Operationsplanung eloquenter Hirntumoren – vom inoperablen zum operablen Hirntumor

Auf Grundlage der vorliegenden Habilitationsschrift kann der Begriff des motorisch- und Sprach-eloquenten Hirntumors nunmehr objektiviert und genauer charakterisiert werden. Bei Patientinnen und Patienten mit bislang als inoperabel eingeschätzten Hirntumoren kann unter Einsatz der nTMS und der nTMS-basierten DTI-Traktografie eine differenziertere Abwägung zwischen Operationsrisiko und möglichem onkologischem Benefit einer Hirntumorresektion erfolgen. Die Standardisierung der Pyramidenbahn-Traktografie im Rahmen der ersten Studie verbesserte mit Integration der funktionellen nTMS-Daten die Traktografie-Qualität und zeichnete sich zudem durch eine ausgezeichnete Interrater-Reliabilität aus. Eine beeinträchtigte Integrität der peritumoralen Pyramidenbahn kann durch die Diffusionsparameter FA und ADC charakterisiert werden und war mit einem erhöhten Risiko für ein neues postoperatives motorisches Defizit assoziiert. Die Erkenntnisse der ersten Arbeit wurden mit Analysen zuvor publizierter Arbeiten genutzt, um in der zweiten Studie die nTMS-basierte Risikostratifizierung bizentrisch zu validieren. Neben der topografischen Analyse (Infiltration des Motorkortex und Bestimmung der Tumor- Trakt-Distanz) erwiesen sich die FA und der RMT, welche die Faserbahnintegrität bzw. die Exzitabilität des motorischen System repräsentieren, als entscheidende Parameter zur V orhersage des Operationsrisikos. So konnte ein verbessertes, auf einer Regressionsbaumanalyse basierendes Risikomodell zur Vorhersage des kurz- und langfristigen motorischen Outcomes entwickelt werden. Im Rahmen der dritten Studie konnte gezeigt werden, dass die präoperative Risikoanalyse die Durchführung des IOMs unterstützen kann, indem subkortikale Stimulationsintensitäten angepasst und unspezifische Phänomene wie transiente/partielle MEP- Amplitudenminderungen differenzierter interpretiert werden können. Somit kann eine hoch individualisierte Behandlungsstrategie für Patientinnen und Patienten mit motorisch- eloquenten Hirntumoren gewährleistet werden. Für die Beurteilung Sprach-eloquenter Hirntumoren kommen sowohl das kortikale rTMS- Sprachmapping (als Negativmapping) sowie die DTI-basierte Traktografie des Sprachnetzwerks zum Einsatz. In der vierten Arbeit offenbarte der Vergleich aller bisher publizierten Algorithmen, dass die Platzierung anatomischer ROIs die besten Traktografie- Ergebnisse hinsichtlich der Darstellbarkeit und Plausibilität der Trakte offenbarte. Dieser Algorithmus wurde von internationalen Experten auch zur Operationsplanung und für das Risiko-Assessment bevorzugt. Die Integration funktioneller rTMS-basierter ROIs ermöglichte die zusätzliche Darstellung von kortiko-subkortikalen Fasern, deren Relevanz für das Sprachoutcome es in weiteren Studien zu untersuchen gilt. Die Cluster-Analyse der fünften Studie identifizierte zwei Hochrisikoareale, die mit dem Auftreten eines neuen postoperativen Sprachdefizits assoziiert waren: 1. die temporo-parieto- occipitale Übergangszone und 2. der Temporalstamm der periinsulären weißen Substanz. Der AF als V ertreter des dorsalen Systems zeigte sich als wichtigste Faserbahn für die Sprachfunktion, deren Verletzung mit dem höchsten Risiko für eine postoperative Sprachstörung assoziiert war. Eine Schädigung des ventralen Faserbahnsystems spielte vor allem dann für das postoperative Sprachoutcome eine Rolle, wenn sowohl die direkte Bahn (IFOF) als auch der indirekte Kreislauf (UF und ILF) betroffen waren. Die hier dargelegten Technologien der nTMS und DTI-Traktografie ermöglichen für motorisch- und Sprach-eloquente Hirntumoren eine differenzierte und individuelle Operationsplanung. Ziel zukünftiger Arbeiten wird es sein, diese Technologien weiter zu optimieren, um Hirntumoroperationen sicherer zu gestalten und damit die individuelle Patientenbehandlung zu verbessern

