Abstract
Background:
Following resection of posterior superior frontal gyrus (PSFG) tumors, patients may experience supplementary motor area (SMA) syndrome consisting of contralateral hemiapraxia and/or speech apraxia. Given the heterogeneity of PSFG tumors, we sought to determine the risk of postoperative deficits and assess predictors of outcomes for all intraparenchymal PSFG tumors undergoing surgery (biopsy or resection), regardless of histology.
Methods:
This is a retrospective single-center cohort study of adult PSFG-region tumors undergoing biopsy or resection by a single surgeon.
Results:
107 consecutive patients undergoing 125 procedures (21 biopsies, 104 resections) fulfilled inclusion/exclusion criteria. Anaplastic astrocytomas were most frequent among resected tumors (39% vs 29%), while glioblastomas were most common among biopsies (38% vs 28%) (p<0.0001). Biopsy patients were more likely to have tumor involvement outside of the SFG (91% vs 63%) (p=0.012), most commonly in the motor cortex (67% vs 31%) (p=0.003). Seizures were the most common presenting symptom among resection patients (p=0.017), while motor deficits were more common in biopsy patients (58% vs 29%) (p<0.001). Immediate postoperative neurological deficits occurred in 71 patients (57%), but only 3 were permanent at 6 months follow-up (2%). Postoperative SMA syndrome occurred in 49 patients (47%) and was significantly associated with involvement of the motor cortex (p=0.019) or cingulate gyrus (p=0.023), which were also significant in multivariate analysis as risk factors SMA syndrome. However, postoperative SMA syndrome was not significantly associated with overall survival (p=0.51). There were no perioperative mortalities but corpus callosum involvement (p=0.003), contrast enhancement (p<0.001), and GBM pathology (p=0.038) predicted worse overall survival in patients undergoing resection.
Conclusion:
Nearly half of all patients undergoing resection of PSFG-region tumors experience a post-operative SMA syndrome. Individuals with corpus callosum and/or motor cortex of maybe at increased risk of experiencing SMA syndrome. However, these deficits are usually transient, and the risk of permanent new deficits is very low (3%). Preoperative characteristics including corpus callosum involvement and tumor enhancement – in addition to pathology – may serve as predictors of overall survival within this patient population.
Keywords: posterior superior frontal gyrus, SMA, supplementary motor area, SMA syndrome, tumor surgery, neurooncology
INTRODUCTION
Neurosurgical outcomes are often classified based on the anatomic locations of relevant lesions, particularly within skull base,1,2 vascular,3 and spinal neurosurgery.4 This approach to evaluating outcomes enables neurosurgeons to provide general counsel on possible risks and outcomes of surgery, regardless of specific pathology. Alternatively, neurosurgical oncology outcome studies tend to be driven primarily by histology, with large-scale studies such as the Glioma Outcomes Project examining outcomes based on a single histological entity (i.e., malignant glioma)5,6 or at most by anatomic location restricted to a single histology (i.e., low grade gliomas of the insular region).7–9 Despite the utility of these studies in predicting outcomes for a single pathology, this overarching approach does not reflect how patients present to neurosurgeons preoperatively when histological diagnosis is usually unknown and cannot be entirely predicted by imaging. This lack of anatomically relevant outcome data independent of histology makes adequate preoperative counseling regarding surgical risks challenging. Here, we use an anatomy-centered approach to determine neurosurgical risk for intra-axial brain tumors, regardless of histology. This provides a more clinically relevant strategy for assessing operative risks and predicting neurosurgical outcomes.
In the present study, we focus on outcomes for tumors in the posterior superior frontal gyrus (PSFG). Notably, this region encompasses the supplementary motor area (SMA) region (Figure 1). The SMA has pertinent functional outcomes associated with intraoperative manipulation of or injury to this area. Specifically, patients may develop a SMA syndrome following resection of the SMA, defined by contralateral hemiapraxia, speech apraxia, or both.10,11 In the literature, case series have reported an incidence of SMA syndrome to ranging from 26% to 89%.12–14 However, SMA syndrome is transient, with most deficits lasting from days to months, though this timeframe is often anecdotal as only a few series have reported on the time course of this syndrome.10,15,16
Figure 1.
The posterior superior frontal gyrus (PSFG) is directly anterior to the medial most portion of the motor cortex and houses the supplementary motor area (SMA). Tumors of the PSFG can invade into neighboring brain structures, examples of which are highlighted in this image. Note that the individual depicted in the image is computer generated and that any resemblance to an actual individual is coincidental.
