Function-guided differences of arcuate fascicle and inferior fronto-occipital fascicle tractography as diagnostic indicators for surgical risk stratification.

BACKGROUND: Several patients with language-eloquent gliomas face language deterioration postoperatively. Persistent aphasia is frequently associated with damage to subcortical language pathways. Underlying mechanisms still need to be better understood, complicating preoperative risk assessment. This study compared qualitative and quantitative functionally relevant subcortical differences pre- and directly postoperatively in glioma patients with and without aphasia. METHODS: Language-relevant cortical sites were defined using navigated transcranial magnetic stimulation (nTMS) language mapping in 74 patients between 07/2016 and 07/2019. Post-hoc nTMS-based diffusion tensor imaging tractography was used to compare a tract's pre- and postoperative visualization, volume and fractional anisotropy (FA), and the preoperative distance between tract and lesion and postoperative overlap with the resection cavity between the following groups: no aphasia (NoA), tumor- or previous resection induced aphasia persistent pre- and postoperatively (TIA_P), and surgery-induced transient or permanent aphasia (SIA_T or SIA_P). RESULTS: Patients with NoA, TIA_P, SIA_T, and SIA_P showed distinct fasciculus arcuatus (AF) and inferior-fronto-occipital fasciculus (IFOF) properties. The AF was more frequently reconstructable, and the FA of IFOF was higher in NoA than TIA_P cases (all p ≤ 0.03). Simultaneously, SIA_T cases showed higher IFOF fractional anisotropy than TIA_P cases (p < 0.001) and the most considerable AF volume loss overall. While not statistically significant, the four SIA_P cases showed complete loss of ventral language streams postoperatively, the highest resection-cavity-AF-overlap, and the shortest AF to tumor distance. CONCLUSION: Functionally relevant qualitative and quantitative differences in AF and IFOF provide a pre- and postoperative pathophysiological and clinically relevant diagnostic indicator that supports surgical risk stratification.

Impact of function-guided glioma treatment on oncological outcome in the elderly.

Introduction: Many patients with high-grade gliomas (HGG) are of older age. Research question: We hypothesize that pre- and intraoperative mapping and monitoring preserve functional status in elderly patients while gross total resection (GTR) is the aim, resulting in overall survival (OS) rates comparable to the general population with HGG. Material and methods: We subdivided a prospective cohort of 168 patients above 65 years with eloquent high-grade gliomas into four groups ([years/cases] 1: 65-69/58; 2: 70-74/47; 3: 75-79/43; 4: >79/20). All patients underwent preoperative noninvasive mapping, which was also used for decision-making, intraoperative neuromonitoring in 138 cases, direct cortical and/or subcortical motor mapping in 66 and 50 cases, and awake language mapping in 11 cases. Results: GTR and subtotal resection (STR) could be achieved in 65% and 28%, respectively. Stereotactic biopsy was performed in 8% of cases. Postoperatively, we found transient and permanent functional deficits in 13% and 11% of cases. Postoperative Karnofsky Performance Scale (KPS) did not differ between subgroups. Patients with long-term follow-up (51%) had a progression-free survival of 5.5 (1-47) months and an overall survival of 10.5 (0-86) months. Discussion and conclusion: The interdisciplinary glioma treatment in the elderly is less age-dependent but must be adjusted to the functional status. Function-guided surgical resections could be performed as usual, with maximal tumor resection being the primary goal. However, less network capacity in the elderly to compensate for deficits might cause higher rates of permanent deficits in this group of patients with more fast-growing malignant gliomas.

Cortical stimulation depth of nTMS investigated in a cohort of convexity meningiomas above the primary motor cortex.

