had left-hemisphere dominance as determined by the Edinburgh inventory. The reasons for initial MRI were: • headaches without any sign of increased intracranial pressure (n = 10); • head trauma (n = 3); • other symptomatic lesion (n = 4; 1 subependymoma, 1 schwannoma, 1 Chiari malformation, 1 pituitary adenoma); • dizziness (n = 1); • research protocol (n = 1). The mean time interval between radiological diagnosis and surgical resection was 21.2 months (range 3–120). Preoperatively, no patient had a neurological deficit; all patients had normal scores at BDAE and a preoperative KPS score of 100. No patient had previous antiepileptic drug therapy or oncological treatment (no chemotherapy, no radiotherapy). A patient with a Maffucci syndrome (case no 1) was diagnosed 10 years previously with a left frontal periventricular benign subependymoma and this was surgically removed (we reviewed the histopathology to confirm this). All gliomas were located in or near eloquent areas within the left dominant hemisphere (supplementary motor area (n = 4), paralimbic system (n = 5; 1 insular, 3 fronto-insular, 1 temporo-insular), frontal lobe (n = 6), temporal lobe (n = 2), and parietal lobe (n = 2). Contrast enhancement was observed in two cases (1 faint and patchy and 1 nodular). A volumetric increase in the size of the tumour was observed in all cases on serial MRI (Fig. 1). The mean glioma volume on preoperative MRI was 51.4 cm3 (range 2–151). 3.2. Intraoperative and early postoperative results In all patients, the cortical and subcortical functional areas were detected by intraoperative stimulation and represented the limits of resection (Fig. 2). There were no adverse events that required the abandonment of the procedure. No intraoperative seizures were observed. No postoperative infection, hematoma or wound-healing problem was observed. In the immediate postsurgical period, a transient worsening was found in 10 patients (52.6%). There were language disorders (n = 7) and supplementary motor area syndromes (n = 3). Two patients with a glioma invading the supplementary motor area and the negative motor network experienced early postoperative seizures in the absence of prophylactic antiepileptic drugs: one presented in a partial status epilepticus at postoperative day 1 (patient no 3) and the other presented with a single seizure at postoperative day 10 (patient no 14). Complete seizure control was achieved with one antiepileptic drug (Levetiracetam) in both patients. The antiepileptic drug was discontinued after 12 months in patient no 3 and maintained in patient no 14 at the patient’s request. Note that 11 of the 17 patients without postoperative seizures were given a prophylactic antiepileptic drug following resection. The mean resection rate was 96.4% (range, 82.4–100). The resection was supratotal in 5 cases (26.3%), total in 5 cases (26.3%), subtotal in 7 cases (36.8%; mean residual volume of 2.1 cm3 , range 1–8.4), and partial in 2 cases (10.6%; residual volume of 6.0 and 12.0 cm3 , respectively; extent of resection of 87.7% and 82.4%, respectively).
Please cite this article in press as: Lima GLO, et al. Surgical resection of incidental diffuse gliomas involving eloquent brain areas. Rationale, functional, epileptological and oncological outcomes. Neurochirurgie (2017), http://dx.doi.org/10.1016/j.neuchi.2016.08.007
Reason for MR examination
Glioma location
Glioma volume at surgery (cm3 , FLAIR sequence)
Time interval from discovery to surgery (months)
Follow-up since discovery (months)
Follow-up since surgery (months)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Male Female Female Male Female Female Female Male Female Female Female Female Male Male Male
26 26 51 50 32 21 18 37 30 26 30 47 19 35 31
Fronto-insular (F3) Frontal (SMA) Frontal (Fronto-orb, F2, F3) Temporal Frontal (SMA) Frontal (SMA) Frontal (PreC) Frontal (Fronto-orb, F2, F3) Frontal (F3) Insular Frontal (F3) Temporal Frontal (F2) Frontal (SMA) Temporo-insular
108 20 143 55 35 7 11 90 34 2 140 10 6 9 25
3 6 120 71 3 42 25 31 3 32 6 24 14 3 6
234 187 161 148 107 82 78 72 70 67 67 55 46 46 45
231 181 41 77 104 40 53 41 67 35 61 31 32 43 39
16 17 18 19
Female Male Male Female
24 23 37 30
Subependymoma Headache Sinusitis Schwannoma Headache Pituitary adenoma Trauma Trauma Headache Headache Headache Dizziness Trauma Research protocol Chiari malformation Headache Headache Dizziness Headache
Fronto-insular (SMA, F2, F3, PreC) Parietal (PostC, IPL) Fronto-insular (F3) Parietal (PostC, SPL)
151 98 20 12.4
4 7 3 3
42 36 25 29
38 29 22 25
Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Postoperative residual glioma volume (cm3 , FLAIR sequence) 5 1 0 0 1 0 1 0 6 0 4 0 0 0 2 8 12 0 0
Early postoperative clinical examination
Early postoperative epileptic seizures
6-month postoperative clinical examination
6-month postoperative epileptic seizures
6-month postoperative KPS
Adjuvant oncological treatment (modality, months)
Dysphasia Mutism akinesia Normal Normal Normal Normal Dysphasia Normal Normal Normal Dysphasia Dysphasia Normal Mutism akinesia Dysphasia Mutism akinesia Dysphasia Dysphasia Normal
No No Yes No No No No No No No No No No Yes No No No No No
Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal
No No No (levetiracetam) No No No No No No No No No No No (levetiracetam) No No No No No
100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
No Yes (RT, 65) No No Yes (CT, 79) No Yes (CT, 40) No Yes (CT, 28) No Yes (CT, 20) No No No Yes (CT, 24) No Yes (RT, 3) No No
CT: chemotherapy; FLAIR: fluid attenuated inversion recovery; GTR: gross-total resection; IPL: inferior parietal lobule; MR: magnetic resonance; RT: radiotherapy; SMA: supplementary motor area; SPL: superior parietal lobule; STR: subtotal resection.
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Table 1 Clinical, imaging, and histopathological characteristics.
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Fig. 1. Incidental diffuse low-grade gliomas are progressive tumours. Example of the spontaneous velocity in diametric expansion of an incidentally discovered left frontal diffuse low-grade glioma through the evolution of its mean tumour diameter over time before oncological treatment while asymptomatic (patient no 8, Centre 2). Each point represents a MR examination. Prior to surgical resection, the tumour grew spontaneously and continuously with a spontaneous velocity of diametric expansion at 3.4 mm/year. A total surgical resection was performed under functional corticosubcortical boundaries using intraoperative functional mapping.
