Neuropsychological Outcomes After Awake Resections of Right Frontal IDH-Mutated Glioma: Insights From a Consecutive Series of 20 Cases.


 Background

Awake surgery for low-grade gliomas is currently considered the best procedure to improve the extent of resection and guarantee a "worth living life" for patients, meaning avoiding not only motor but also cognitive deficits. However, tumors located in the right hemisphere, especially in the right frontal lobe, are still rarely operated on in awake condition; one of the reasons possibly being that there is little information in the literature describing the rates and nature of long-lasting neuropsychological deficits following resection of right frontal glioma.
Objective

To investigate long-term cognitive deficits after awake surgery in right frontal IDH-mutated glioma.
Methods

We retrospectively analyzed a consecutive series of awake surgical resections between 2012 and 2020 for right frontal IDH-mutated glioma. We studied the patients' subjective complaints and objective neuropsychological evaluations, both before and after surgery. Our results were then put in perspective with the literature.
Results

Twenty surgical cases (including 5 cases of redo surgery) in eighteen patients (medium age: 42.5 [range 26–58]) were included in the study. The median preoperative volume was 37 cc; WHO grading was II, III and IV in 70%, 20%, and 10% of cases, respectively. Preoperatively, few patients had related subjective cognitive or behavioral impairment, while evaluations revealed mild deficits in 45% of cases, most often concerning executive functions, attention, working memory and speed processing. Immediate postoperative evaluations showed severe dysexecutive syndrome in 75% of cases but also attentional deficits (65%), spatial neglect (60%) and behavioral disturbances (apathy, aprosodia/amimia, emotional sensitivity, anosognosia). Four months after surgery, although psychometric z-scores were unchanged at the group level, individual evaluations showed a slight decrease in performance in 9/20 cases (dysexecutive syndrome, speed processing, attention, semantic cognition, social cognition).
Conclusion

Our results are generally consistent with those of the literature, confirming that the right frontal lobe is a highly eloquent area and highlighting the importance of operating these patients in awake conditions.


Introduction
Over the past decade, numerous studies have provided cumulative evidence that the extent of resection is a strong predictor of prolonged survival in (IDHmutated) diffuse low-grade glioma (DLGG) patients [8,9,35,56]. Importantly, the effect of surgery has been observed regardless of the IDH-mutated subtypes − 1p19q-codeleted oligodendroglioma or 1p19q noncodeleted astrocytoma [21,36,62]. Accordingly, surgical resection of DLGG is now considered the rst option in the guidelines. However, most patients seek not only for a longer life but also for a life that is worth living (according to their own de nition). This problem has been conceptualized as oncofunctional balance [13,16,42,43], and subspecialized neurosurgeons must face the challenge of optimizing this oncofunctional balance. Whereas noninvasive preoperative functional imaging tools (functional and structural MRI, magnetoencephalography, transcranial magnetic stimulation) are helpful in the rst approach of individualized functional mapping (especially in regard to determining language lateralization [46]), the best methodology for functional preservation is to awake the patient and perform continuous intraoperative mapping of cognitive tasks through the use of direct electrical stimulation (DES) [19]. The e ciency of this method has been demonstrated for motor and speech functions [12]. Despite the awareness that functions hosted by the right hemisphere are as important as those hosted by the left hemisphere [6,38,61], there are only a few teams opting for awake surgery in right-sided tumors, especially for tumors located in the frontal lobes. One possible explanation would be that there is no study in the literature providing a comprehensive overview of the long-lasting neuropsychological de cits that can be observed after resection of glioma located in the right frontal lobe. Indeed, previous reports in this eld were often focused on a single task/function and were somehow neuroscience-oriented [49,51,63]. As proposed recently, the introduction of a new intraoperative task in awake surgery should be grounded on studies demonstrating that patients operated on without this monitoring do indeed experience debilitating long-lasting neuropsychological de cits [44]. The goal of the present paper is thus to contribute to our knowledge about the frequency and nature of the neuropsychological risks when operating IDH-mutated glioma in the right frontal lobe.

Inclusion criteria
We retrospectively reviewed our consecutive database of cases operated on in awake condition since 2011. We selected all cases with an IDH-mutated glioma located in the right frontal lobe. Clinical and radiological data were retrieved through electronic medical les and the Picture and Archiving Communication System (PACS), respectively.