Specific DTI seeding and diffusivity-analysis improve the quality and prognostic value of TMS-based deterministic DTI of the pyramidal tract

Object Navigated transcranial magnetic stimulation (nTMS) combined with diffusion tensor imaging (DTI) is used preoperatively in patients with eloquent-located brain lesions and allows analyzing non-invasively the spatial relationship between the tumor and functional areas (e.g. the motor cortex and the corticospinal tract [CST]). In this study, we examined the diffusion parameters FA (fractional anisotropy) and ADC (apparent diffusion coefficient) within the CST in different locations and analyzed their interrater reliability and usefulness for predicting the patients' motor outcome with a precise approach of specific region of interest (ROI) seeding based on the color-coded FA-map. Methods Prospectively collected data of 30 patients undergoing bihemispheric nTMS mapping followed by nTMS-based DTI fiber tracking prior to surgery of motor eloquent high-grade gliomas were analyzed by 2 experienced and 1 unexperienced examiner. The following data were scrutinized for both hemispheres after tractography based on nTMS-motor positive cortical seeds and a 2nd region of interest in one layer of the caudal pons defined by the color-coded FA-map: the pre- and postoperative motor status (day of discharge und 3 months), the closest distance between the tracts and the tumor (TTD), the fractional anisotropy (FA) and the apparent diffusion coefficient (ADC). The latter as an average within the CST as well as specific values in different locations (peritumoral, mesencephal, pontine). Results Lower average FA-values within the affected CST as well as higher average ADC-values are significantly associated with deteriorated postoperative motor function (p = 0.006 and p = 0.026 respectively). Segmental analysis within the CST revealed that the diffusion parameters are especially disturbed on a peritumoral level and that the degree of their impairment correlates with motor deficits (FA p = 0.065, ADC p = 0.007). No significant segmental variation was seen in the healthy hemisphere. The interrater reliability showed perfect agreement for almost all analyzed parameters. Conclusions Adding diffusion weighted imaging derived information on the structural integrity of the nTMS-based tractography results improves the predictive power for postoperative motor outcome. Utilizing a second subcortical ROI which is specifically seeded based on the color-coded FA map increases the tracking quality of the CST independently of the examiner's experience. Further prospective studies are needed to validate the nTMS-based prediction of the patient's outcome

MRI-Based Risk Assessment for Incomplete Resection of Brain Metastases

Recent studies demonstrated that gross total resection of brain metastases cannot always be achieved. Subtotal resection (STR) can result in an early recurrence and might affect patient survival. We initiated a prospective observational study to establish a MRI-based risk assessment for incomplete resection of brain metastases.Peer Reviewe

Effectiveness of Immune Checkpoint Inhibition vs Chemotherapy in Combination With Radiation Therapy Among Patients With Non–Small Cell Lung Cancer and Brain Metastasis Undergoing Neurosurgical Resection

Importance: Patients with brain metastases from non-small cell lung cancer (NSCLC) have regularly been excluded from prospective clinical trials that include therapy with immune checkpoint inhibitors (ICIs). Clinical data demonstrating benefit with ICIs, specifically following neurosurgical brain metastasis resection, are scarce. Objective: To evaluate and compare the association of radiation therapy with ICIs vs classic therapy involving radiation therapy and chemotherapy regarding overall survival in a cohort of patients who underwent NSCLC brain metastasis resection. Design, setting and participants: This single-center 1:1 propensity-matched comparative effectiveness study at the largest neurosurgical clinic in Germany included individuals who had undergone craniotomy with brain metastasis resection from January 2010 to December 2021 with histologically confirmed NSCLC. Of 1690 patients with lung cancer and brain metastasis, 480 were included in the study. Key exclusion criteria were small-cell lung cancer, lack of tumor cells by means of histopathological analysis on brain metastasis resection, and patients who underwent biopsy without tumor resection. The association of overall survival with treatment with radiation therapy and chemotherapy vs radiation therapy and ICI was evaluated. Exposures: Radiation therapy and chemotherapy vs radiation therapy and ICI following craniotomy and microsurgical brain metastasis resection. Main outcomes and measures: Median overall survival. Results: From the whole cohort of patients with NSCLC (N = 384). 215 (56%) were male and 169 (44%) were female. The median (IQR) age was 64 (57-72) years. The 2 cohorts of interest included 108 patients (31%) with radiation therapy and chemotherapy and 63 patients (16%) with radiation therapy and ICI following neurosurgical metastasis removal (before matching). Median (IQR) follow-up time for the total cohort was 47.9 (28.2-70.1) months with 89 patients (23%) being censored and 295 (77%) dead at the end of follow-up in December 2021. After covariate equalization using propensity score matching (62 patients per group), patients receiving radiation therapy and chemotherapy after neurosurgery had significantly lower overall survival (11.8 months; 95% CI; 9.1-15.2) compared with patients with radiation therapy and ICIs (23.0 months; 95% CI; 20.3-53.8) (P < .001). Conclusions and relevance: Patients with NSCLC brain metastases undergoing neurosurgical resection had longer overall survival when treated with radiation therapy and ICIs following neurosurgery compared with those receiving platinum-based chemotherapy and radiation. Radiation and systemic immunotherapy should be regularly evaluated as a treatment option for these patients

