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Setup presentation and clinical outcome analysis of treating highly language-eloquent gliomas via preoperative navigated transcranial magnetic stimulation and tractography

Setup presentation and clinical outcome analysis of treating highly language-eloquent gliomas via... NEUROSURGICAL FOCUS Neurosurg Focus 44 (6):E2, 2018 Setup presentation and clinical outcome analysis of treating highly language-eloquent gliomas via preoperative navigated transcranial magnetic stimulation and tractography 1–3 2,3 2,3 2 Nico Sollmann, MD, PhD, Anna Kelm, Sebastian Ille, MD, Axel Schröder, 1,3 2 2 2,3 Claus Zimmer, MD, Florian Ringel, MD, Bernhard Meyer, MD, and Sandro M. Krieg, MD, MBA 1 2 3 Department of Diagnostic and Interventional Neuroradiology, Department of Neurosurgery, and TUM-Neuroimaging Center, Klinikum rechts der Isar, Technische Universität München, Germany OBJECTIVE Awake surgery combined with intraoperative direct electrical stimulation (DES) and intraoperative neuro- monitoring (IONM) is considered the gold standard for the resection of highly language-eloquent brain tumors. Different modalities, such as functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG), are commonly added as adjuncts for preoperative language mapping but have been shown to have relevant limitations. Thus, this study presents a novel multimodal setup consisting of preoperative navigated transcranial magnetic stimulation (nTMS) and nTMS-based diffusion tensor imaging fiber tracking (DTI FT) as an adjunct to awake surgery. METHODS Sixty consecutive patients (63.3% men, mean age 47.6 ± 13.3 years) suffering from highly language-elo- quent left-hemispheric low- or high-grade glioma underwent preoperative nTMS language mapping and nTMS-based DTI FT, followed by awake surgery for tumor resection. Both nTMS language mapping and DTI FT data were available for resection planning and intraoperative guidance. Clinical outcome parameters, including craniotomy size, extent of resec- tion (EOR), language deficits at different time points, Karnofsky Performance Scale (KPS) score, duration of surgery, and inpatient stay, were assessed. RESULTS According to postoperative evaluation, 28.3% of patients showed tumor residuals, whereas new surgery-re- lated permanent language deficits occurred in 8.3% of patients. KPS scores remained unchanged (median preoperative score 90, median follow-up score 90). CONCLUSIONS This is the first study to present a clinical outcome analysis of this very modern approach, which is increasingly applied in neurooncological centers worldwide. Although human language function is a highly complex and dynamic cortico-subcortical network, the presented approach offers excellent functional and oncological outcomes in patients undergoing surgery of lesions affecting this network. https://thejns.org/doi/abs/10.3171/2018.3.FOCUS1838 KEYWORDS awake surgery; brain tumor; direct electrical stimulation; language mapping; navigated transcranial magnetic stimulation n modern neurooncology, awake surgery combined language mapping during surgery, which aims to detect with intraoperative direct electrical stimulation (DES) and spatially enclose language-related cortical and subcor- I and intraoperative neuromonitoring (IONM) ree fl cts tical structures as an efc fi ient way to reduce postoperative 6,46 the standard for resection of language-eloquent brain tu- language dec fi its. Within the context of the so-called 19,46,48,61,62 mors. This approach is favored over resection oncofunctional balance, a minimum rate of postoperative under general anesthesia due to the fact that it allows for dec fi its should be achieved in combination with maximum ABBREVIATIONS AP = anterior-posterior; BOLD = blood oxygenation level–dependent; DES = direct electrical stimulation; DTI = diffusion tensor imaging; DTI FT = DTI fiber tracking; EOR = extent of resection; fMRI = functional MRI; GTR = gross-total resection; HGG = high-grade glioma; IONM = intraoperative neuromonitoring; KPS = Karnofsky Performance Scale; LGG = low-grade glioma; MEG = magnetoencephalography; nTMS = navigated transcranial magnetic stimulation; rMT = resting motor threshold; STR = subtotal resection. SUBMITTED