While outcomes in large series of peri-rolandic surgery have been reported, PSFG tumor outcomes have been limited to gliomas rather than all intra-axial tumors.17,18 Here, we present a large institutional series of consecutive patients receiving surgery for PSFG tumors, performed by a single surgeon. Our study aims to determine the risk of postoperative deficits, identify the time course of SMA syndrome, and assess prognostic factors for all intraparenchymal PSFG tumors undergoing surgery (biopsy or resection) regardless of histology.
METHODS
Data source and selection criteria
This is a retrospective cohort study assessing outcomes for PSFG lesions. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement. This study was approved by our institutional board review (IRB) committee under IRB#15–001684. This was a retrospective review of a prospective Departmental database to identify patients with intraaxial PSFG tumors undergoing surgery (biopsy or resection) with the senior author (IFP) between July 1, 2008 and January 1, 2020. Adults (≥18 years) with intraaxial tumors (confirmed by histology) centered in the PSFG – defined as the posterior one-fourth of the SFG – were eligible. Patients were excluded if the majority of their tumor volume was located outside of the PSFG or if the tumor was extraaxial. Location of the lesions was confirmed via examination of preoperative MRIs.
Covariates of interest
The electronic medical record and imaging were reviewed to determine demographics, date of first diagnosis, prior treatment(s), date of surgery, pathology, extension of the lesion beyond the PSFG, surgical adjuncts (intraoperative MRI [iMRI], motor mapping), preoperative deficits, immediate postoperative neurological deficits, permanent neurological deficits, readmission, and survival. Karnofsky Performance Status (KPS) score preoperatively and at 3 months postoperative was recorded. Extent of resection was determined using volumetric analysis through comparing preoperative and postoperartive MRIs. Gross total resection (GTR) was defined as ≥95% extent of resection and subtotal resection (STR) was <95% reduction of tumor volume as determined by post-gadolinium (GAD) T1 MRI in the case of contrast-enhancing tumors and IDH-mutant tumors or fluid-attenuated inversion recovery (FLAIR) MRI in the case of non-contrast-enhancing tumors.
Primary outcomes included immediate postoperative neurological deficits, permanent neurological deficits (persisting > 3 months), local/regional complications, systemic complications, and overall survival. Early complications were defined as those arising during the hospital course, whereas late complications were defined as those arising following discharge from the hospital but within 3 months of surgery. SMA syndrome was defined as new contralateral hemiapraxia and/or speech apraxia in individuals without preoperative motor weakness or aphasia. Length of SMA syndrome was collected as a continuous variable. For patients in which the date of SMA syndrome resolution could not be determined exactly, they were instead grouped according to duration of symptoms: <1 week, 1 week-1 month, 1 month-3 months, or > 3 months. Readmission was defined as a hospital readmission within 30 days of discharge following surgery. Permanent deficits were considered new/worsened postoperative deficits that were present at 6 months postoperative. Neurological improvement was measured at 6 months postoperative and was defined as improvement in the preoperative baseline (i.e. improvement of preoperative deficits). Survival status of alive patients was confirmed within patient charts and using publicly available data. Overall survival of patients who were deceased was determined from the date of first diagnosis to the date of death. Censored survival was determined from the date of first diagnosis to the date of last follow-up.