3.3. Histopathological analyses Histopathological examination confirmed the tumours to be WHO Grade II gliomas. Note that microfoci of endothelial proliferation were identified within the glioma core in five patients that were classified as grade II in Centre 1 and as transitional grade II–III in Centre 2.
six patients at a mean 42.7 months (range 20–79) post-surgery. Tumour progression requiring adjuvant oncological treatment was observed significantly more frequently in patients with a partial or a subtotal resection (75%) than in patients with a total or a supratotal resection (P < 0.001). The median survival without progression requiring oncological treatment was longer in patients with a total or a supratotal resection (significance not reached) than in patients with a partial or a subtotal resection (65 months, P = 0.006) (Fig. 3).
3.4. Six-month functional outcomes All patients improved after a personalized functional rehabilitation in all cases. Six months after surgery, all 19 patients had totally recovered, with no permanent neurological deficit and normal scores at BDAE. Seventeen patients had returned to normal social and professional life (full-time working in all cases) at their 6-month evaluation. Of the two patients that did not return to work, one was in post-retirement (patient no 3) and the other was undergoing radiotherapy (patient no 17). Except for the patient undergoing radiotherapy, the postoperative KPS was at 100 in the 18 other cases. No patient had on-going epilepsy, including after antiepileptic drug therapy discontinuation, and including the two patients with early postoperative seizures. Note that no improvement in headache was observed postoperatively in patients with presenting preoperatively with headaches. 3.5. Follow-up and survival analyses Of the 19 patients, one had immediate postoperative radiotherapy (patient no 17) for a transitional WHO grade II–III glioma; the other patients underwent radiological and clinical surveillance. The mean duration of follow-up was 62.4 months (range 21–231) from surgery, and 83.8 months (range 24–234 months) from radiological diagnosis. During the follow-up period, no patient died, and adjuvant oncological treatment was required for tumour progression in
4. Discussion Early and maximal safe resection with the aim of improving both oncological and epileptological outcomes has been recently proposed for incidental DLGG [17,22,25,26]. We propose a shift in the philosophy of treating asymptomatic gliomas towards a “preventive” maximal functional-based resection [8,15]. In this series of 19 cases, neurosurgeons hyperspecialized in surgical neuro-oncology at two institutions performed functional-based resections using cortical and subcortical direct electrical stimulations under awake conditions with the same onco-functional balance philosophy [39]. The functional and oncological results were similar in the treatment of incidental DLGG and they confirm the reproducibility of the conceptual approach of this onco-functional balance philosophy of DLGG resection. Based on the surgical resection technique with margins at the intraoperative cortical and subcortical functional boundaries [38], 52.6% of the patients had a transient deficit. Interestingly, the rate of postoperative transient deficit was lower in incidental DLGG than in symptomatic ones, which can be explained by a relative longer distance between the lesion and eloquent cortical and subcortical areas in incidental DLGG, as supported by a higher rate of supratotal resection according to functional-based boundaries. The transient postoperative deficit was resolved in all cases after a personalized linguistic and physiotherapeutic functional rehabilitation. In fact, six months after surgery, the 19 patients had totally recovered
Please cite this article in press as: Lima GLO, et al. Surgical resection of incidental diffuse gliomas involving eloquent brain areas. Rationale, functional, epileptological and oncological outcomes. Neurochirurgie (2017), http://dx.doi.org/10.1016/j.neuchi.2016.08.007
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Fig. 2. Functional-based resections of incidental diffuse low-grade gliomas located in eloquent brain areas. A. Example of a left frontal incidentally discovered diffuse lowgrade glioma in a 35-year-old right-handed man with normal neurological examination results and enjoying a normal life (patient no 14, Centre 2). Due to an objective tumour growth on follow-up MRI (velocity of diametric expansion at 6.7 mm/year), surgery was proposed 3 months after MR discovery. Intraoperative photograph taken during awake surgery showing the view before and after a supratotal glioma removal, which was achieved according to corticosubcortical boundaries detected by direct intraoperative electrical stimulation mapping throughout glioma resection. Results of the cortical mapping: primary motor cortex of the face (1, 2, 3) and the hand (4, 5), speech arrest (21) on the ventral premotor cortex, anarthria (20), vocalization (11). Results of the subcortical mapping after glioma resection: inhibition of voluntary movements and speech arrest (31) corresponding to the motor control network, inhibition of both movement of upper limb and speech (32, 33) corresponding to the frontal aslant tract and the fronto-striatal tract, phonemic paraphasia (34,35) corresponding to the projection of the long segment of the superior longitudinal fasciculus (arcuate fasciculus). B. Example of a left parietal incidentally discovered diffuse low-grade glioma in a 30-year-old right-handed woman with normal neurological examination results and enjoying a normal life (patient no 19, Centre 2). Due to an objective tumour growth on follow-up MRI (velocity of diametric expansion at 4.1 mm/year), surgery was proposed 3 months after MR discovery. Intraoperative photograph taken during awake surgery illustrates the view before and after a total glioma removal, which was achieved according to corticosubcortical boundaries detected by direct intraoperative electrical stimulation mapping throughout glioma resection. Results of cortical mapping: primary motor cortex of the face (3) and of the upper limb (1,2), primary sensory cortex of the upper limb (hand, 10, 14; upper limb, 11, 12, 13). Results of subcortical mapping after glioma resection: paresthesia on the lower limb (20) and on the chest (21). The tag line represents one centimeter. C. Example of a left parietal incidentally discovered diffuse glioma in a 23-year-old right-handed man with normal neurological examination results and enjoying a normal life (patient no 17, Centre 2). Due to an objective tumour growth on follow-up MRI (velocity of diametric expansion at 8.4 mm/year), surgery was proposed 7 months after MR discovery. Intraoperative photograph taken during awake surgery shows the view before and after a partial glioma removal, which was achieved according to corticosubcortical boundaries detected by direct intraoperative electrical stimulation mapping throughout glioma resection. Results of the cortical mapping: primary sensory cortex of the tongue (10), mouth (11), and hand (12, 13, 14), calculation error (40). Results of the subcortical mapping after glioma resection: paresthesia on the hand (15, 16, 17, 18), on the mouth and the tongue (19,20), phonemic paraphasia (30,31) corresponding to the projection of the long segment of the superior longitudinal fasciculus (arcuate fasciculus). The tag lines represent one centimeter.