BACKGROUND: In clinical routine, navigated transcranial magnetic stimulation (nTMS) is usually applied down to 25 mm. Yet, besides clinical experience and mathematical models, the penetration depth remains unclear. This study aims to investigate the maximum cortical stimulation depth of nTMS in patients with meningioma above the primary motor cortex, causing a displacement of the primary motor cortex away from the skull. NEW METHOD: nTMS stimulation data was reviewed regarding the maximum depth of stimulations eliciting motor-evoked potentials (MEPs). Additionally, electric field values and stimulation intensity were analyzed. RESULTS: Out of a consecutive cohort of 17 meningioma cases, 3 cases of meningioma located in motor-eloquent regions of the upper extremity and 3 cases of the lower extremity were analyzed after fulfilling all inclusion criteria. Regarding the upper extremity motor representations, the MEP could be elicited at a stimulation depth of up to 44 mm, with an electric field of 69 V/m. These results were found in 1 case with the maximum potential distance to the cortex being higher than the maximum stimulation depth eliciting MEPs. For the lower extremities, a maximum depth of 40 mm was recorded (electric field 64 V/m). COMPARISON WITH EXISTING METHODS: None available CONCLUSIONS: The effect of nTMS is not limited to superficial cortical stimulation alone. Depending on electric-field intensity and focality, nTMS stimulation can be applied at a depth of 44 mm. In all cases, electric field strength was comparable and no superficial cortex with comparable electric field strength was observed to elicit MEPs.

Cortical Location of Language Function May Differ between Languages While White Matter Pathways Are Similar in Brain Lesion Patients.

The neural representation of language can be identified cortically using navigated repetitive transcranial magnetic stimulation and subcortically using the fiber tracking of diffusion tensor imaging. We investigated how cortical locations of language and language-eloquent white matter pathways differ in 40 brain lesion patients speaking various languages. Error rates related to stimulations at single sites in the frontal and parietal lobe differed significantly between Balto-Slavic and Indo-European languages. Error rates related to stimulations at single sites in the temporal lobe differed significantly between bilingual individuals. No differences were found in the white matter language pathway volumes between Balto-Slavic and Indo-European languages nor between bilingual patients. These original and exploratory data indicate that the underlying subcortical structure might be similar across languages, with initially observed differences in the cortical location of language depending on the semantic processing, but these could not be confirmed using detailed statistical analyses pointing at a similar cortical and subcortical network.

Interhemispheric connections in the maintenance of language performance and prognosis prediction: fully connected layer-based deep learning model analysis.

OBJECTIVE: Language-related networks have been recognized in functional maintenance, which has also been considered the mechanism of plasticity and reorganization in patients with cerebral malignant tumors. However, the role of interhemispheric connections (ICs) in language restoration remains unclear at the network level. Navigated transcranial magnetic stimulation (nTMS) and diffusion tensor imaging fiber tracking data were used to identify language-eloquent regions and their corresponding subcortical structures, respectively. METHODS: Preoperative image-based IC networks and nTMS mapping data from 30 patients without preoperative and postoperative aphasia as the nonaphasia group, 30 patients with preoperative and postoperative aphasia as the glioma-induced aphasia (GIA) group, and 30 patients without preoperative aphasia but who developed aphasia after the operation as the surgery-related aphasia group were investigated using fully connected layer-based deep learning (FC-DL) analysis to weight ICs. RESULTS: GIA patients had more weighted ICs than the patients in the other groups. Weighted ICs between the left precuneus and right paracentral lobule, and between the left and right cuneus, were significantly different among these three groups. The FC-DL approach for modeling functional and structural connectivity was also tested for its potential to predict postoperative language levels, and both the achieved sensitivity and specificity were greater than 70%. Weighted IC was reorganized more in GIA patients to compensate for language loss. CONCLUSIONS: The authors' method offers a new perspective to investigate brain structural organization and predict functional prognosis.

Impacting the Treatment of Highly Eloquent Supratentorial Cerebral Cavernous Malformations by Noninvasive Functional Mapping-An Observational Cohort Study.