Statistical analysis
Continuous variables were summarized by median (interquartile range, IQR) and categorical variables by number of events n (%). For continuous variables, Wilcoxon rank sum text with continuity correction was used to compare medians between groups and for categorical variables, Fisher’s exact to compare proportions. Two-sided statistical tests were used. Kaplan Meier curves with 2-tailed log-rank tests were used to compared overall survival differences between groups. Association with SMA syndrome was quantified using odds ratios (ORs) with 95% CIs assessed with univariate and multivariate logistic regression analysis. In addition, association with survival was quantified using hazard ratios (HRs) with 95% confidence intervals (CIs) assessed with univariate and multivariate Cox proportional hazard models. Variables in univariate analysis that achieved a statistical significance of p=0.05 or less were included in multivariate analysis. The nominal significance level for all analyses was set at p=0.05. Statistical analysis was performed using R statistic software, version 4.2.1.19
RESULTS
Patient Population
We identified a cohort of 106 individuals undergoing a total of 123 procedures for PSFG tumors. The median age of the cohort was 46 years with a near equal representation of males and females (46% vs. 54%, respectively). Astrocytomas were the most commonly encountered lesion, representing 46 cases within the cohort (37%), followed by 36 patients with glioblastomas (GBMs) (29%), 20 with oligodendrogliomas (16%), and 10 with metastatic intracranial lesions (8%). Surgical resection was performed in 102 cases (83%) and biopsy in 21 (17%). Baseline characteristics of the total cohort and biopsy vs resection patients are depicted in Table 1. Patients underwent biopsy or resection at the discretion of the senior surgeon (IFP) based on tumor characteristics, co-morbidities, and patient preference. Patients that received biopsy were more likely to have right sided lesions compared to resection patients (48% vs. 38%, p<0.001) and lesional involvement outside of the PSFG (91% vs. 62%, p=0.011), of which motor cortex demonstrated the greatest degree of statistical significance (67% vs. 31%, p=0.005). Additionally, biopsy patients were more likely to have GBMs (38% vs. 27%), while resection patients were more likely to have astrocytomas (39% vs. 29%) (p<0.001). Overall, individuals in the biopsy cohort had an overall worse neurological baseline with lower KPS scores (80 vs. 90, p<0.001) and being more likely to present with motor deficits (71% vs. 24%, p<0.001) compared to individuals receiving resection. However, pre-operative seizures were present in a higher proportion of individuals undergoing resection than biopsy (58% vs. 29%, p=0.017). There were no other statistically significant differences in presentation between the two patient groups.
Table 1.
Baseline PSFG tumor population characteristics.
| Patient characteristics | Total (n=123) |
Biopsy (n=21) |
Resection (n=102) |
p-value |
|---|---|---|---|---|
| Age | 46 (36–58) | 54 (40–63) | 45 (36–57) | 0.116 |
| Females | 66 (54%) | 9 (43%) | 57 (56%) | < 0.001 |
| BMI | 26.55 (24.07–29.58) | 27.54 (23.97–29.38) | 26.49 (24.13–29.61) | 0.662 |
| Time between diagnosis and surgery (months) | 2(0–32) | 1 (0–10) | 2 (0–35) | 0.099 |
| Location | ||||
| Right side | 49 (40%) | 10 (48%) | 39 (38%) | < 0.001 |
| Outside PSFG involvement | 82 (67%) | 19 (91%) | 63 (62%) | 0.011 |
| Motor cortex | 46 (37%) | 14 (67%) | 32 (31%) | 0.005 |
| Cingulate gyrus | 15 (12%) | 4 (19%) | 11 (11%) | 0.286 |
| Deep white matter | 30 (24%) | 4 (19%) | 26 (26%) | 0.781 |
| Corpus callosum | 21 (17%) | 6 (29%) | 15 (15%) | 0.198 |
| Radiology | ||||
| Enhancement | 65 (53%) | 13 (62%) | 52 (51%) | 0.473 |
| fMRI | 32 (26%) | 2 (10%) | 30 (29%) | 0.098 |
| Pathology | ||||
| Astrocytoma | 46 (37%) | 6 (29%) | 40 (39%) | < 0.001 |
| Glioblastoma | 36 (29%) | 8 (38%) | 28 (27%) | |
| Oligodendroglioma | 20 (16%) | 2 (10%) | 18 (18%) | |
| Metastasis | 10 (8%) | 2 (10%) | 8 (8%) | |
| Other | 11 (9%) | 3 (14%) | 8 (8%) | |
| Glioma WHO Grade | ||||
| II | 26 (25%) | 3 (19%) | 23 (26%) | < 0.001 |
| III | 40 (39%) | 5 (31%) | 35 (40%) | |
| IV | 38 (37%) | 8 (50%) | 30 (34%) | |
| Presentation | ||||
| Seizures | 65 (53%) | 6 (29%) | 59 (58%) | 0.017 |
| Motor | 39 (32%) | 15 (71%) | 24 (24%) | < 0.001 |
| Aphasia | 16 (13%) | 3 (14%) | 13 (13%) | 0.736 |
| Headache | 14 (11%) | 2 (10%) | 12 (12%) | > 0.99 |
| Other | 8 (6%) | 1 (5%) | 7 (7%) | > 0.99 |
| Incidental | 14 (11%) | 2 (10%) | 12 (12%) | > 0.99 |
| Previous Biopsy | 12 (10%) | 4 (19%) | 8 (8%) | 0.123 |
| Previous Resection | 41 (33%) | 3 (14%) | 38 (37%) | 0.045 |
| Previous Radiation | 29 (24%) | 4 (19%) | 25 (25%) | 0.780 |
| Preop KPS | 90 (80–90) | 80 (70–90) | 90 (90–90) | < 0.001 |
Abbreviations: Gross total resection: GTR. KPS: Karnofsky performance score. Not applicable: N/A. Posterior superior frontal gyrus: PSFG.