January 27, 2018. ACCEPTED March 19, 2018. INCLUDE WHEN CITING DOI: 10.3171/2018.3.FOCUS1838. ©AANS 2018, except where prohibited by US copyright law Neurosurg Focus Volume 44 • June 2018 1 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC N. Sollmann et al. tumor resection, thus ideally leading to optimal postoper- Only patients who were diagnosed with a left-hemispheric 2,10,36,47 ative quality of life and prolonged patient survival. perisylvian brain tumor (according to preoperative imag- However, the gold standard of awake surgery with ing) that was postoperatively confirmed to be a low-grade DES and IONM can be supported by various preopera- glioma (LGG) or high-grade glioma (HGG) according to tive adjuncts that allow for mapping of language func- histopathological examination were included for this post tion prior to tumor resection, which enables the treating hoc analysis of our prospectively collected cohort data. The enrolled patients underwent preoperative nTMS lan- neurosurgeon to assess functionally critical cortical and subcortical structures in advance. Among the most com- guage mapping (and nTMS-based DTI FT) in addition to mon options in clinical routine, functional MRI (fMRI) consecutive awake surgery for tumor resection, including and magnetoencephalography (MEG) have been applied DES and IONM. Exclusion criteria were age less than 18 16,35,39,40,43,44 successfully. In addition, navigated transcra- years, metallic implants (e.g., cochlear implant, cardiac pacemaker, or deep brain stimulation electrodes) as con- nial magnetic stimulation (nTMS) has been introduced traindications for nTMS language mapping, and preopera- recently as a novel technique for preoperative language 42,56,63 tive aphasia to a degree that would not allow preoperative mapping in patients with brain tumors. By using a magnetic coil, magnetic pulses can be delivered over pre- or intraoperative language testing. selected areas of the scalp of a patient, and these pulses can be spatially related to the respective patient’s individ- Clinical Examinations ual cortical anatomy, thanks to an integrated neuronavi- Prior to surgery, each patient underwent standardized 45,54 gation unit. The pulses develop into an electric e fi ld clinical examinations, which covered testing of sensory that is then capable of stimulating nervous tissue of the function, coordination, muscle strength, and cranial nerve brain and can result in transient language disturbances of function. Furthermore, the patient’s Karnofsky Perfor- different kinds when language-related structures are af- mance Scale (KPS) score was assessed. Language abil- 18,34,63 fected by the induced electric e fi ld. Because this ap- ity was evaluated by neuropsychologists using the Aachen proach primarily allows one to parcellate the stimulated Aphasia Test, which was supplemented by further den fi i - 23,24,29,31,53 cortex into language-positive and language-negative sites, tions of aphasia grades: 1) no dec fi it (grade 0); 2) nTMS language mapping has been combined with diffu- mild dec fi it (grade 1; normal speech comprehension and/ sion tensor imaging b fi er tracking (DTI FT) to allow the or conversational speech with slight amnesic aphasia, ad- neurosurgeon to also gain information about subcortical equate communication ability); 3) medium dec fi it (grade 38,52,55 language-related structures. 2; minor disruption of speech comprehension and/or con- The novel approach of nTMS language mapping and versational speech, adequate communication ability); and nTMS-based DTI FT is increasingly used in specialized 4) severe dec fi it (grade 3; major disruption of speech com - neurooncological centers, and standardized mapping pro- prehension and/or conversational speech, clear impair- 30,54 tocols and clinical worko fl w have been established. ment of communication ability). However, the distinct impact of nTMS language mapping The clinical examinations were repeated postoperative- on clinical treatment and outcome has only been analyzed ly during the inpatient stay and during follow-up examina- in 1 previous study, which did not routinely apply nTMS- tions in the outpatient clinic. This ear- based DTI FT in addition to cortical mapping. lier