Operative techniques
Monitored anesthesia care, which consists of sedation while preserving spontaneous ventilation without any airway instrumentation, was used during the nonawake periods [3]. Sedation was achieved by a mixture of propofol and remifentanil, with additional use of dexmedetomidine in the last cases. Patients were prepared through a systematic protocol that includes hypnotic techniques [4,39].
All cases were operated on by the senior author, with the naked eye (cases 1 to 8) or surgical loops (cases 10 to 20). Surgical microscope was used for case 9. Electrical stimulation was used as previously reported [11,41,45]. Monitoring was performed by a speech therapist (MB, IP, SL, CPT) and assessed, at the discretion of the surgeon: motor functions (continuous repetitive movement of left superior limb), counting, picture object naming, nonverbal semantic association, and the test "read the mind in the eyes". Resection was stopped when a functional boundary was encountered.

Imaging
All patients underwent the same imaging protocol, as previously described [11,40,45]. In this study, the extent of resection was estimated on FLAIR sequences and computed as (1 -residual volume/initial volume). Surgical cavities were segmented with MI-Brain software (Sherbrooke, Canada) on 3D-T1 images and resized to a resolution of 1x1x1 mm 3 . Images were then registered to the MNI template using the Antsregistration algorithm and displayed with MRIcro-GL software. In cases 8, 11, 13-20, language fMRI was performed to con rm the left lateralization of language networks, following the same methodology as previously reported [46].

Neuropsychological testing
Patients were thoroughly evaluated neuropsychologically by a speech therapist (MB, IP, SL, CPT) just before, immediately after, and four months after the surgery. After a short interview with the patient, aiming to record spontaneous complaints, the evaluation assessed language, memory, executive and visuospatial functions, and social cognition. The most common tests were administered to all patients, whereas some tests were added in a patient-speci c approach, as expected for evaluations performed in a clinical rather than research context.  [22], -nonverbal semantic association (pyramid and palm tree test -PPTT - [34], or BEC-S in the very last patients [47]. Tasks tapping attention and executive functions comprised: -forward and backward digit span (testing working memory) [25], -Paced Auditory Serial Addition Test (PASAT) (testing working memory and sustained attention) [ [1]). Finally, social cognition was evaluated with the Read the Mind in the Eyes test [5], facial emotion recognition [17,20], and faux pas recognition [20,59].
For each patient, speech therapists wrote a synthetic conclusion summarizing the patient's performance in terms of nosological entities (dysexecutive syndrome, attention disorder, short-term memory impairment, etc.). In the results section, we listed for each patient and for each evaluation the key words retrieved from these conclusions. We claim that this approach allows us to obtain a picture of patients' functions that is easier to grasp and interpret than the full set of raw psychometric scores. The main scores and their corresponding z-scores are nonetheless also given at the group level. Moreover, z-scores were used to categorize each patient as having a long-term impairment in one domain when at least one test z-score of that domain decreased by 1.5 units or more.

Statistical methods
We used a bilateral Student's t-test to compare the mean values of the different cognitive scores between preoperative and immediate postoperative evaluations and between preoperative and late (4 months) postoperative evaluations. Signi cance was set at a p-value of 0.05. All analysis were performed under XLSTAT software.

Patients characteristics
Twenty surgical cases in eighteen patients were included in the study (two patients operated on twice). Among the 20 cases, 5 were redo surgeries. Symptoms motivating the rst MRI were generalized seizures in 13 out of 18 patients and persisting headaches in one patient. Radiological discovery was incidental in 4 patients. Median age at surgery was 42.5 years (range 26-58). All patients were right-handed, except one patient (case 5) who was ambidextrous. Left lateralization of language networks was con rmed in the 10 patients in whom fMRI was performed. Patients were working at the time of their surgery in seventeen out of twenty cases. Patients characteristics are summarized in Table 1. Table 1 Patients and tumors characteristics. GS = generalized seizure ; ID = incidental discovery ; RH = right-handed, Amb = ambidextrous ; MFG = middle frontal gyrus SFG = superior frontal gyrus ; IFG = inferior frontal gyrus ; OII = grade II oligodendroglioma ; AII = grade II astrocytoma ; OIII = grade III oligodendroglioma ; GBM glioblastoma ; NA = not applicable. Tumor characteristics The median preoperative volume was 37 cc (mean 51 cc, range 1,7 cc -175 cc). Preferential locations were the posterior part of the superior frontal gyrus (SFG), followed by the anterior frontal lobe, the middle frontal gyrus (MFG), and inferior frontal gyrus (IFG). Contrast enhancement was present in 4 cases.