Intra-Operative and Surgical Outcomes
General intra-operative and post-operative outcomes are shown in Table 2. Intraoperative MRI was utilized in 49% of cases and motor mapping (a combination of somatory sensory evoked potentials, cortical and subcortical stimulation mapping in all patients undergoing motor mapping was utilized in 50% of cases. All cases of motor mapping were performed asleep. Both adjuncts were used at the discretion of the senior surgeon (IFP) and were primarily reserved for planned resection in patients with non-enhancing tumors and based on the availability of the iMRI. Intra-operative MRI and motor mapping were used for one biopsy patient where pre-operative fMRI suggested potential for safe resection that was contradicted by intra-operative motor mapping findings. 5-aminolevulinic acid (5-ALA) was only used for two patients that underwent resection of GBMs. For resection patients, the median extent of resection was 99.5% with GTR being achieved in 72 cases (71%). Immediate new postoperative neurological symptoms occurred in 57% of the cohort. However, only three patients experienced permanent deficits (3%): one case of worsened preexisting hemiparesis, one case of new hemiparesis, and one case of speech hesitancy. In these three cases, all patients had GTR of GBMs under iMRI and with motor mapping. Neurological improvement at 6-months postoperative was documented in 64 cases (68%). There were no perioperative mortalities. At most recent follow-up, 46% of the cohort was alive with a median overall survival of 31 months.
Table 2.
Intraoperative and postoperative outcomes.
| Total (n=123) |
Biopsy (n=21) |
Resection (n=102) |
p-value | |
|---|---|---|---|---|
| Overall % of resection | NA | NA | 99.5 (87–100) | NA |
| GTR | NA | NA | 72 (71%) | NA |
| STR | NA | NA | 29 (29%) | |
| Intraop seizure | 6 (5%) | 0 (0%) | 6 (6%) | 0.588 |
| LOS (Median, Mean) | 2, 3.14 | 2, 2.76 | 2, 3.22 | 0.016 |
| Disposition | ||||
| Home | 98 (80%) | 18 (86%) | 80 (78%) | |
| Inpatient rehabilitation | 21 (17%) | 2 (10%) | 19 (19%) | < 0.001 |
| Skilled Nursing facility | 4 (3%) | 1 (5%) | 3 (3%) | |
| Readmission within 30 days | 2 (2%) | 0 (0%) | 2 (2%) | > 0.99 |
| Postop KPS | 90 (90–90) | 80 (70–90) | 90 (90–90) | < 0.001 |
| KPS change | 0 (0–0) | 0 (−2.5 – 0) | 0 (0–0) | 0.068 |
| Immediate new postop neuro symptoms | 71 (57%) | 3 (14%) | 68 (65%) | < 0.001 |
| Worsened motor deficit | 11 (9%) | 3 (14%) | 8 (8%) | 0.398 |
| Worsened aphasia | 7 (6%) | 0 (0%) | 7 (7%) | 0.602 |
| Headache | 3 (2%) | 0 (0%) | 3 (3%) | > 0.99 |
| Seizures during hospitalization | 16 (13%) | 2 (10%) | 14 (14%) | > 0.99 |
| Seizures after discharge | 10 (9%) | 0 (0%) | 10 (10%) | < 0.001 |
| Other early postop complications | ||||
| Local/regional complication | 5 (4%) | 1 (5%) | 4 (4%) | > 0.99 |
| Systemic complication | 6 (5%) | 0 (0%) | 6 (6%) | 0.588 |
| Long-term complications | ||||
| Permanent new neurological deficits | 3 (3%) | 0 (0%) | 3 (3%) | > 0.99 |
| Local/regional complication | 4 (3%) | 0 (0%) | 4 (4%) | > 0.99 |
| Systemic complication | 2 (2%) | 0 (0%) | 2 (2%) | > 0.99 |
| Neurological improvement | 64 (68%) | 0 (0%) | 64 (77%) | < 0.001 |
| Perioperative mortality | 0 (0%) | 0 (0%) | 0 (0%) | NA |
| Vital status at most recent follow-up | ||||
| Alive | 52 (46%) | 7 (35%) | 45 (49%) | 0.326 |
| Dead | 60 (54%) | 13 (65%) | 47 (51%) | |
| Unknown | 11 | 1 | 10 | |
| Median overall survival (months) | 31 | 15 | 34 | 0.130 |
Abbreviations: 95% Confidence interval: 95%CI; Karnofsky performances score: KPS. Length of stay: LOS; NA. Not applicable