Präoperative Risikostratifizierung für das funktionelle Ergebnis bei Tumorresektionen in motorischen Arealen

Introduction. Navigated transcranial magnetic stimulation (nTMS) has been established as a noninvasive examination method to identify preoperatively functional motor areas in patients with brain tumors in presumed motor eloquent areas. The aim of this study was to analyze in how far the data provided by nTMS can be used to predict the risk for the occurence of a new or the aggravation of a preoperatively existing paresis. Methods. One hundred thirteen patients who were operated with glioma in presumed motor eloquent areas in our department between October 2007 and December 2014 were prospectively included for bihemispheric, preoperative nTMS mapping. The examination results were transferred to the operation planning software iPlan 2.0 (Brain Lab) and fiber tracking of the corticospinal tract based on diffusion tensor imaging was performed. Univariate analyses were used to detect any correlations between the nTMS-derived variables and the postoperative motor status on day 7 (= day of discharge) and after 3 months. For creating a predictive model for the motor outcome, significant variables were included into multiple ordinal logistic regression analysis. Results. Deterioration of the motor status was observed in 20% of cases after 7 days and in 22% of cases after 3 months. A new permanent deficit never occured when the subcortical distance between the corticospinal tract and the tumor was greater than 8 mm and the motor cortex was not infiltrated (p = 0.014). Patients with a pathological interhemispheric excitability of the motor system (interhemispheric resting motor threshold [RMT] ratio 110%) had a higher risk to suffer from a new paresis on day 7 (p = 0.031). On the other hand, patients with a preoperative deficit never regained motor function when the RMT was significantly higher in the tumorous hemisphere than in the healthy hemisphere (RMT ratio > 110%). Conclusion. The risk stratification model allows to quantify the likelihood for worsening or improvement of motor function based on objective functional-anatomical and neurophysiological data. The data can be utilized to decide about the necessity for intraoperative neurophysiological monitoring and to establish an individualized treatment plan in consent with the patient.Einleitung. Für Patienten mit einem motorisch-eloquent gelegenen Hirntumor hat sich die navigierte transkranielle Magnetstimulation (nTMS) als nicht-invasive Untersuchungsmethode etabliert, um motorisch-funktionelle Areale präoperativ zu identifizieren. Das Ziel dieser Studie war es zu analysieren, ob und inwiefern sich die durch die nTMS-Untersuchung bereitgestellten Daten dazu eignen, das Risiko für das Auftreten einer neuen oder der Verschlechterung einer bereits präoperativ bestehenden Parese in Form eines statistisch prädiktiven Models zu stratifizieren. Methoden. Einhundertdreizehn Patienten, die zwischen Oktober 2007 und Dezember 2014 an einem hirneigenen Tumor in (potenziell) motorisch-eloquenter Lage in der Klinik für Neurochirurgie der Charité operiert wurden, unterzogen sich präoperativ der bihemisphärischen nTMS-Untersuchung. Anschließend erfolgte die Evaluation in der OP- Planungssoftware iPlan 2.0 (Brain Lab), mit welcher eine auf Diffusions- Tensor-Bildgebung basierende Faserbahndarstellung des kortikospinalen Traktes erfolgte. Mit den prospektiv gesammelten Daten erfolgte zunächst eine univariate Analyse bzgl. des motorischen Status nach 7 Tagen (= Entlassungstag) und 3 Monaten. Anschließend wurde mithilfe der signifkanten Variablen eine multiple ordinale logistische Regressionsanalyse durchgeführt, um Prädiktoren für das motorische Outcome der Patienten zu identifizieren. Ergebnisse. Ein verschlechterter motorischer Status wurde in 20% der Fälle nach 7 Tagen und in 22% der Fälle nach 3 Monaten beobachtet. Patienten erlitten nie ein neues motorisches Defizit, wenn der minimale subkortikale Abstand zwischen dem Tumor und der nTMS-basierten Darstellung des kortikospinalen Traktes größer als 8mm war und keine kortikale tumoröse Infiltration des Motorkortex nachweisbar war (p = 0.014). Eine postoperative motorische Verschlechterung nach 7 Tagen war mit einem pathologischen interhemisphärischen Erregungsverhältnis (interhemisphärischer „resting motor threshold“ (RMT)-Quotient 110%) assoziiert (p = 0.031). Eine präoperative Parese bildete sich bei Patienten, deren RMT-Quotient > 110% lag, nie zurück. Zusammenfassung. Die auf anatomisch-funktionellen und neurophysiologischen Daten basierende Risikostratifizierung erlaubt es, die Wahrscheinlichkeit für eine motorisch-funktionelle Verschlechterung bzw. Besserung zu quantifizieren. Diese Information kann genutzt werden, um die Notwendigkeit von intraoperativem neurophysiologischen Monitoring einzuschätzen und in Konsens mit dem Patienten eine individualisierte Behandlungsstrategie festzulegen