Please cite this article in press as: Lima GLO, et al. Surgical resection of incidental diffuse gliomas involving eloquent brain areas. Rationale, functional, epileptological and oncological outcomes. Neurochirurgie (2017), http://dx.doi.org/10.1016/j.neuchi.2016.08.007
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Fig. 3. Total and supratotal resections of incidental diffuse low-grade gliomas improve survival without progression requiring oncological treatment. A. Kaplan-Meier estimates of survival without progression requiring oncological treatment since radiological discovery by extent of surgical resection (total and supratotal resections versus subtotal and partial resections). The median survival without progression requiring oncological treatment was longer in patients with a total or a supratotal resection (blue curve, median not reached) than in patients with a partial or a subtotal resection (blue curve, median 65 months, P = 0.006). B. Example of a left frontal incidentally discovered diffuse glioma (top MR examination) in a 51-year-old right-handed woman with normal neurological examination results and enjoying a normal life (patient no 3, Centre 2). Due to objective tumour growth on follow-up MRI (velocity of diametric expansion at 1.9 mm/year), a supratotal resection was achieved according to corticosubcortical boundaries detected by direct intraoperative electrical stimulation mapping throughout glioma resection 120 months after MR discovery. The histopathological diagnosis demonstrated a transitional form of WHO grade II to WHO grade III oligodendroglioma with microfoci of endothelial proliferation (immunoreactivity for IDH1R132, presence of a 1p/19q codeletion). The patient declined any adjuvant oncological treatment (proposal for radiotherapy followed by adjuvant chemotherapy). At 58 months following surgery, no tumour progression was observed (down MR examination).
(no permanent neurological deficit, normal scores at BDAE, KPS at 100 except for the patient undergoing radiotherapy, there were long-term no seizures) and 17 were working full time. Of note, of the two patients that did not return to work six months postoperatively, one was already retired and the other was undergoing radiotherapy. These excellent functional outcomes – achieved at two different institutions hyperspecialized in surgical neurooncology – demonstrate the reproducibility and the safety of early maximal functional-based resection with cortical and subcortical direct electric stimulations within functional boundaries. Two patients with no antiepileptic drug prophylaxis experienced
a brief episode of early postoperative seizures. Early postoperative seizures, mainly within the first 3-months postoperatively, are thought to occur in up to 10% for all intracranial tumours and in up to 25% in DLGG [29]. To reduce the risk of adverse events during the preventive surgical resection of asymptomatic patients harbouring an incidental DLGG, the pros and cons of antiepileptic drugs should be discussed with the patient. Despite the absence of a dedicated trial, the present results (no early postoperative seizure in patients with postoperative antiepileptic drug prophylaxis) and a previous series support the prophylactic administration of antiepileptic drug therapy in the perioperative period [29].
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Large resections until cortico-subcortical boundaries were performed: complete resection in 52.6% of cases (including supratotal resections in 26.3%), subtotal resections in 36.8% of cases and two partial resections of 87.7 and 82.4% of the tumour, respectively. No postoperative complications were observed. It has previously been shown that incidental DLGG and symptomatic DLGG share similar clinical, imaging, histopathological, and molecular features [17,25]. As compared to symptomatic DLGG, incidental DLGG classically present with a smaller volume tumour and a less frequent involvement of eloquent areas that may explain the absence of clinical symptom and the larger extent of surgical resection. In the present series, the extent of resection (mean 96.7%) is comparable to other series of incidental DLGG [17,22,25,26,29] despite the tumour location close to or within eloquent areas within the dominant hemisphere and the larger tumour volumes at treatment. These results – achieved in two different institutions hyperspecialized in surgical neuro-oncology – demonstrate the reproducibility and the effectiveness of an early maximal functional-based resection with cortical and subcortical direct electric stimulation within functional boundaries. They show the benefit of early surgical management especially the improved chances of a total or supratotal resection. In this series of incidental DLGG treated while asymptomatic, postoperative progression requiring adjuvant oncological treatments were observed. These observations highlight the fact that incidental DLGG are progressive tumours with the same potential for progression as their symptomatic counterparts, further bolstering the argument for their early treatment, as previously suggested [17,22,25,26,40]. A previous series of 16 patients with DLGG undergoing a supratotal resection found there was no malignant transformation observed after a follow-up period of 8 years [27]; no progression requiring adjuvant oncological treatments was required in patients with total or supratotal resection in the present series. This highlights the oncological impact of large resection encompassing the infiltrated brain parenchyma beyond MRI-defined abnormalities [33,41]. The small sample size and the relative short follow-up dictate prudence in generating potential guidelines for practical management of incidental DLGG. However, the present results suggest that: • large functional-based resection until cortico-subcortical boundaries using direct electrical stimulation under awake conditions is feasible with low surgical morbidity and good outcomes; • the philosophical approach of a “preventive” and maximal functional-based resection in incidental DLGG, to maximize the extent of resection before glioma growth and migration is reproducible across centres hyperspecialized in surgical neurooncology [40]; • similar to symptomatic DLGG, smaller tumour volume together with a lower duration of glioma evolution, is associated with a higher chance of supratotal resection [33], and with an improved prognosis, this argues in favour of early, preventive and aggressive surgical treatment of incidental DLGG when radiological tumour growth is observed on MRI [17]. As previously stated, a dedicated neurosurgical team is mandatory to achieve excellent outcomes in surgical neuro-oncology [42]. Here, such a proposal for preventive surgery is conceivable only if the reliability of this treatment is optimal, with maximal resection and minimal morbidity, meaning that patients with incidental DLGG should be referred to centres hyperspecialized in surgical neuro-oncology [15]. Last, the preventive management of incidental DLGG with the idea that their early detection and treatment could contribute to a possible cure for these tumours support a screening policy [13,15].