BACKGROUND: Cerebral cavernous malformations (CCM) may cause cavernoma-related epilepsy (CRE) and intracranial hemorrhage (ICH). Functional mapping has shown its usefulness during the resection of eloquent lesions including the treatment of brain arteriovenous malformations. OBJECTIVE: To evaluate the impact of noninvasive functional mapping on decision-making and resection of eloquently located CCM. METHODS: Of 126 patients with intracranial cavernomas, we prospectively included 40 consecutive patients (31.7%) with highly eloquent CCM between 2012 and 2020. We performed functional mapping via navigated transcranial magnetic stimulation (nTMS) motor mapping in 30 cases and nTMS language mapping in 20 cases. Twenty patients suffered from CRE. CCM caused ICH in 18 cases. RESULTS: We used functional mapping data including function-based tractography in all cases. Indication toward (31 cases) or against (9 cases) CCM resection was influenced by noninvasive functional mapping in 36 cases (90%). We resected CCMs in 24 cases, and 7 patients refused the recommendation for surgery. In 19 and 4 cases, we used additional intraoperative neuromonitoring and awake craniotomy, respectively. Patients suffered from transient postoperative motor or language deficits in 2 and 2 cases, respectively. No patient suffered from permanent deficits. After 1 yr of follow-up, anti-epileptic drugs could be discontinued in all patients who underwent surgery but 1 patient. CONCLUSION: Surgery-related deficit rates are low even for highly eloquent CCM and seizure outcome is excellent. The present results show that noninvasive functional mapping and function-based tractography is a useful tool for the decision-making process and during microsurgical resection of eloquently located CCM.

Navigated repetitive transcranial magnetic stimulation improves the outcome of postsurgical paresis in glioma patients - A randomized, double-blinded trial.

BACKGROUND: Navigated repetitive transcranial magnetic stimulation (nrTMS) is effective therapy for stroke patients. Neurorehabilitation could be supported by low-frequency stimulation of the non-damaged hemisphere to reduce transcallosal inhibition. OBJECTIVE: The present study examines the effect of postoperative nrTMS therapy of the unaffected hemisphere in glioma patients suffering from acute surgery-related paresis of the upper extremity (UE) due to subcortical ischemia. METHODS: We performed a randomized, sham-controlled, double-blinded trial on patients suffering from acute surgery-related paresis of the UE after glioma resection. Patients were randomly assigned to receive either low frequency nrTMS (1 Hz, 15 min) or sham stimulation directly before physical therapy for 7 consecutive days. We performed primary and secondary outcome measures on day 1, on day 7, and at a 3-month follow-up (FU). The primary endpoint was the change in Fugl-Meyer Assessment (FMA) at FU compared to day 1 after surgery. RESULTS: Compared to the sham stimulation, nrTMS significantly improved outcomes between day 1 and FU based on the FMA (mean [95% CI] +31.9 [22.6, 41.3] vs. +4.2 [-4.1, 12.5]; P = .001) and the National Institutes of Health Stroke Scale (NIHSS) (-5.6 [-7.5, -3.6] vs. -2.4 [-3.6, -1.2]; P = .02). To achieve a minimal clinically important difference of 10 points on the FMA scale, the number needed to treat is 2.19. CONCLUSION: The present results show that patients suffering from acute surgery-related paresis of the UE due to subcortical ischemia after glioma resection significantly benefit from low-frequency nrTMS stimulation therapy of the unaffected hemisphere. CLINICAL TRIAL REGISTRATION: Local institutional registration: 12/15; ClinicalTrials.gov number: NCT03982329.

Tractography for Subcortical Resection of Gliomas Is Highly Accurate for Motor and Language Function: ioMRI-Based Elastic Fusion Disproves the Severity of Brain Shift.