study investigated different types of brain tumors but Magnetic Resonance Imaging showed that postoperative language dec fi its were signifi - Imaging was performed on a 3-T MRI scanner (Achie- cantly less frequent in patients who underwent preopera- va, Philips Medical Systems, or Verio, Siemens Health- tive nTMS language mapping when compared to a control care). Our standard minimum preoperative and follow-up group without preoperative nTMS language mapping, and protocol in patients harboring brain tumors includes a a trend toward fewer unexpected tumor residuals was ob- FLAIR sequence, a 3D T1-weighted gradient echo se- served. quence with and without application of a contrast agent Against this background, this study presents the first (gadopentetate dimeglumine; Magnograf, Marotrast detailed analysis of using preoperative functional data GmbH), and DTI sequences with 6, 15, or 32 orthogonal derived from both nTMS language mapping and nTMS- diffusion directions. Immediate postoperative imaging based DTI FT as an adjunct to awake surgery. The study was performed within the first 48 hours subsequent to sur - evaluates the impact of this approach on functional and gery, again using FLAIR and T1-weighted sequences as neurooncological outcome measures among patients suf- well as diffusion-weighted and T2*-weighted imaging to fering from highly language-eloquent gliomas. search for ischemic events or intracranial bleeding. Methods Preoperative nTMS Patients and Enrollment nTMS Language Mapping Written informed consent was obtained from all pa- Language mapping was performed prior to surgery by tients. The study protocol was approved by the local ethics nTMS (eXimia NBS system; version 3.2.2 or 4.3, Nexstim committee and was followed in accordance with the Dec- Plc.). The 3D T1-weighted sequence of the respective pa- laration of Helsinki. tient was uploaded to the nTMS system and used during 42,45,54,63 All enrolled patients were treated at our neurosurgi- stimulation for neuronavigation purposes (Fig. 1). cal department between January 2011 and October 2017. After the resting motor threshold (rMT) was determined, 2 Neurosurg Focus Volume 44 • June 2018 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC N. Sollmann et al. tive surgical planning and for intraoperative application during tumor removal. Awake Surgery All patients underwent awake surgery for tumor remov- al within the scope of an asleep-awake-asleep approach 19,37,61,62 using DES and IONM as previously published. The saved data set, including nTMS results of the respec- tive patient, was available on intraoperative navigational screens during the whole procedure (BrainLAB Curve, BrainLAB AG; Fig. 2). Bupivacaine was applied for anesthesia of the galea and dura, and sedation was achieved by infusion of remifent- anil and propofol. The sedation was stopped approximate- ly 20 minutes prior to DES, which was applied during performance of an object-naming, verb-generation, and action-naming task, with the task performance evaluated by a neuropsychologist. DES used both bipolar (corti- cal stimulation) and monopolar (cortical and subcortical stimulation) electrodes (Inomed Medizintechnik GmbH) and was guided by the results of the preoperative data provided by nTMS and nTMS-based DTI FT (Fig. 2). A surface electroencephalogram was recorded to detect in- FIG. 1. Preoperative nTMS. This figure depicts nTMS language mapping traoperative seizures. Cortical sites adjacent to the ongo- with a 3D T1-weighted MRI sequence for neuronavigation purposes. 26,27 ing resection were stimulated at least 3 times. Criteria Both language-negative nTMS sites (gray) and language-positive nTMS for limiting the extent of resection (EOR) during surgery sites (white) are displayed. The colored arrow indicates the currently were strictly based on functional borders rather than on selected stimulation point and visualizes the localization and angula- anatomical imaging to achieve the most optimal EOR. tion of the induced electric field as chosen during pulse application. Only language-positive nTMS sites (white) were exported and used for subsequent nTMS-based DTI FT and during awake surgery. The figure Analysis of Clinical Outcome is derived from nTMS