Patients undergoing resection experienced more immediate new postoperative neurological symptoms than biopsy patients (65% vs. 14%, p<0.001) but no significant differences in permanent new neurological deficits (3% vs. 0%, p>0.99). There were no significant differences systemic or local/regional complications between the two groups. However, more patients in the resection group experienced neurological improvement at 6-months follow-up compared to the biopsy group (77% vs. 0%, p<0.001). Length of stay was generally short (median 2 days) for the overall cohort though, as expected, biopsy patients had a shorter for biopsy than resection (mean 2.76 vs. mean 3.22, p=0.016). Further, disposition after surgery was distinct between groups with a higher proportion of biopsy patients discharged home compared to resection (86% vs. 78%) and a higher proportion of resection patients discharged to inpatient rehabilitations compared to biopsy patients (19% vs. 10%) (p<0.001). However, there were no significant differences in 30-day readmission rates or permanent deficits between the two groups. Resection patients had higher 3-month postoperative KPS scores than biopsy patients (90 vs. 80, p<0.001) but this was similar to their pre-operative KPS (Table 1) and no significant differences were seen between groups for KPS change from pre-op to post-op. The median survival for resection patients was 34 months compared to a median survival of 15 months in biopsy patients, though this did not reach statistical significance (p=0.130).
Post-operative SMA syndrome: time course and baseline associations
No patients undergoing biopsy experienced a post-operative SMA syndrome. Among 102 patients undergoing resection, 48 experienced a postoperative SMA syndrome (47%). By definition, all SMA syndromes represented temporary contralateral motor apraxia +/− speech apraxia. There were no instances of speech apraxia in patients undergoing resection involving the non-dominant hemisphere. Patients whose tumors extended to the motor cortex or cingulate gyrus were more likely to develop SMA syndrome (44% vs. 20%, p=0.018; 19% vs. 4%, p=0.023) (Table 3). However, there were no significant differences in tumor side, additional brain structure involvement, pathology, grade, or patient presentation. While extent of resection was not statistically significant, though there was a paradoxical trend that a higher proportion of STR patients developed SMA syndrome (33% vs. 25%). However, within our STR group, 17 patients (58%) had involvement of the motor cortex and/or cingulate gyrus (26%), compared to 20 patients (28%) with motor cortex and/or cingulate gyrus involvement in the GTR group. Therefore, this trend may reflect the brain areas involved rather than reflecting differences in tumor volume removed.
Table 3.
Baseline characteristics of the 102 patients undergoing resection (excluding biopsies) comparing SMA syndrome vs patients without SMA.
| Patient characteristics | No SMA (n=54) |
SMA (n=48) |
p-value |
|---|---|---|---|
| Age | 49 (38–58) | 40 (33–54) | 0.089 |
| Females | 29 (54%) | 29 (59%) | 0.692 |
| Location | |||
| Right side | 19 (35%) | 20 (42%) | 0.545 |
| Outside SFG involvement | 30 (56%) | 33 (69%) | 0.221 |
| Motor cortex | 11 (20%) | 21 (44%) | 0.018 |
| Cingulate gyrus | 2 (4%) | 9 (19%) | 0.023 |
| Deep white matter | 13 (24%) | 13 (27%) | 0.821 |
| Corpus callosum | 6 (11%) | 9 (19%) | 0.402 |
| Pathology | |||
| Astrocytoma | 20 (37%) | 20 (42%) | 0.210 |
| Glioblastoma | 18 (33%) | 10 (21%) | |
| Oligodendroglioma | 6 (11%) | 12 (25%) | |
| Metastasis | 4 (7%) | 4 (8%) | |
| Other | 6 (11%) | 2 (4%) | |
| Grade | |||
| II | 12 (26%) | 11 (26%) | 0.094 |
| III | 14 (30%) | 21 (50%) | |
| IV | 20 (44%) | 10 (24%) | |
| Presentation | |||
| Seizures | 27 (50%) | 32 (67%) | 0.110 |
| Motor | 13 (24%) | 11 (23%) | > 0.99 |
| Aphasia | 8 (15%) | 5 (10%) | 0.564 |
| Headache | 7 (13%) | 5 (10%) | 0.765 |
| Other | 3 (6%) | 4 (8%) | 0.704 |
| Incidental | 9 (17%) | 3 (6%) | 0.130 |
| Previous Biopsy | 5 (9%) | 3 (6%) | 0.719 |
| Previous Resection | 24 (44%) | 14 (29%) | 0.151 |
| Previous Radiation | 20 (37%) | 5 (10%) | 0.002 |
| Preop KPS | 90 (82–90) | 90 (90–90) | 0.474 |
| Extent of resection | |||
| Overall % of resection | 100 (95–100) | 98 (82–100) | 0.190 |
| STR | 13 (25%) | 16 (33%) | 0.382 |
| GTR | 40 (76%) | 32 (67%) |
Abbreviations: Gross total resection: GTR. KPS: Karnofsky performance score. Posterior superior frontal gyrus: PSFG. Subtotal resection: STR.