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Original article
Surgical resection of incidental diffuse gliomas involving eloquent brain areas. Rationale, functional, epileptological and oncological outcomes G.L.O. Lima a,b,c , E. Dezamis b,c , R. Corns d , O. Rigaux-Viode b,c , S. Moritz-Gasser g , A. Roux b,c , H. Duffau e,f,g,1 , J. Pallud b,c,e,∗,1 a
Department of Neurosurgery, Onofre Lopes University Hospital, Rio Grande do Norte Federal University, Natal, RN, Brazil Department of Neurosurgery, Sainte-Anne Hospital, 1, rue Cabanis, 75674 Paris cedex 14, France c Paris Descartes University, Sorbonne Paris Cité, Paris, France d Department of Neurosurgery, Leeds General Infirmary, Leeds, United Kingdom e Réseau d’étude des gliomes (REG), Groland, France f Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center, Montpellier, France g Inserm U1051, Institute for Neuroscience of Montpellier, Montpellier, France b
a r t i c l e
i n f o
Article history: Received 7 May 2016 Received in revised form 22 July 2016 Accepted 22 August 2016 Available online xxx Keywords: Awake craniotomy Diffuse low-grade glioma Incidental Outcomes Surgery
a b s t r a c t Objective. – Incidentally discovered diffuse low-grade gliomas progress in a fashion similar to their symptomatic counterparts. Their early detection allows more effective pre-emptive and individualized oncological treatment. We assessed the safety and efficacy of maximal safe resection according to functional boundaries for incidental diffuse low-grade gliomas in eloquent areas. Material and methods. – Two-centre retrospective series of adult patients with incidental diffuse lowgrade gliomas located within/close to eloquent areas in the dominant hemisphere, treated with maximal surgical resection according to functional boundaries under intraoperative functional cortico-subcortical monitoring under awake conditions, and with a minimal follow-up of 24 months. Results. – The series included 19 patients (8 men, 11 women) with no preoperative neurological deficit but with a radiologically enlarged glioma. No intraoperative seizure, postoperative infection, haematoma or wound-healing problem was observed. In the immediate postsurgical period, a transient neurological worsening occurred in 10 patients. The resection (mean rate 96.4%; range, 82.4–100) was supratotal in 5 cases, total in 5 cases, subtotal in 7 cases, and partial in 2 cases. Six months after surgery, all patients recovered after functional rehabilitation, with no permanent neurological deficit, Karnofsky Performance Status was 100 (except for one patient who received early postoperative radiotherapy) and no seizures were observed. The survival without progression requiring oncological treatment was significantly longer in patients with a total/supratotal resection than in patients with a partial/subtotal resection. Conclusions. – These results suggest the reproducibility, safety, and effectiveness of an early maximal functionally based resection within cortico-subcortical functional boundaries for incidental diffuse lowgrade gliomas in adults in centres hyperspecialized in surgical neuro-oncology. © 2016 Elsevier Masson SAS. All rights reserved.
1. Introduction World Health Organization (WHO) grade II glioma (diffuse lowgrade glioma [DLGG]) is a heterogeneous group of brain tumours
∗ Corresponding author. Department of Neurosurgery, Sainte-Anne Hospital, 1, rue Cabanis, 75674 Paris cedex 14, France. E-mail address: [email protected] (J. Pallud). 1 These authors participated equally in this work.
characterized by slow and continuous growth [1–3], with a preferential migration along white matter tracts [4,5] and by an evolution towards a higher grade of malignancy [3,6]. Due to their constant evolution, an active therapeutic attitude is now recommended, with early surgery as the first therapy [6–8]. Intraoperative mapping, with maximal safe resection according to functional boundaries, is associated with a longer overall survival while minimizing morbidity and maintaining quality of life [6,9–12]. The management of DLGG is switching towards a personalized and long-term multistage approach. Each case is individually
http://dx.doi.org/10.1016/j.neuchi.2016.08.007 0028-3770/© 2016 Elsevier Masson SAS. All rights reserved.
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tailored based on clinical, radiological, and histomolecular factors, thus supporting personalized, functional, and preventive neurooncology [8]. The natural history of DLGG development can be summarized in four stages [13–15]: • the biological birth without any symptom and below the detection limit of routine MRI; this is the occult stage; • at some point, the glioma becomes visible on MRI, yet the patient remains asymptomatic; this is the clinically silent stage; • the glioma elicits clinical symptoms, most commonly epileptic seizures; this is the symptomatic stage; • at some point in time, the glioma progresses from its rather indolent behaviour to that of a higher grade glioma, ultimately killing the patient due to brain invasion and spread; this is the malignant transformation. The “clinically silent” period has recently been estimated to last approximately 14 years [14]. When symptomatic, DLGG are usually revealed by inaugural seizures in young adults with no or mild neurological and neuropsychological deficits [7,16]. However, the long period of evolution while asymptomatic but detectable on MRI explains why DLGG can be incidentally discovered on MRI in up to 0.3% of the healthy population [17–19]. This corresponds to 3% of diagnosed primary brain tumours in clinical practice [20]. This early detection represents an opportunity to apply preventive oncological treatment with a maximal chance of efficacy [8,17]. This type of approach has to be supported by evidence of radiological progression of the incidentally discovered DLGG. Previous studies have shown that incidental DLGG are progressive tumours with: • • • •
a constant rate of growth similar to that of symptomatic DLGG; insidious but objective neuropsychological impairments [21]; a natural tendency towards becoming a symptomatic DLGG; histopathological and molecular findings similar to those of symptomatic DLGG; • a risk of malignant transformation [17,22–27].
In addition, the glioma can be discovered late in its natural history, as either a secondary anaplastic glioma or a secondary glioblastoma, after the malignant but silent transformation of the DLGG [28]. All these observations support the benefits of early intervention for incidental DLGG. However, the management of incidental DLGG involving eloquent brain areas is ill defined and requires further investigation [26,29]. Here we report a two-centre study aiming at assessing the safety and efficacy of early and preventive intervention for incidental DLGG with maximal surgical resection according to functional boundaries under intraoperative functional cortico-subcortical monitoring under awake conditions. Specifically, we assessed the postoperative outcomes, the oncological control, and functional status (including epileptic seizure control, neuropsychological assessments, ability to work).