When using preoperative tractography intraoperatively, inaccuracies due to brain shift might occur. Intraoperative tractography is rarely performed. Elastic fusion (EF) is a tool developed to compensate for brain shift, gravity, and tissue resection based on intraoperative images. Our hypothesis was that preoperative tractography is accurate and adjustments of tractography by intraoperative magnetic resonance imaging (ioMRI)-based EF (IBEF) compensate for brain shift. Between February 2018 and June 2019, 78 patients underwent eloquent (46 motor, 32 language) glioma resection in our department using intraoperative MRI. Mean distances between the resection cavity and tractography were analyzed and correlated with clinical outcomes. The mean ± standard deviation (range) distance after the application of IBEF was 5.0 ± 2.9 mm (0-10 mm) in patients without surgery-related motor deficits compared with 1.1 ± 1.6 mm (0-5 mm) in patients who showed new permanent surgery-related motor deficits postoperatively (p < 0.001). For language, the distance was 0.7 ± 1.2 mm (0-2 mm) in patients with new permanent deficits compared with 3.1 ± 4.5 mm (0-14 mm) in patients without new permanent surgery-related language deficits (p = 0.541). Preoperative tractography corrected by IBEF for subcortical resection of gliomas is highly accurate. However, at least for such subcortical anatomy, the severity of brain shift was considerably overestimated in the past.

Non-Invasive Mapping for Effective Preoperative Guidance to Approach Highly Language-Eloquent Gliomas-A Large Scale Comparative Cohort Study Using a New Classification for Language Eloquence.

Objective: A considerable number of gliomas require resection via direct electrical stimulation (DES) during awake craniotomy. Likewise, the feasibility of resecting language-eloquent gliomas purely based on navigated repetitive transcranial magnetic stimulation (nrTMS) has been shown. This study analyzes the outcomes after preoperative nrTMS-based and intraoperative DES-based glioma resection in a large cohort. Due to the necessity of making location comparable, a classification for language eloquence for gliomas is introduced. Methods: Between March 2015 and May 2019, we prospectively enrolled 100 consecutive cases that were resected based on preoperative nrTMS language mapping (nrTMS group), and 47 cases via intraoperative DES mapping during awake craniotomy (awake group) following a standardized clinical workflow. Outcome measures were determined preoperatively, 5 days after surgery, and 3 months after surgery. To make functional eloquence comparable, we developed a classification based on prior publications and clinical experience. Groups and classification scores were correlated with clinical outcomes. Results: The functional outcome did not differ between groups. Gross total resection was achieved in more cases in the nrTMS group (87%, vs. 72% in the awake group, p = 0.04). Nonetheless, the awake group showed significantly higher scores for eloquence than the nrTMS group (median 7 points; interquartile range 6-8 vs. 5 points; 3-6.75; p < 0.0001). Conclusion: Resecting language-eloquent gliomas purely based on nrTMS data is feasible in a high percentage of cases if the described clinical workflow is followed. Moreover, the proposed classification for language eloquence makes language-eloquent tumors comparable, as shown by its correlation with functional and radiological outcomes.

Intraoperative MRI-based elastic fusion for anatomically accurate tractography of the corticospinal tract: correlation with intraoperative neuromonitoring and clinical status.

OBJECTIVE: Tractography is a useful technique that is standardly applied to visualize subcortical pathways. However, brain shift hampers tractography use during the course of surgery. While intraoperative MRI (ioMRI) has been shown to be beneficial for use in oncology, intraoperative tractography can rarely be performed due to scanner, protocol, or head clamp limitations. Elastic fusion (EF), however, enables adjustment for brain shift of preoperative imaging and even tractography based on intraoperative images. The authors tested the hypothesis that adjustment of tractography by ioMRI-based EF (IBEF) correlates with the results of intraoperative neuromonitoring (IONM) and clinical outcome and is therefore a reliable method. METHODS: In 304 consecutive patients treated between June 2018 and March 2020, 8 patients, who made up the basic study cohort, showed an intraoperative loss of motor evoked potentials (MEPs) during motor-eloquent glioma resection for a subcortical lesion within the corticospinal tract (CST) as shown by ioMRI. The authors preoperatively visualized the CST using tractography. Also, IBEFs of pre- and intraoperative images were obtained and the location of the CST was compared in relation to a subcortical lesion. In 11 patients (8 patients with intraoperative loss of MEPs, one of whom also showed loss of MEPs on IBEF evaluation, plus 3 additional patients with loss of MEPs on IBEF evaluation), the authors examined the location of the CST by direct subcortical stimulation (DSCS). The authors defined the IONM results and the functional outcome data as ground truth for analysis. RESULTS: The maximum mean ± SD correction was 8.8 ± 2.9 (range 3.8-12.0) mm for the whole brain and 5.3 ± 2.4 (range 1.2-8.7) mm for the CST. The CST was located within the lesion before IBEF in 3 cases and after IBEF in all cases (p = 0.0256). All patients with intraoperative loss of MEPs suffered from surgery-related permanent motor deficits. By approximation, the location of the CST after IBEF could be verified by DSCS in 4 cases. CONCLUSIONS: The present study shows that tractography after IBEF accurately correlates with IONM and patient outcomes and thus demonstrates reliability in this initial study.