language mapping in a patient harboring a large The following parameters were assessed to evaluate the left-hemispheric HGG affecting the supramarginal and angular gyrus. clinical outcome. Craniotomy Size The craniotomy size was measured in anterior-poste- language mapping was performed with 80%–120% of the rior (AP) and lateral directions based on postoperative individual rMT and 5–7 Hz according to a standardized 30,32,42,57 MRI. The overall size was then calculated. protocol using an object-naming task. Subsequent to nTMS language mapping, the video and Duration of Surgery and Inpatient Stay audio data were analyzed with the aim of detecting nam- The data on duration of the surgical procedure and in- ing errors of the following categories: no responses, per- patient stay were extracted from the patient charts. formance errors, neologisms, phonological paraphasias, 30,32,34,42,57 and semantic paraphasias. Hesitation errors were Extent of Resection not routinely taken into account. Stimulation sites that The EOR was assessed macroscopically by the surgi- showed naming errors of the above-mentioned categories cal team intraoperatively and by postoperative evaluation. were den fi ed as language-positive, whereas all other stim - ulation sites were classie fi d as language-negative. Postoperative evaluation included postoperative and fol- low-up MRI and PET, if available. We differentiated be- nTMS-Based DTI FT tween gross-total resection (GTR; no residual tumor pres- ent macroscopically at the end of surgery, in MRI, and All language-positive sites were transferred to an ex- in PET) and subtotal resection (STR). Any tumor residual ternal server for deterministic nTMS-based DTI FT that was confirmed by postoperative evaluation but was (BrainLAB iPlan Net server, version 3.0.1; BrainLAB not expected by the neurosurgeons was den fi ed as “unex - AG). The group of language-positive sites was first fused pected residual.” with the preoperatively acquired MRI sequences. Then, these sites were den fi ed as a region of interest, and trac- Language Deficit tography was conducted with a minimum b fi er length of 100 mm and a preden fi ed fractional anisotropy of 0.1 or Language function was assessed preoperatively, post- 0.15, enabling visualization of language-related subcor- operatively (on postoperative day 5), and during follow-up 38,52,54,55 tical tracts. The resulting data set—consisting of examinations (with the first regular follow-up 3 months preoperative MRI sequences, language-positive sites, and after surgery) according to the above-mentioned grades nTMS-based tractography—was then saved for preopera- (see Clinical Examinations above). Transient aphasia was Neurosurg Focus Volume 44 • June 2018 3 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC N. Sollmann et al. FIG. 2. Neuronavigation during awake surgery. This figure illustrates the integration of language mapping data by nTMS including nTMS-based DTI FT into neuronavigation during surgery. MRI fused with language-positive nTMS sites (purple) and nTMS-based DTI FT of language-related pathways (purple) was available on intraoperative navigational screens during the entire surgical pro- cedure. In addition to data derived from nTMS language mapping and tractography, motor-positive nTMS sites (green) and nTMS- based DTI FT of the corticospinal tract (yellow) are shown in this illustrative case of a patient suffering from a left-hemispheric HGG affecting the supramarginal and angular gyrus. den fi ed as any new or worsened dec fi it due to surgery that Prism, which was also used for the generation of graphs resolved within the regular follow-up interval. Permanent (version 7.0, GraphPad Software Inc.). aphasia was den fi ed as any new or aggravated dec fi it due to surgery that did not resolve to the preoperative status Results within the regular follow-up interval. Study Population KPS Score Overall, 60 patients suffering from left-hemispheric LGG or HGG full fi led the inclusion criteria and were en - The KPS score was determined preoperatively, post- rolled in the present study. All included patients under- operatively (on postoperative day 5), and during follow-up went preoperative nTMS language mapping followed by examinations (with the first regular follow-up 3 months af - awake surgery at our neurosurgical department. Forty-v fi e ter surgery). The preoperative scores were then compared patients (75%) also underwent preoperative nTMS-based against the scores registered during these later examina- DTI FT (nTMS-based tractography was not routinely per- tions. formed in patients during the years 2011–2013). Table 1 shows relevant patient-related characteristics. Statistical Analysis The parameters assessed in this study are presented as Craniotomy Size means ± standard deviations, medians, ranges, or abso- lute/relative frequencies. Results are shown either for all The AP extent of the craniotomy was 7.5 ± 1.4 cm patients together or separately for patients suffering from (range 4.1–10.4 cm). Furthermore, the lateral extent mea- LGG or HGG. Values were calculated using GraphPad sured 5.0 ± 2.1 cm (range 1.5–8.9 cm). The resulting over- 4 Neurosurg Focus Volume 44 • June 2018 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC N. Sollmann et al. TABLE 1. Patient-related characteristics Variable Value Age (yrs) Mean ± SD 47.6 ± 13.3 Range 23.9–73.9 Sex (%) Male 63.3 Female 36.7 WHO tumor grade (% of patients)* I 1.7 II 21.7 III 30.0 IV 46.6 Max tumor diameter (cm)† Mean ± SD 3.7 ± 1.4 FIG. 3. Extent of resection. This bar chart shows the percentage of Range 1.4–7.4 patients in whom GTR or STR was achieved according to postoperative evaluation, including evaluation of imaging. The fractions were calcu- Time to follow-up (mos) lated in relation to the total number of patients enrolled suffering from Mean ± SD 21.3 ± 16.0 either an LGG (n = 14 patients) or HGG (n = 46 patients). Range 3.0–63.6 Overall, 60 patients were enrolled, who suffered from either LGG (n = 14 patients) or HGG (n = 46 patients). was also recorded in terms of the postoperative (range * According to postoperative histopathological evaluation. 50–100; LGG: median 90, range 70–100; HGG: median † According to measurements during preoperative imaging. 85, range 50–100) and follow-up states (range 50–100; LGG: median 90, range 80–100; HGG: median 90, range all area of the craniotomy accounted for 37.6 ± 17.6 cm (range 10.1–80.1 cm ). TABLE 2. Language deficits % of Patients Extent of Resection Deficit LGG HGG According to intraoperative macroscopic evaluation of Preop the EOR by the surgical team, tumor residuals were pres- ent in 11 patients (18.3%; LGG, 5 patients, 35.7%; HGG, 6 Grade 0 85.7 41.3 patients, 13.0%) at the end of the surgical procedure. Ac- Grade 1 14.3 23.9 cording to postoperative evaluation including evaluation Grade 2 0.0 32.6 of imaging, 17 patients (28.3%; LGG, 6 patients, 42.9%; Grade 3 0.0 2.2 HGG, 11 patients, 23.9%) showed tumor residuals. Unex- Postop pected tumor residuals were found in 6 patients (10.0%; Grade 0 42.9 26.1 LGG, 1 patient, 7.1%; HGG, 5 patients, 10.9%). Figure 3 shows the fractions of GTR or STR according to postop- Grade 1 35.7 32.6 erative evaluation. Grade 2 21.4 28.3 Grade 3 0.0 13.0 Language Deficits Follow-up Transient language dec fi its were found in 19 patients Grade 0 78.6 47.8 (31.7%; LGG, 7 patients, 50.0%; HGG, 12 patients, 26.1%). Grade 1 21.4 26.1 Furthermore, 5 patients (8.3%; LGG, 1 patient, 7.1%; Grade 2 0.0 23.9 HGG, 4 patients, 8.7%) suffered from a new surgery-relat- ed permanent worsening of language function. However, Grade 3 0.0 2.2 none of the patients with surgery-related permanent defi - Surgery-related cits presented with an aphasia grade 3 at the first regular Transient 50.0 26.1 follow-up. Table 2 and Fig. 4 provide a detailed overview Permanent 7.1 8.7 of the language status at different time points. This table shows the relative frequencies of patients who suffered from dif- ferent grades of language deficits (grade 0 = no deficit, grade 1 = mild deficit, Karnofsky Performance Scale Score grade 2 = medium deficit, grade 3 = severe deficit) according to preoperative, The median preoperative KPS score was 90 (range 60– postoperative (on postoperative day 5), and follow-up examinations, with the 100; LGG: median 95, range 80–100; HGG: median 90, first regular follow-up occurring 3 months after surgery. Furthermore, data on range 60–100), and the same overall median KPS score