Surgical results
The mean extent of resection was 93% (range 37.5% − 100%), and the mean residual volume was 4.9 cc (range 0 cc -40 cc). Resections were complete in 55% of surgeries. Figure 2 shows the surgical cavities after registration to the MNI template.
None of the patients presented long-lasting postoperative motor de cits. Two patients presented incomplete akinesia, which resolved within a couple of days. This akinesia affected both the upper and lower extremities (case 2) or only the upper extremity (case 10). One patient (case 1) had an epidural hematoma requiring evacuation at postoperative day 3. One patient (case 15) had a wound infection requiring bone ap removal 3 months after the surgery and a cranioplasty 6 months later.

Mapping results
All mapping results are given in Table 2 and Fig. 1. For all 19 patients in whom the precentral gyrus was exposed, stimulation generated positive motor responses. Sites generating motor arrest (of speech and/or of upper limb movement) were seen in 12 cases. No reproducible cortical sites were found when monitoring nonverbal semantic association (PPTT) or emotion recognition (RME). When stimulating the white matter, positive motor responses were seen in 5 cases (upper limb on 1 site, lower limb in 5 sites). White matter sites of upper extremity motor arrest were observed in 12 cases. Eye movements with loss of contact were noted in 3 cases. No reproducible sites were found when testing the PPTT or RME. Finally, stimulation of white matter generated in two patients (cases 17 & 19) made it impossible to perform the 1-back naming task combined with continuous repetitive movement of the upper extremity. In both cases, patients spontaneously reported an attentional disorder: one patient said 'I do not know, I did not pay attention', and the other said 'I do not know, I did not see the last image'.  (3) Thumb movement (4) Fingers movement (5) Eyes closing (8) Counting while moving UE 1.5 mA UE MA (7) Complete MA (10) Group-level analysis of neuropsychological quantitative evaluations Table 3 gives the quantitative means of the raw scores and z-scores for picture naming, Rey gure copy, verbal uencies, Trail Making Test (B-A), Stroop (con ict), and Bells' test. Preoperatively, all z-score means were in the normal range (> -1.0), in accordance with almost normal cognitive functioning in IDHmutated glioma patients. In the immediate postoperative period, a statistically signi cant (p < 0.05) deterioration was observed for verbal uencies, TMT B-A, Stroop test and Bells' test. At the late postoperative evaluation, none of these scores signi cantly differed from their preoperative values. Table 3 Group-level analysis of cognitive performances. Raw scores and z-scores of the main cognitive tasks are given at preoperative, immediate postoperative and late postoperative evaluations. The values in bold are considered as pathologic (z-scores < -1.5), while values with a star differed signi cantly (p < 0.05) from their preoperative values. Rey Figure   Individual-level analysis of preoperative neuropsychological evaluation Preoperatively, patients rarely reported spontaneous cognitive or behavioral disorders. (see Table 4). The most common complaints were distractibility (30% of cases), followed by fatigability (20%) and irritability (15%). Neuropsychological evaluations demonstrated mild de cits (see Table 5). These de cits comprised elements of dysexecutive syndrome in 45% of cases, attention disorders in 45% of cases, and verbal short-term memory impairment in 45% of cases. Speed processing was also slightly below the average in 50% of cases. Of note, di culties with high-level semantic cognition (conceptualizing or grasping implicit) were observed in 20% of cases.  Individual-level analysis of immediate postoperative evaluation At the immediate (within one week postsurgery) postoperative evaluation, 75% of cases had marked dysexecutive syndrome (see Table 6). Attention capabilities were also strongly impacted in 65% of cases. Left unilateral spatial neglect (USN) was detected in 60% of cases. Behavioral disturbances included apathy (30% of cases), aprosodia/amimia (45% of cases), and emotional sensitivity (10% of cases). Of note, anosognosia was observed in 25% of cases. Individual-level analysis of postoperative neuropsychological evaluation All but 4 patient cases underwent intensive cognitive rehabilitation for a period of four months. Patients performed this cognitive training in the outpatient speech therapy clinics nearest to their home.
At 4 months postsurgery, the complaints most commonly reported by patients were fatigability (65% of cases), distractibility (45% of cases) and di culties coping with multitasking (30% of cases) (see Table 7). Uncommon complaints included reduced speed processing, lack of motivation, di culties with time (either for time perception or for schedule management), urinary urgency, irritability, mood disorder, loss of bimanual coordination, language disorder and sleep disorder. Objective neuropsychological evaluations con rmed these self-reported lamentations (see Table 8). Executive abilities and attention were the main affected functions, together with verbal short-term memory. Interestingly, signs of USN almost completely resolved (two patient cases with very mild persisting signs of left USN). Importantly, a small proportion of patients had persistent disorders of high-level semantic cognition (grasping implicit or metaphors) and/or an impairment of social cognition. Overall, when comparing the pre-and postoperative evaluations, 9 out of 20 cases demonstrated decreased performance in at least one domain among executive functions, speed processing, attention, spatial cognition, semantic cognition, and social cognition.