within or near eloquent brain areas. All surgery was performed by the same neurosurgeons at each institution. Inclusion criteria were: • adult patients older than 18 at the time of radiological diagnosis; • incidental DLGG defined as a previously undetected and incidental tumour at the time of imaging diagnosis that was an unexpected discovery and unrelated to the purpose of the MRI examination [17]; • glioma location within or close to eloquent areas in the dominant hemisphere [30]; • maximal surgical resection according to functional boundaries under intraoperative functional cortico-subcortical monitoring under awake conditions using the asleep-awake-asleep protocol previously described [31–33]; • minimum postoperative follow-up of 24 months. 2.2. Evaluation methods Data on the following parameters were collected: gender, age at radiological diagnosis, reason for initial investigation, tumour location, time interval between radiological diagnosis and surgery, preoperative tumour volume and surgically resected volume (evaluated on pre- and postoperative MRI using Fluid Attenuated Inversion Recovery [FLAIR] sequence), histopathological diagnosis according to the WHO classification version 2007 [34], postoperative oncological treatment, duration of follow-up, malignant transformation, and survival. In addition, the patients’ neurological status and language functions were evaluated pre- and postoperatively at six months after surgery. Handedness was assessed using the standardized Edinburgh inventory. Language evaluation was performed using the Boston Diagnostic Aphasia Examination and a test of picture naming (DO80 test). Finally, the patients’ functional status was evaluated by means of the Karnofsky Performance Status (KPS) [16] before and after the surgery. 2.3. Magnetic resonance imaging evaluation The tumour volume was calculated using region of interest measurements of abnormal signal on FLAIR or T2-weighted sequences, as previously described [35]. Postoperatively, the volume of the residual tumour (if any) was calculated using the same method on an MRI obtained at 3 months after surgery. In all cases, at least two MRIs at a 3-month interval were performed before surgery, to estimate the rate of radiological growth, using the method described above [35]. The extent of resection was defined as “total” when no residual abnormal signal was present on FLAIR or T2-weighted sequence, as “supratotal” when a margin of parenchyma was removed around the preoperative FLAIR or T2-weighted sequence signal abnormality, with a larger volume of surgical cavity as compared with the presurgical tumour volume, as previously described [33], and as “subtotal” when the postoperative residual signal was less than 10 cm3 [36]. All other cases were considered a partial resection.
2. Methods
2.4. Surgical procedure
2.1. Data source
In all cases, intraoperative functional cortical and subcortical direct electrostimulation mapping was performed using the “asleep-awake-asleep” protocol in the two institutions, as previously reported [26,32,37]. Cerebral sulci and gyri were first identified using intraoperative ultrasonography. Functional mapping used a bipolar electrode (5-mm space between tips; Centre 1, Nimbus, Newmedic, Hemodia; Centre 2, Osiris NeuroStimulator, Inomed, Madison WI) delivering a biphasic current (pulse frequency 60 Hz; pulse phase duration 1 ms). The entire exposed
This prospective study examined a consecutive series of 19 patients who underwent maximal functional-based surgical resection at two different neurosurgical institutions (Centre 1: Gui de Chauliac University Hospital of Montpellier, France, between December 1998 and December 2010, France; Centre 2: Sainte-Anne Hospital Center–University Paris Descartes, France, between January 2010 and December 2013) for an incidental DLGG located
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cortex was stimulated and all responsive sites were re-stimulated three times for confirmation; all the other sites were stimulated at least three times. The current intensity used for individual patients was determined by progressively increasing the amplitude in 0.5 to 1 mA increments until a functional response was elicited (baseline 1 mA, maximum 4 mA in Centre 1, 6 mA in Centre 2). In all cases in which the central region was exposed, sensorimotor mapping was first performed to confirm the positive responses (movement and/or paraesthesia). The patient was then asked to perform language tasks: counting (regular rhythm, from 1 to 10, repetitively) and picture naming (DO80) with the goal to identify the essential cortical sites known to be inhibited by stimulation. Before naming each picture, the patient was asked to read a short phrase, namely the French translation of “this is a etc.” to check that there were no seizures generating complete speech arrest if the patient was not able to name the picture. For the picture naming task, DO80 was used pre- and postoperatively. The patient was never informed when the brain was stimulated. The duration of each stimulation was about 4 s. At least 1 picture was presented without stimulation in between each actual stimulation, and in order to avoid seizures, no site was stimulated twice in succession. The types of language disturbances (speech arrest, anomia, phonetic/phonemic/semantic paraphasia, slowness with initiation disturbances and perseverations) were classified by a senior speech therapist (Centre 1: SMG; Centre 2: ORV) using a classification previously described [31]. Each eloquent area was marked with a sterile numbered tag (0.25 cm2 ) on the brain surface and its location was correlated with the anatomical landmarks previously identified by ultrasonography. The glioma was then removed by alternating resection and electrostimulation for subcortical functional mapping. Using the same stimulation parameters, including current intensity, the functional pathways were followed progressively from the cortical eloquent areas already mapped to the depth of the resection. The patient had to continuously perform the naming task and right limb movement throughout the glioma resection, especially when the resection came close to the subcortical eloquent structures, which were also identified by functional inhibition during stimulation as at the cortical level. Thus, we were able to detect the subcortical tracts involved in language and sensorimotor functions in the white matter tracts. To optimize the tumour removal, with function preservation, all resections were pursued until eloquent structures were encountered around the surgical cavity. Thus, resection was performed according to individual functional cortical and subcortical boundaries. This means that there was no margin left around the eloquent areas, both within the grey matter and the white matter [38]. As a consequence, when possible, the resection was extended beyond the tumour limits visible on preoperative MR imaging and on intraoperative ultrasonography [33]. Intraoperative photographs of the functional mapping were routinely performed before and after resection. 2.5. Endpoints Survival without progression requiring oncological was measured from the date of histopathological diagnosis to the date of a new oncological treatment administered for clinical/imaging progression. For surviving patients, these intervals were censored at the date of last follow-up [16]. Univariate analyses were carried out using the Fisher’s exact tests for comparing categorical variables. Unadjusted survival curves for survival before progression requiring an oncological treatment was plotted by the KaplanMeier method and statistical significance was assessed using the log rank test. A P-value of less than 0.05 was considered significant. Analyses were performed using JMP 11.0.0 (SAS Institute Inc., Cary, NC).