Symptoms were most commonly present for less than a month (61%) though a minority had symptoms that persisted for between 3–6 months (13%) (Figure 2). Thirty-one patients with SMA syndrome (63%) ultimately required either inpatient or outpatient physical therapy following their discharge. Univariate logistic regression revealed 4 variables that were significantly associated with increased risk of SMA syndrome (Supplemental Table 1), of which cingulate gyrus and motor cortex lesional involvement remained significant in multivariate analysis (OR:7.37, 95% CI:1.49–58.69, p=0.03; OR:2.80, 95% CI:1.07–7.67, p=0.04; respectively) (Figure 3). In addition, it is worth noting that five of the six patients that experienced SMA syndrome >3 months duration had lesional involvement of the motor cortex and/or cingulate gyrus.
Figure 2.
(A) Recovery of SMA syndrome in all patients within our study (n = 48) categorized based on four timeframes: < 1 week, 1 week to 3 months, 1 to 3 months, or > 3 months. (B) Recovery of SMA syndrome based on number of days in 29 patients within our cohort with more discrete timeline of their SMA syndrome recorded in the electronic medical record. Note that all 48 patients who experienced SMA syndrome were not included in this graph as discrete information for the excluded patients was not readily available in-patient records.
Figure 3.
Multivariate logistic regression analysis of factors that were statistically significant in univariate analysis for risk of postoperative SMA syndrome in the resection cohort.
Survival after resection
Univariate Cox hazard model of risk of death over time revealed 9 variables that were significantly associated with mortality risk (Supplemental Table 2). Multivariate analysis showed that corpus callosum involvement and contrast enhancement of the lesion were significantly associated with increased mortality risk (HR:6.48, 95% CI:2.35–17.87, p<0.001; HR:6.23, 95% CI:1.88–20.68, p=0.003; respectively) (Figure 4). In addition, GBM pathology was significantly associated with increased mortality risk in multivariate analysis (HR:5.66, 95% CI:1.10–29.10, p=0.038). Importantly, there were no differences in survival duration between patients that developed SMA syndrome and those that did not (p = 0.51) (Supplemental Figure 1). Additional Kaplan Meier curves for survival time based on corpus callosum involvement, contrast enhancement, preoperative seizures, and pathology can be found in Supplemental Figure 2.
Figure 4.
Multivariate COX regression analysis of factors that were statistically significant in univariate analysis for risk of mortality in the resection cohort.
DISCUSSION
In this study, we examined PSFG tumors regardless of histology and specifically assessed factors at presentation that predicted postoperative deficits and long-term outcomes after surgery. We demonstrate that selected PSFG tumors can be safely resected with low risk for permanent worsening. In addition, while the majority of patients may experience a postoperative neurological deficit following PSFG tumor resection including SMA syndrome, the vast majority of these symptoms are transient and over half of patients are neurologically improved compared to pre-operatively by 6 months after surgery. Finally, although histopathology predicted overall survival as expected, we also identified additional preoperative characteristics which predict overall survival and could be utilized for preoperative patient counseling in a clinical setting.