Predicting the Extent of Resection of Motor-Eloquent Gliomas Based on TMS-Guided Fiber Tracking

Background: Surgical planning with nTMS-based tractography is proven to increase safety during surgery. A preoperative risk stratification model has been published based on the M1 infiltration, RMT ratio, and tumor to corticospinal tract distance (TTD). The correlation of TTD with corticospinal tract to resection cavity distance (TRD) and outcome is needed to further evaluate the validity of the model. Aim of the study: To use the postop MRI-derived resection cavity to measure how closely the resection cavity approximated the preoperatively calculated corticospinal tract (CST) and how this correlates with the risk model and the outcome. Methods: We included 183 patients who underwent nTMS-based DTI and surgical resection for presumed motor-eloquent gliomas. TTD, TRD, and motor outcome were recorded and tested for correlations. The intraoperative monitoring documentation was available for a subgroup of 48 patients, whose responses were correlated to TTD and TRD. Results: As expected, TTD and TRD showed a good correlation (Spearman’s ρ = 0.67, p &lt; 0.001). Both the TTD and the TRD correlated significantly with the motor outcome at three months (Kendall’s Tau-b 0.24 for TTD, 0.31 for TRD, p &lt; 0.001). Interestingly, the TTD and TRD correlated only slightly with residual tumor volume, and only after correction for outliers related to termination of resection due to intraoperative monitoring events or the proximity of other eloquent structures (TTD ρ = 0.32, p &lt; 0.001; TRD ρ = 0.19, p = 0.01). This reflects the fact that intraoperative monitoring (IOM) phenomena do not always correlate with preoperative structural analysis, and that additional factors influence the intraoperative decision to abort resection, such as the adjacency of other vulnerable structures. The TTD was also significantly correlated with variations in motor evoked potential (MEP) responses (no/reversible decrease vs. irreversible decrease; p = 0.03). Conclusions: The TTD approximates the TRD well, confirming the best predictive parameter and giving strength to the nTMS-based risk stratification model. Our analysis of TRD supports the use of the nTMS-based TTD measurement to estimate the resection preoperatively, also confirming the 8 mm cutoff. Nevertheless, the TRD proved to have a slightly stronger correlation with the outcome as the surgeon’s experience, anatomofunctional knowledge, and MEP observations influence the expected EOR