Follow-up
Out of the seventeen patients working at the time of surgery, twelve (70%) resumed their professional activity within 6 months after the surgery. All patients but one were alive at the last follow-up: one patient (case 10) died after 3 years of glioma evolution. Median follow-up was 42 months (range 12-102 months).

Discussion
Our results provide a comprehensive overview of the cognitive dysfunctions that might remain four months after awake resection of IDH-mutated glioma located to the right frontal lobe. Such knowledge can help neurosurgeons better inform their patients about the (mild) cognitive risks that come with resection of a right frontal IDH-mutated glioma. We would like to put our results in perspective with the previous literature.

Motor control
In the present series, only two patients experienced transient akinesia, which is typical of SMA syndrome. For both of them, akinesia occurred intraoperatively before sites of motor arrest could be properly identi ed. In all other patients, such sites were detected and preserved, thus avoiding transient postoperative akinesia, as previously reported [53]. It should be emphasized that it is now recognized that the recovery of SMA syndrome is incomplete and that disorders of ne motor movements might persist, in particular regarding bimanual coordination, a subjective complaint reported by one patient (case 2). Of note, two patients also reported urge incontinence, as previously observed [15]. These symptoms hampered their quality of life but improved under 5 mg solifenacine succinate twice daily.

Neuropsychological outcomes: group-level analysis
Our group-level analysis could not capture the mild long-term de cits encountered in this selected group of patients. Although we cannot rule out that this is due to the small size of the series, such a result is in good accordance with the high level of recovery observed in this patient population (thanks to the e cient implementation of plasticity mechanisms) [37]. It can be hypothesized that such favorable cognitive outcomes -in spite of a large extent of resection -were achieved thanks to intraoperative mapping relying on tasks tapping cognitive control abilities. As an alternative hypothesis, averaging at the group level might have balanced improved and deteriorated patients' scores. Hence, we next investigated evaluations at the individual level by analyzing patients' self-reported complaints, quantitative changes in psychometric z-scores, and objective qualitative conclusions found in the written reports of the speech therapists.

Neuropsychological outcomes: individual-level analysis
Very few studies have preoperatively explored the cognitive functioning of patients with right frontal glioma, and even fewer have reported subjective complaints, as explained by the patients themselves. Eight out of the fteen patients with an incidental glioma studied by Cochereau et al.
[10] had a tumor located in the right frontal lobe. Five out of the eight had subjective complaints, including tiredness, altered attention, and irritability. Our results are perfectly in line with this study, as fatigability, distractibility and irritability were reported by 20, 30 and 15% of patients in our series, respectively (see Table 4). Objective evaluations demonstrated de cits in working memory and/or executive functions in four out of the eight patients reported by Cochereau et al. Similarly, we found that executive functions, short-term working memory, and attention were the most commonly impacted domains, with almost half of the patients being affected (see Table 5). It is worth emphasizing that these de cits were very mild, in accordance with the high rate of patients with professional activity just before the surgery (17 out of 20 patient cases). Interestingly, impairments of high-level semantic cognition (grasping metaphors or implicit) were diagnosed in 20% of cases. Such troubles have been previously reported after resection of right hemispheric glioma [58] and deserve further speci c investigations. Of note, we found a low rate of preoperative disturbance in social cognition, which is also in line with a recent report [63].
While almost every patient presented cognitive deterioration at the immediate postoperative evaluations, slight impairment in at least one domain (among executive functions, attention, speed processing, spatial cognition, semantic cognition, or social cognition) was detected at the four-month evaluation in only 9 cases out of 20. Nonetheless, the decline was slight enough that a remarkably high proportion (70%) of patients working preoperatively could resume their work within six months after the surgery. Again, this good outcome suggests that awake cognitive mapping could have contributed to preserving the patients' socioprofessional life.
Our results are in line with a previous study [28] reporting a decline in executive functions and/or speed processing and/or attention in 32% of cases (both left and right hemispheres). Resection map symptom mapping highlighted the right frontal lobe as being the location most at risk [28]. Such results were further con rmed by studies in 77 low-grade glioma patients, including 27 cases of right frontal location [55]: preoperative impairments in verbal memory, nger tapping, symbol digit coding, cognitive exibility, verbal uency and sustained attention were observed, with further deterioration at three months for sustained attention. Two other recent studies also emphasized the risk regarding inhibition capabilities (as measured by Stroop's task) when operating in the right frontal lobe [50,51]. Regarding visuospatial cognition, long-lasting left USN was found in one-third of patients in whom resection of right hemispheric tumors encompassed the SFG and MFG [49]. In our series, whereas USN was found in 60% of cases in the immediate postoperative period, mild signs of USN were found in only 10% of cases four months later (in particular, none of the patients deviated at the line bisection task). To explain the difference between the two series, it is tempting to put forward the following hypothesis, already mentioned in [49]: persistent de cits would be caused by the cumulative effect of resecting both the rst and second branches of the superior longitudinal fasciculus, a situation that might have been less frequent in the present series.
Performances in social cognition declined in two patients, in accordance with a previous report [30]. It should be noted that we failed to identify reproducible stimulation sites disturbing the RME task, contrary to previous reports [31,63]. The lack of experience of the team regarding this kind of mapping likely explains this difference. An alternative explanation could be that the stimulated area is too small compared to the cortical area supporting the function. This latter hypothesis could be tested by simultaneously stimulating two sites, as recently suggested [23]. Similarly, we found no reproducible sites when testing the nonverbal semantic association task (PPTT), contrary to previous reports [32,33]. It can be hypothesized that the identi cation of such sites would have contributed to preventing the postoperative semantic cognition disorders (implicit and/or metaphors understanding) found in three cases.
Finally, objective evaluations and subjective complaints overlapped only partially. Some dysfunctions reported by patients were indeed not captured by the battery of tasks we used. Such functions include fatigability, irritability, or multitasking. Speci c tasks should be designed to objectify and quantify these kinds of impairments.