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3. Results 3.1. Clinical and imaging findings Patient characteristics are summarized in Table 1. The series consisted of 19 patients (8 men and 11 women) with a mean age of 32.8 years at diagnosis (range, 18–51). Eighteen out of 19 patients were right-handed, all of them had left-hemisphere dominance as determined by the Edinburgh inventory. The reasons for initial MRI were: • headaches without any sign of increased intracranial pressure (n = 10); • head trauma (n = 3); • other symptomatic lesion (n = 4; 1 subependymoma, 1 schwannoma, 1 Chiari malformation, 1 pituitary adenoma); • dizziness (n = 1); • research protocol (n = 1). The mean time interval between radiological diagnosis and surgical resection was 21.2 months (range 3–120). Preoperatively, no patient had a neurological deficit; all patients had normal scores at BDAE and a preoperative KPS score of 100. No patient had previous antiepileptic drug therapy or oncological treatment (no chemotherapy, no radiotherapy). A patient with a Maffucci syndrome (case no 1) was diagnosed 10 years previously with a left frontal periventricular benign subependymoma and this was surgically removed (we reviewed the histopathology to confirm this). All gliomas were located in or near eloquent areas within the left dominant hemisphere (supplementary motor area (n = 4), paralimbic system (n = 5; 1 insular, 3 fronto-insular, 1 temporo-insular), frontal lobe (n = 6), temporal lobe (n = 2), and parietal lobe (n = 2). Contrast enhancement was observed in two cases (1 faint and patchy and 1 nodular). A volumetric increase in the size of the tumour was observed in all cases on serial MRI (Fig. 1). The mean glioma volume on preoperative MRI was 51.4 cm3 (range 2–151). 3.2. Intraoperative and early postoperative results In all patients, the cortical and subcortical functional areas were detected by intraoperative stimulation and represented the limits of resection (Fig. 2). There were no adverse events that required the abandonment of the procedure. No intraoperative seizures were observed. No postoperative infection, hematoma or wound-healing problem was observed. In the immediate postsurgical period, a transient worsening was found in 10 patients (52.6%). There were language disorders (n = 7) and supplementary motor area syndromes (n = 3). Two patients with a glioma invading the supplementary motor area and the negative motor network experienced early postoperative seizures in the absence of prophylactic antiepileptic drugs: one presented in a partial status epilepticus at postoperative day 1 (patient no 3) and the other presented with a single seizure at postoperative day 10 (patient no 14). Complete seizure control was achieved with one antiepileptic drug (Levetiracetam) in both patients. The antiepileptic drug was discontinued after 12 months in patient no 3 and maintained in patient no 14 at the patient’s request. Note that 11 of the 17 patients without postoperative seizures were given a prophylactic antiepileptic drug following resection. The mean resection rate was 96.4% (range, 82.4–100). The resection was supratotal in 5 cases (26.3%), total in 5 cases (26.3%), subtotal in 7 cases (36.8%; mean residual volume of 2.1 cm3 , range 1–8.4), and partial in 2 cases (10.6%; residual volume of 6.0 and 12.0 cm3 , respectively; extent of resection of 87.7% and 82.4%, respectively).
Please cite this article in press as: Lima GLO, et al. Surgical resection of incidental diffuse gliomas involving eloquent brain areas. Rationale, functional, epileptological and oncological outcomes. Neurochirurgie (2017), http://dx.doi.org/10.1016/j.neuchi.2016.08.007
Reason for MR examination
Glioma location
Glioma volume at surgery (cm3 , FLAIR sequence)
Time interval from discovery to surgery (months)
Follow-up since discovery (months)
Follow-up since surgery (months)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Male Female Female Male Female Female Female Male Female Female Female Female Male Male Male
26 26 51 50 32 21 18 37 30 26 30 47 19 35 31
Fronto-insular (F3) Frontal (SMA) Frontal (Fronto-orb, F2, F3) Temporal Frontal (SMA) Frontal (SMA) Frontal (PreC) Frontal (Fronto-orb, F2, F3) Frontal (F3) Insular Frontal (F3) Temporal Frontal (F2) Frontal (SMA) Temporo-insular
108 20 143 55 35 7 11 90 34 2 140 10 6 9 25
3 6 120 71 3 42 25 31 3 32 6 24 14 3 6
234 187 161 148 107 82 78 72 70 67 67 55 46 46 45
231 181 41 77 104 40 53 41 67 35 61 31 32 43 39
16 17 18 19
Female Male Male Female
24 23 37 30
Subependymoma Headache Sinusitis Schwannoma Headache Pituitary adenoma Trauma Trauma Headache Headache Headache Dizziness Trauma Research protocol Chiari malformation Headache Headache Dizziness Headache
Fronto-insular (SMA, F2, F3, PreC) Parietal (PostC, IPL) Fronto-insular (F3) Parietal (PostC, SPL)
151 98 20 12.4
4 7 3 3
42 36 25 29
38 29 22 25
Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Postoperative residual glioma volume (cm3 , FLAIR sequence) 5 1 0 0 1 0 1 0 6 0 4 0 0 0 2 8 12 0 0
Early postoperative clinical examination
Early postoperative epileptic seizures
6-month postoperative clinical examination
6-month postoperative epileptic seizures
6-month postoperative KPS
Adjuvant oncological treatment (modality, months)
Dysphasia Mutism akinesia Normal Normal Normal Normal Dysphasia Normal Normal Normal Dysphasia Dysphasia Normal Mutism akinesia Dysphasia Mutism akinesia Dysphasia Dysphasia Normal
No No Yes No No No No No No No No No No Yes No No No No No
Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal
No No No (levetiracetam) No No No No No No No No No No No (levetiracetam) No No No No No
100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
No Yes (RT, 65) No No Yes (CT, 79) No Yes (CT, 40) No Yes (CT, 28) No Yes (CT, 20) No No No Yes (CT, 24) No Yes (RT, 3) No No
CT: chemotherapy; FLAIR: fluid attenuated inversion recovery; GTR: gross-total resection; IPL: inferior parietal lobule; MR: magnetic resonance; RT: radiotherapy; SMA: supplementary motor area; SPL: superior parietal lobule; STR: subtotal resection.
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Table 1 Clinical, imaging, and histopathological characteristics.
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Fig. 1. Incidental diffuse low-grade gliomas are progressive tumours. Example of the spontaneous velocity in diametric expansion of an incidentally discovered left frontal diffuse low-grade glioma through the evolution of its mean tumour diameter over time before oncological treatment while asymptomatic (patient no 8, Centre 2). Each point represents a MR examination. Prior to surgical resection, the tumour grew spontaneously and continuously with a spontaneous velocity of diametric expansion at 3.4 mm/year. A total surgical resection was performed under functional corticosubcortical boundaries using intraoperative functional mapping.