Preoperative nTMS and Intraoperative Neurophysiology - A Comparative Analysis in Patients With Motor-Eloquent Glioma

Background The resection of a motor-eloquent glioma should be guided by intraoperative neurophysiological monitoring (IOM) but its interpretation is often difficult and may (unnecessarily) lead to subtotal resection. Navigated transcranial magnetic stimulation (nTMS) combined with diffusion-tensor-imaging (DTI) is able to stratify patients with motor-eloquent lesion preoperatively into high- and low-risk cases with respect to a new motor deficit. Objective To analyze to what extent preoperative nTMS motor risk stratification can improve the interpretation of IOM phenomena. Methods In this monocentric observational study, nTMS motor mapping with DTI fiber tracking of the corticospinal tract was performed before IOM-guided surgery for motor-eloquent gliomas in a prospectively collected cohort from January 2017 to October 2020. Descriptive analyses were performed considering nTMS data (motor cortex infiltration, resting motor threshold (RMT), motor evoked potential (MEP) amplitude, latency) and IOM data (transcranial MEP monitoring, intensity of monopolar subcortical stimulation (SCS), somatosensory evoked potentials) to examine the association with the postoperative motor outcome (assessed at day of discharge and at 3 months). Results Thirty-seven (56.1%) of 66 patients (27 female) with a median age of 48 years had tumors located in the right hemisphere, with glioblastoma being the most common diagnosis with 39 cases (59.1%). Three patients (4.9%) had a new motor deficit that recovered partially within 3 months and 6 patients had a persistent deterioration (9.8%). The more risk factors of the nTMS risk stratification model (motor cortex infiltration, tumor-tract distance (TTD) 8mm deteriorated. Irreversible MEP amplitude decrease >50% was associated with worse motor outcome in all patients, while a MEP amplitude decrease <= 50% or lower SCS intensities <= 4mA were particularly correlated with a postoperative worsened motor status in nTMS-stratified high-risk cases. No patient had postoperative deterioration of motor function (except one with partial recovery) when intraoperative MEPs remained stable or showed only reversible alterations. Conclusions The preoperative nTMS-based risk assessment can help to interpret ambiguous IOM phenomena (such as irreversible MEP amplitude decrease <= 50%) and adjustment of SCS stimulation intensity

Specific DTI seeding and diffusivity-analysis improve the quality and prognostic value of TMS-based deterministic DTI of the pyramidal tract

Object: Navigated transcranial magnetic stimulation (nTMS) combined with diffusion tensor imaging (DTI) is used preoperatively in patients with eloquent-located brain lesions and allows analyzing non-invasively the spatial relationship between the tumor and functional areas (e.g. the motor cortex and the corticospinal tract [CST]). In this study, we examined the diffusion parameters FA (fractional anisotropy) and ADC (apparent diffusion coefficient) within the CST in different locations and analyzed their interrater reliability and usefulness for predicting the patients' motor outcome with a precise approach of specific region of interest (ROI) seeding based on the color-coded FA-map. Methods: Prospectively collected data of 30 patients undergoing bihemispheric nTMS mapping followed by nTMS-based DTI fiber tracking prior to surgery of motor eloquent high-grade gliomas were analyzed by 2 experienced and 1 unexperienced examiner. The following data were scrutinized for both hemispheres after tractography based on nTMS-motor positive cortical seeds and a 2nd region of interest in one layer of the caudal pons defined by the color-coded FA-map: the pre- and postoperative motor status (day of discharge und 3months), the closest distance between the tracts and the tumor (TTD), the fractional anisotropy (FA) and the apparent diffusion coefficient (ADC). The latter as an average within the CST as well as specific values in different locations (peritumoral, mesencephal, pontine). Results: Lower average FA-values within the affected CST as well as higher average ADC-values are significantly associated with deteriorated postoperative motor function (p=0.006 and p=0.026 respectively). Segmental analysis within the CST revealed that the diffusion parameters are especially disturbed on a peritumoral level and that the degree of their impairment correlates with motor deficits (FA p=0.065, ADC p=0.007). No significant segmental variation was seen in the healthy hemisphere. The interrater reliability showed perfect agreement for almost all analyzed parameters. Conclusions: Adding diffusion weighted imaging derived information on the structural integrity of the nTMS-based tractography results improves the predictive power for postoperative motor outcome. Utilizing a second subcortical ROI which is specifically seeded based on the color-coded FA map increases the tracking quality of the CST independently of the examiner's experience. Further prospective studies are needed to validate the nTMS-based prediction of the patient's outcome. Keywords: Navigated transcranial magnetic stimulation (nTMS), Brain tumor surgery, Glioma, Motor outcome, Diffusion tensor imaging, Fractional anisotropy, Apparent diffusion coefficien