PSFG lesions and SMA syndrome
By virtue of housing the SMA, the PSFG has involvement in motor planning and initiation of the contralateral hemibody20 and has a rich interconnectivity to other motor pathways including prefrontal cortex via the pre-SMA, cingulate motor areas, and motor cortex.21 In addition, the frontal aslant tract (a language-associated deep frontal tract connecting the dominant SMA to the frontal operculum) contributes to speech motor control.22,23 Given the functionality of this area, resection of lesions in the PSFG has the potential to produce profound motor apraxia and/or speech apraxia.11,12,14,24 Earlier studies thought SMA syndrome occurred in all cases of PSFG resection, though these studies only consisted of small case series.25,26 More contemporary case series have reported the incidence of SMA syndrome to range from 26% to nearly 85%;11,14 however, these studies are still limited by their small samples sizes. On the other hand, a larger case series by Kim et al. reported that 53% of the 43 patient cohort experienced SMA syndrome following resection of the PSFG due to pharmacologically intractable epilepsy.13 Similarly, within our cohort of 102 intraparenchymal PSFG tumor resections, we found the incidence of SMA syndrome to be 47%.
Given its high prevalence following PSFG tumor resection, identifying predictive factors for postoperative SMA syndrome has been a focus of previous research. Studies have found that resection of the cingulate gyrus is significantly associated with higher risk of SMA syndrome development and longer recovery times.13,14,27,28 For example, in a series of 90 patients undergoing resection of gliomas based in the cingulate gyrus, SMA syndrome was the most common postoperative deficit (20%).29 Similarly, in our study, patients with lesional involvement of the cingulate gyrus were at increased risk to develop SMA syndrome (p = 0.03). We also found the same to be true of the motor cortex (p = 0.04). We do not feel that this necessarily reflects perioperative injury to these specific areas (cingulate gyrus or motor cortex). Rather, resection of a tumor centered in the PSFG that involves these areas may require additional manipulation of the SMA region which increases the risk of a postoperative SMA syndrome.
It has been suggested previously that extent of resection correlates directly with the incidence of SMA syndrome.12,14,30 For example, Russell et al. found that SMA syndrome occurred in 37% of patients who had greater than 90% resection, compared to 20% SMA incidence in the 50–90% volume reduction group.14 In our study, we did not find any significant differences in postoperative SMA frequency based on EOR, but this could reflect patient numbers in our specific cohort.
Despite the high prevalence of SMA syndrome, the outcomes are generally favorable as most deficits are transient and plasticity of the SMA has been credited for the temporary nature of the syndrome. The transient nature of this phenomenon has been explained by the plasticity of the SMA with the potential for the migration of speech SMA to the contralateral hemisphere as demonstrated through functional magnetic resonance imaging.31–33 In addition, diffuse tensor imaging studies have revealed that there is connectivity between the contralateral SMA and ipsilateral motor cortex via the corpus callosum, which allows for this regain of function phenomenon.34 This notion can potentially explain the two cases of permanent SMA syndrome described by Baker et al. following complete disconnection of the SMA callosal fibers.35 Alternatively, there have also been reports of recurrent SMA syndrome following repeat resection of SMA tumors, thereby supporting that some SMA function may organize to the adjacent ipsilateral cortex.36
For many patients, clinical improvement of SMA syndrome is seen within the first post-operative week, with full resolution occurring between two to nine weeks.10,16 However, some studies have reported minor deficits lasting between six and nine months.13 Recently, a novel study by Tuncer et al. proposed that SMA syndrome consists of an acute and chronic phase with: 1) the acute phase consisting of hemiparesis +/− mutism and resolving within days-weeks and 2) the chronic phase consisting of fine motor deficits, which can lasts up to months postoperatively. In our series, all cases of SMA syndrome were temporary and commonly lasted less than one month (61%) with majority of our cohort utilizing inpatient or outpatient physical therapy as part of their recovery process (63%). It is important to note that the temporary nature of the dense motor symptoms associated with SMA syndrome allowed for inpatient rehabilitation programs to be effectively utilized by many of our patients given their high potential for recovery. Further, given that patients with lesional involvement of the corpus callosum and/or motor cortex were at increased risk for prolonged SMA syndrome, it may be particularly importance for use of physical therapy in the recovery process for this patient population.
Long term outcomes after PSFG tumor surgery
Despite the relative safety of PSFG tumor resection, there are still minor risks for developing permanent deficits that remained at 12 months postoperative.17,37 Given that the PSFG lies adjacent to the motor cortex, any unnoticed damage to the subcortical white matter, especially the corticospinal tracts, could results in permanent deficits. Further, Peraud et al. noted that the majority of patients in their cohort with tumor extension into the precentral gyrus has persistent motor deficits one-year postoperatively, thus demonstrating the vulnerability to injury of the peri-rolandic area.17 Intraoperative electrical cortical stimulation, i.e. motor mapping, has been established as an effective tool that enables PSFG tumor resection without compromising the surrounding eloquent structures, thereby reducing the risk of potential permanent deficits.38 In our practice, we utilize motor mapping for the majority of our cases, especially in cases where a non-enhancing tumor is centered within the PSFG but directly adjacent to or involving the motor cortex. However, in our experience, resection without motor mapping can be achieved in select masses that come to the cortical surface and have prominent enhancement on preoperative imaging. In addition, we will often employ the use of iMRI for resection of PSFG tumors in order to maximize safe resection and avoid compromise of eloquent structures. However, limited numbers of iMRI at an institution and scheduling availability may preclude the ability to use this adjunct for patient cases.