3.3. Histopathological analyses Histopathological examination confirmed the tumours to be WHO Grade II gliomas. Note that microfoci of endothelial proliferation were identified within the glioma core in five patients that were classified as grade II in Centre 1 and as transitional grade II–III in Centre 2.
six patients at a mean 42.7 months (range 20–79) post-surgery. Tumour progression requiring adjuvant oncological treatment was observed significantly more frequently in patients with a partial or a subtotal resection (75%) than in patients with a total or a supratotal resection (P < 0.001). The median survival without progression requiring oncological treatment was longer in patients with a total or a supratotal resection (significance not reached) than in patients with a partial or a subtotal resection (65 months, P = 0.006) (Fig. 3).
3.4. Six-month functional outcomes All patients improved after a personalized functional rehabilitation in all cases. Six months after surgery, all 19 patients had totally recovered, with no permanent neurological deficit and normal scores at BDAE. Seventeen patients had returned to normal social and professional life (full-time working in all cases) at their 6-month evaluation. Of the two patients that did not return to work, one was in post-retirement (patient no 3) and the other was undergoing radiotherapy (patient no 17). Except for the patient undergoing radiotherapy, the postoperative KPS was at 100 in the 18 other cases. No patient had on-going epilepsy, including after antiepileptic drug therapy discontinuation, and including the two patients with early postoperative seizures. Note that no improvement in headache was observed postoperatively in patients with presenting preoperatively with headaches. 3.5. Follow-up and survival analyses Of the 19 patients, one had immediate postoperative radiotherapy (patient no 17) for a transitional WHO grade II–III glioma; the other patients underwent radiological and clinical surveillance. The mean duration of follow-up was 62.4 months (range 21–231) from surgery, and 83.8 months (range 24–234 months) from radiological diagnosis. During the follow-up period, no patient died, and adjuvant oncological treatment was required for tumour progression in
4. Discussion Early and maximal safe resection with the aim of improving both oncological and epileptological outcomes has been recently proposed for incidental DLGG [17,22,25,26]. We propose a shift in the philosophy of treating asymptomatic gliomas towards a “preventive” maximal functional-based resection [8,15]. In this series of 19 cases, neurosurgeons hyperspecialized in surgical neuro-oncology at two institutions performed functional-based resections using cortical and subcortical direct electrical stimulations under awake conditions with the same onco-functional balance philosophy [39]. The functional and oncological results were similar in the treatment of incidental DLGG and they confirm the reproducibility of the conceptual approach of this onco-functional balance philosophy of DLGG resection. Based on the surgical resection technique with margins at the intraoperative cortical and subcortical functional boundaries [38], 52.6% of the patients had a transient deficit. Interestingly, the rate of postoperative transient deficit was lower in incidental DLGG than in symptomatic ones, which can be explained by a relative longer distance between the lesion and eloquent cortical and subcortical areas in incidental DLGG, as supported by a higher rate of supratotal resection according to functional-based boundaries. The transient postoperative deficit was resolved in all cases after a personalized linguistic and physiotherapeutic functional rehabilitation. In fact, six months after surgery, the 19 patients had totally recovered
Please cite this article in press as: Lima GLO, et al. Surgical resection of incidental diffuse gliomas involving eloquent brain areas. Rationale, functional, epileptological and oncological outcomes. Neurochirurgie (2017), http://dx.doi.org/10.1016/j.neuchi.2016.08.007
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Fig. 2. Functional-based resections of incidental diffuse low-grade gliomas located in eloquent brain areas. A. Example of a left frontal incidentally discovered diffuse lowgrade glioma in a 35-year-old right-handed man with normal neurological examination results and enjoying a normal life (patient no 14, Centre 2). Due to an objective tumour growth on follow-up MRI (velocity of diametric expansion at 6.7 mm/year), surgery was proposed 3 months after MR discovery. Intraoperative photograph taken during awake surgery showing the view before and after a supratotal glioma removal, which was achieved according to corticosubcortical boundaries detected by direct intraoperative electrical stimulation mapping throughout glioma resection. Results of the cortical mapping: primary motor cortex of the face (1, 2, 3) and the hand (4, 5), speech arrest (21) on the ventral premotor cortex, anarthria (20), vocalization (11). Results of the subcortical mapping after glioma resection: inhibition of voluntary movements and speech arrest (31) corresponding to the motor control network, inhibition of both movement of upper limb and speech (32, 33) corresponding to the frontal aslant tract and the fronto-striatal tract, phonemic paraphasia (34,35) corresponding to the projection of the long segment of the superior longitudinal fasciculus (arcuate fasciculus). B. Example of a left parietal incidentally discovered diffuse low-grade glioma in a 30-year-old right-handed woman with normal neurological examination results and enjoying a normal life (patient no 19, Centre 2). Due to an objective tumour growth on follow-up MRI (velocity of diametric expansion at 4.1 mm/year), surgery was proposed 3 months after MR discovery. Intraoperative photograph taken during awake surgery illustrates the view before and after a total glioma removal, which was achieved according to corticosubcortical boundaries detected by direct intraoperative electrical stimulation mapping throughout glioma resection. Results of cortical mapping: primary motor cortex of the face (3) and of the upper limb (1,2), primary sensory cortex of the upper limb (hand, 10, 14; upper limb, 11, 12, 13). Results of subcortical mapping after glioma resection: paresthesia on the lower limb (20) and on the chest (21). The tag line represents one centimeter. C. Example of a left parietal incidentally discovered diffuse glioma in a 23-year-old right-handed man with normal neurological examination results and enjoying a normal life (patient no 17, Centre 2). Due to an objective tumour growth on follow-up MRI (velocity of diametric expansion at 8.4 mm/year), surgery was proposed 7 months after MR discovery. Intraoperative photograph taken during awake surgery shows the view before and after a partial glioma removal, which was achieved according to corticosubcortical boundaries detected by direct intraoperative electrical stimulation mapping throughout glioma resection. Results of the cortical mapping: primary sensory cortex of the tongue (10), mouth (11), and hand (12, 13, 14), calculation error (40). Results of the subcortical mapping after glioma resection: paresthesia on the hand (15, 16, 17, 18), on the mouth and the tongue (19,20), phonemic paraphasia (30,31) corresponding to the projection of the long segment of the superior longitudinal fasciculus (arcuate fasciculus). The tag lines represent one centimeter.