NTMS based tractography and segmental diffusion analysis in patients with brainstem gliomas: Risk stratification and clinical potential

Introduction: Surgery on the brainstem level is associated with a high-risk of postoperative morbidity. Recently, we have introduced the combination of navigated transcranial magnetic stimulation (nTMS) and diffusion tensor imaging (DTI) tractography to define functionally relevant motor fibers tracts on the brainstem level to support operative planning and risk stratification in brainstem cavernomas. Research question: Evaluate this method and assess it's clinical impact for the surgery of brainstem gliomas. Material and methods: Patients with brainstem gliomas were examined preoperatively with motor nTMS and DTI tractography. A fractional anisotropy (FA) value of 75% of the individual FA threshold (FAT) was used to track descending corticospinal (CST) and -bulbar tracts (CBT). The distance between the tumor and the somatotopic tracts (hand, leg, face) was measured and diffusion parameters were correlated to the patients’ outcome. Results: 12 patients were enrolled in this study, of which 6 underwent surgical resection, 5 received a stereotactic biopsy and 1 patient received conservative treatment. In all patients nTMS mapping and somatotopic tractography were performed successfully. Low FA values correlated with clinical symptoms revealing tract alteration by the tumor (p = 0.049). A tumor-tract distance (TTD) above 2 mm was the critical limit to achieve a safe complete tumor resection. Discussion and conclusion: nTMS based DTI tractography combined with local diffusion analysis is a valuable tool for preoperative visualization and functional assessment of relevant motor fiber tracts, improving planning of safe entry corridors and perioperative risk stratification in brainstem gliomas tumors. This technique allows for customized treatment strategy to maximize patients’ safety

Bicentric validation of the navigated transcranial magnetic stimulation motor risk stratification model.

OBJECTIVE The authors sought to validate the navigated transcranial magnetic stimulation (nTMS)-based risk stratification model. The postoperative motor outcome in glioma surgery may be preoperatively predicted based on data derived by nTMS. The tumor-to-tract distance (TTD) and the interhemispheric resting motor threshold (RMT) ratio (as a surrogate parameter for cortical excitability) emerged as major factors related to a new postoperative deficit. METHODS In this bicentric study, a consecutive prospectively collected cohort underwent nTMS mapping with diffusion tensor imaging (DTI) fiber tracking of the corticospinal tract prior to surgery of motor eloquent gliomas. The authors analyzed whether the following items were associated with the patient's outcome: patient characteristics, TTD, RMT value, and diffusivity parameters (fractional anisotropy [FA] and apparent diffusion coefficient [ADC]). The authors assessed the validity of the published risk stratification model and derived a new model. RESULTS A new postoperative motor deficit occurred in 36 of 165 patients (22%), of whom 20 patients still had a deficit after 3 months (13%; n3 months = 152). nTMS-verified infiltration of the motor cortex as well as a TTD ≤ 8 mm were confirmed as risk factors. No new postoperative motor deficit occurred in patients with TTD > 8 mm. In contrast to the previous risk stratification, the RMT ratio was not substantially correlated with the motor outcome, but high RMT values of both the tumorous and healthy hemisphere were associated with worse motor outcome. The FA value was negatively associated with worsening of motor outcome. Accuracy analysis of the final model showed a high negative predictive value (NPV), so the preoperative application may accurately predict the preservation of motor function in particular (day of discharge: sensitivity 47.2%, specificity 90.7%, positive predictive value [PPV] 58.6%, NPV 86.0%; 3 months: sensitivity 85.0%, specificity 78.8%, PPV 37.8%, NPV 97.2%). CONCLUSIONS This bicentric validation analysis further improved the model by adding the FA value of the corticospinal tract, demonstrating the relevance of nTMS/nTMS-based DTI fiber tracking for clinical decision making