Functional Reorganization of Cortical Language Function in Glioma Patients-A Preliminary Study.

Background: Functional reorganization (FR) was shown in glioma patients by direct electrical stimulation (DES) during awake craniotomy. This option for repeated mapping is available in cases of tumor recurrence and after decision for a second surgery. Navigated repetitive transcranial magnetic stimulation (nrTMS) has shown a high correlation with results of DES during awake craniotomy for language-negative sites (LNS) and allows for a non-invasive evaluation of language function. This preliminary study aims to examine FR in glioma patients by nrTMS. Methods: A cohort of eighteen patients with left-sided perisylvian gliomas underwent preoperative nrTMS language mapping twice. The mean time between mappings was 17 ± 12 months. The cortex was separated into anterior and posterior language-eloquent regions. We defined a tumor area and an area without tumor (WOT). Error rates (ER = number of errors per number of stimulations) and hemispheric dominance ratios (HDR) were calculated as the quotient of the left- and right-sided ER. Results: In cases in which most language function was located near the tumor during the first mapping, we found significantly more LNS in the tumor area during the second mapping as compared to cases in which function was not located near the tumor (p = 0.049). Patients with seizures showed fewer LNS during the second mapping. We found more changes of cortical language function in patients with a follow-up time of more than 13 months and lower WHO-graded tumors. Conclusion: Present results confirm that nrTMS can show FR of LNS in glioma patients. Its extent, clinical impact and correlation with DES requires further evaluation but could have a considerable impact in neuro-oncology.

Risk factors for unplanned discontinuation of scheduled treatment in elderly patients with castration-resistant prostate cancer: results of the IBuTu study.

PURPOSE: To gain knowledge about the factors associated with discontinuation of scheduled treatment in elderly men with castration-resistant prostate cancer (CRPC). METHODS: Patients ≥ 70 years with CRPC starting a new line of treatment were included in a prospective cohort study. A geriatric assessment (CGA) was performed at baseline, including comorbidity, mobility, functional/mental/nutritional status, as well as depression. Furthermore, pain intensity, quality of life, ECOG-performance status, and physicians' and patients' perception of health were documented. Reasons for and factors associated with discontinuation of scheduled treatment were analysed by univariate and multivariate analysis. RESULTS: After inclusion of 177 of 300 planned patients, the study was closed due to slow recruitment. 160 patients were eligible for final analysis. Median age was 77.5 years. 46% received chemotherapy, and 54% hormonal treatment. Discontinuation of scheduled treatment occurred in 91 patients (57.6%). The main reasons were progressive disease/death in 63%, adverse events/toxicity in 22%, and withdrawal of consent in 8%. In bivariate analyses, factors associated with discontinuation of treatment were age ≥ 80 years, ECOG PS ≥ 2, compromised/poor health status (physicians'/patients' assessment), and compromised functional or nutritional status. In multivariate analysis, the only remaining factor independently associated with discontinuation of scheduled treatment was impairment of activities of daily living (ADL < 100 points) (OR = 4.2 for discontinuation; p < 0.05). CONCLUSION: Despite limitations due to early termination of the study, our results demonstrate that discontinuation of scheduled treatment was common, and that compromised ADL seems to be a significant risk factor for treatment failure in elderly patients with CRPC.