Limitations
Finally, our study has several limitations, including all those that come with a retrospective design and a small sample size, making it di cult to generalize de nitive conclusions. However, the fact that cases were consecutively reported and that the management was the same for all patients partly compensated for these limitations. The cognitive evaluations were performed by four different speech therapists, and this might have introduced heterogeneity in the qualitative reports, but this is compensated by the extensive quantitative data of our test battery. Furthermore, patients were evaluated only at 4 months, so we cannot rule out that a different pattern of de cits would have been seen one year later. However, there are some data in the literature demonstrating that, in general, the cognitive recovery curve reaches a plateau after 4 months (see, for example, [52] for spatial attention and awareness). Hence, although this is not proven, we made the reasonable assumption that the 4-month measure is a good proxy of the 1-year measure. Last but not least, the small size of our series did not allow us to perform a multivariate analysis that would have included all regressors known to in uence cognitive recovery, including age, preoperative cognitive status, somatic gene polymorphisms [2], location and extent of resection, and growth rate of residual tumor. We thus emphasize the need to share data between centers to address such important questions.

Conclusion
Overall, the present study supports the idea that the right frontal lobe should be considered a highly eloquent area, given the high rate of persistent mild neuropsychological impairments found 4 months after surgery. There is still much to do to better understand the neuronal networks sustaining these highlevel functions and, most importantly, to better understand how resection will impact those networks, in particular for differentiating damages that will be restorable through plasticity-mediated reorganization from those that will overwhelm the potentialities of plasticity and cause de nitive de cits. This is a real challenge, considering the high degree of individual variability of topographical organization and plasticity of cognitive networks and meta-networks [14,29].
Finally, the encouraging high rate of work resumption gives support to the assumption that awake surgery could have a positive impact on the patients' socioprofessional life: intraoperative monitoring of executive functions, semantic cognition and social cognition in an awake patient appears to be currently the best method to preserve these functions, thus giving to each individual patient the best chances to return to a normal socioprofessional life. Such an assumption deserves con rmation from future studies with larger samples.

Declarations
Funding. No funding was received for this research.
Con ict of Interest: All authors certify that they have no a liations with or involvement in any organization or entity with any nancial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or non nancial interest (such as personal or professional relationships, a liations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee of Lariboisière Hospital and with the 1964 Helsinki declaration and its later amendments. The study was approved by the local ethics committee Pôle Neurosciences of Lariboisière hospital. Informed consent was obtained from all individual participants included in the study.

Figure 1
Photographies of intraoperative functional mappings for the 20 cases. No photography was found for case 5.

Figure 2
Surgical cavities for the 20 cases after registration in the MNI template.