In the present study, we only documented permanent deficits in three patients undergoing resection (3%), only two of which resulted in motor deficits. Within these cases, one patient had worsening of preoperative hemiparesis and one patient developed new hemiparesis. Additionally, these two patients had GBM tumors and ultimately died from disease with one year following resection. Given the aggressive nature of these tumors, it is difficult to distinguish symptoms of tumor progression from surgery-related permanent deficits six months after surgery. Overall, these findings suggest that patients that present with significant preoperative deficits (i.e. hemiparesis) and/or those with high grade lesions may be at a higher risk for the development of longer lasting deficits (i.e. greater than six months postoperative).
Surgical management of PSFG tumors remains somewhat controversial within the neurosurgical community. For instance, Müller et al. recently reported discrepancies in surgical decision making for biopsy versus resection between two groups of neurosurgeons in the rates of resection versus biopsy for GBM tumors of the right superior frontal gyrus despite having similar patient characteristics between the groups.18 However, patients undergoing resection of right superior frontal gyrus GBMs had longer survival than those receiving biopsy.18 Similarly, we found that patients receiving resection for their PSFG tumor can have more favorable postoperative outcomes than patients that only receive biopsy as demonstrated by low risk of permanent neurological deficits and increased rate of neurological improvement. Therefore, we believe that surgery should be considered if a patient’s tumor is amenable to resection despite PSFG involvement. Further, despite the rare instances of permanent deficits as reported in the literature,17,35,37 resection of PSFG tumors – regardless of their histology – is relatively safe procedure, especially when combined with intraoperative neuromonitoring, and may be beneficial to increase postoperative quality of life.
As to be expected, pathological diagnoses of GBM was associated with worse overall survival compared to patients with other pathologies in our study. However, alongside pathological diagnosis, we also identified preoperative characteristics to predict survival and could be utilized for preoperative patient counseling in a clinical setting. For instance, we found that patients with contrast enhancement had increased mortality risk and worse overall survival, as these lesions likely represent higher grade tumors such as GBM or metastases. Similar to other reports in the glioma literature,39–41 corpus callosum involvement also served as a negative prognostic marker in our study with increased mortality risk and decreased survival length regardless of the histology.
Limitations of this study
This study is subject to the inherent limitations and biases of all retrospective studies. While the decision to include all intra-axial tumors centered in the PSFG undergoing surgery regardless of histology or decision to undergo biopsy versus resection was taken to allow assessment of prognostic factors for outcome assessble at presentation in clinic, the series’ heterogeneity and reflection of a single surgeon (IFP) may impact generalizability. For instance, while extent of resection was not significant in our cohort for overall survival despite being known in neurooncology that GTR improves survival, this could be a reflection of comparing STR of a low-grade glioma to GTR of a high-grade glioma. Therefore, patient counseling should always be adjusted upon histological confirmation of the lesion. Another limitation associated with our study was the lack of an external elevation set, therefore limiting its generalizability. Future multicentric studies should be performed to increase sample size to provide for testing and validating subset groups and for better external validity. Finally, it is worth noting that our cohort includes patients with tumors that extend beyond the PSFG, whose locations may influence the findings reported in our study. While we chose to include these patients in better capture the spectrum of PSFG tumors in the general population, additional analyses of tumors confined only to the PSFG would be of benefit.
Conclusions
Nearly half of all patients undergoing resection for PSFG-region tumors experience a post-operative SMA syndrome. Patients with lesional involvement of the motor cortex involvement or cingulate gyrus may be at increased risk of developing SMA syndrome. However, these deficits are usually transient, and the risk of new permanent deficits is very low (3%). Although resection can be associated higher rates of immediate new postoperative neurological symptoms compared to biopsy patients, these patients may have a greater improvement of functionality following their postoperative course. Preoperative parameters such as corpus callosum involvement and tumor enhancement, along with pathology, may serve as predictors of overall survival within this patient population.
Supplementary Material
References
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