Please cite this article in press as: Lima GLO, et al. Surgical resection of incidental diffuse gliomas involving eloquent brain areas. Rationale, functional, epileptological and oncological outcomes. Neurochirurgie (2017), http://dx.doi.org/10.1016/j.neuchi.2016.08.007
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Fig. 3. Total and supratotal resections of incidental diffuse low-grade gliomas improve survival without progression requiring oncological treatment. A. Kaplan-Meier estimates of survival without progression requiring oncological treatment since radiological discovery by extent of surgical resection (total and supratotal resections versus subtotal and partial resections). The median survival without progression requiring oncological treatment was longer in patients with a total or a supratotal resection (blue curve, median not reached) than in patients with a partial or a subtotal resection (blue curve, median 65 months, P = 0.006). B. Example of a left frontal incidentally discovered diffuse glioma (top MR examination) in a 51-year-old right-handed woman with normal neurological examination results and enjoying a normal life (patient no 3, Centre 2). Due to objective tumour growth on follow-up MRI (velocity of diametric expansion at 1.9 mm/year), a supratotal resection was achieved according to corticosubcortical boundaries detected by direct intraoperative electrical stimulation mapping throughout glioma resection 120 months after MR discovery. The histopathological diagnosis demonstrated a transitional form of WHO grade II to WHO grade III oligodendroglioma with microfoci of endothelial proliferation (immunoreactivity for IDH1R132, presence of a 1p/19q codeletion). The patient declined any adjuvant oncological treatment (proposal for radiotherapy followed by adjuvant chemotherapy). At 58 months following surgery, no tumour progression was observed (down MR examination).
(no permanent neurological deficit, normal scores at BDAE, KPS at 100 except for the patient undergoing radiotherapy, there were long-term no seizures) and 17 were working full time. Of note, of the two patients that did not return to work six months postoperatively, one was already retired and the other was undergoing radiotherapy. These excellent functional outcomes – achieved at two different institutions hyperspecialized in surgical neurooncology – demonstrate the reproducibility and the safety of early maximal functional-based resection with cortical and subcortical direct electric stimulations within functional boundaries. Two patients with no antiepileptic drug prophylaxis experienced
a brief episode of early postoperative seizures. Early postoperative seizures, mainly within the first 3-months postoperatively, are thought to occur in up to 10% for all intracranial tumours and in up to 25% in DLGG [29]. To reduce the risk of adverse events during the preventive surgical resection of asymptomatic patients harbouring an incidental DLGG, the pros and cons of antiepileptic drugs should be discussed with the patient. Despite the absence of a dedicated trial, the present results (no early postoperative seizure in patients with postoperative antiepileptic drug prophylaxis) and a previous series support the prophylactic administration of antiepileptic drug therapy in the perioperative period [29].
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Large resections until cortico-subcortical boundaries were performed: complete resection in 52.6% of cases (including supratotal resections in 26.3%), subtotal resections in 36.8% of cases and two partial resections of 87.7 and 82.4% of the tumour, respectively. No postoperative complications were observed. It has previously been shown that incidental DLGG and symptomatic DLGG share similar clinical, imaging, histopathological, and molecular features [17,25]. As compared to symptomatic DLGG, incidental DLGG classically present with a smaller volume tumour and a less frequent involvement of eloquent areas that may explain the absence of clinical symptom and the larger extent of surgical resection. In the present series, the extent of resection (mean 96.7%) is comparable to other series of incidental DLGG [17,22,25,26,29] despite the tumour location close to or within eloquent areas within the dominant hemisphere and the larger tumour volumes at treatment. These results – achieved in two different institutions hyperspecialized in surgical neuro-oncology – demonstrate the reproducibility and the effectiveness of an early maximal functional-based resection with cortical and subcortical direct electric stimulation within functional boundaries. They show the benefit of early surgical management especially the improved chances of a total or supratotal resection. In this series of incidental DLGG treated while asymptomatic, postoperative progression requiring adjuvant oncological treatments were observed. These observations highlight the fact that incidental DLGG are progressive tumours with the same potential for progression as their symptomatic counterparts, further bolstering the argument for their early treatment, as previously suggested [17,22,25,26,40]. A previous series of 16 patients with DLGG undergoing a supratotal resection found there was no malignant transformation observed after a follow-up period of 8 years [27]; no progression requiring adjuvant oncological treatments was required in patients with total or supratotal resection in the present series. This highlights the oncological impact of large resection encompassing the infiltrated brain parenchyma beyond MRI-defined abnormalities [33,41]. The small sample size and the relative short follow-up dictate prudence in generating potential guidelines for practical management of incidental DLGG. However, the present results suggest that: • large functional-based resection until cortico-subcortical boundaries using direct electrical stimulation under awake conditions is feasible with low surgical morbidity and good outcomes; • the philosophical approach of a “preventive” and maximal functional-based resection in incidental DLGG, to maximize the extent of resection before glioma growth and migration is reproducible across centres hyperspecialized in surgical neurooncology [40]; • similar to symptomatic DLGG, smaller tumour volume together with a lower duration of glioma evolution, is associated with a higher chance of supratotal resection [33], and with an improved prognosis, this argues in favour of early, preventive and aggressive surgical treatment of incidental DLGG when radiological tumour growth is observed on MRI [17]. As previously stated, a dedicated neurosurgical team is mandatory to achieve excellent outcomes in surgical neuro-oncology [42]. Here, such a proposal for preventive surgery is conceivable only if the reliability of this treatment is optimal, with maximal resection and minimal morbidity, meaning that patients with incidental DLGG should be referred to centres hyperspecialized in surgical neuro-oncology [15]. Last, the preventive management of incidental DLGG with the idea that their early detection and treatment could contribute to a possible cure for these tumours support a screening policy [13,15].
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Please cite this article in press as: Lima GLO, et al. Surgical resection of incidental diffuse gliomas involving eloquent brain areas. Rationale, functional, epileptological and oncological outcomes. Neurochirurgie (2017), http://dx.doi.org/10.1016/j.neuchi.2016.08.007