surgery-related transient or permanent language deficits are provided. Neurosurg Focus Volume 44 • June 2018 5 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC N. Sollmann et al. fMRI and MEG are most frequently applied. However, both have been shown to harbor relevant limitations when considering mapping of tumor-affected brains. Concern- ing fMRI, it has been demonstrated that the blood oxy- genation level–dependent (BOLD) contrast lacks accuracy in patients with changed intracranial oxygen levels, which are regularly present in the vicinity of gliomas due to their glucose and oxygen consumption from surrounding brain 13,15,22,51 tissue. In contrast to BOLD fMRI, preoperative MEG in patients harboring brain tumors is not reported to severely suffer from altered oxygen levels. However, MEG represents a more expensive alternative that is not widely available. Furthermore, preoperative MEG has primarily been applied to assess language lateralization without dis- tinct detection of specic fi language-related sites because it identie fi s regions of cortical activity without testing of 12,28,41,63 single areas, as DES does. Another limitation is re- lated to analysis algorithms: a dipole analysis is commonly FIG. 4. Language deficits. This bar chart illustrates the percentage of used, which is known to be sensitive to noise and the se- patients who showed improved, unchanged, or worse language per- formance when comparing the preoperative to the follow-up results of lection of model parameters. More robust methods are clinical examination. The fractions were calculated in relation to the currently developed for preoperative MEG applications; total number of patients enrolled suffering from either an LGG (n = 14 however, the goal of any analysis mostly remains to deter- patients) or HGG (n = 46 patients). mine language lateralization without gaining explicit data 20,21 about single language-related sites. Due to the shortcomings reported for fMRI and MEG, 50–100). The median difference in KPS scores when com - nTMS has been recently introduced as an alternative for paring the preoperative to the follow-up state was 0 (range language mapping in patients harboring perisylvian brain -30 to 20; LGG: median 0, range -20 to 10, HGG: median 42,56,63 tumors. The approach uses noninvasive but targeted 0, range -30 to 20). stimulation of the brain with the aim of eliciting language disturbances during performance of a task; thus, the tech- Duration of Surgery and Inpatient Stay nique is principally comparable to DES during awake sur- For all enrolled patients combined, the duration of the gery, which ree fl cts the current gold standard in functional entire awake procedure from the skin incision to the su- 60–62 brain mapping. The noninvasive nature of nTMS en- ture at the end of surgery was 256.5 ± 52.7 minutes (range ables its preoperative application as a neurosurgical tool for 156.0–405.0 minutes). The median inpatient stay was 9.0 resection planning and guidance, which has been shown to days (range 4.0–34.0 days). be safe and well tolerated. Moreover, preoperative nTMS language mapping has already been compared to preoper- Discussion ative fMRI and MEG in combination with DES, with the result that nTMS correlates well with DES for neurosurgi- Preoperative Language Mapping 26,56,63 cal applications. In this context, preoperative nTMS This study presented the combination of preopera- detected language-related cortical sites in the vicinity of tive nTMS language mapping with nTMS-based DTI FT an HGG that correlated well with DES, whereas fMRI and awake surgery for the resection of highly language- failed to demonstrate the same sites and wrongly indicated eloquent brain tumors as a modern setup. It furthermore language dominance within the unaffected hemisphere. analyzed a variety of clinical outcome parameters of this Furthermore, nTMS language maps were shown to corre- novel approach, which has not yet been undertaken for this late well with those generated by DES, while MEG lacked combination. the same level of correlation in a cohort consisting of 12 The need for individual language mapping is based on patients suffering from language-eloquent tumors. the high potential of plastic reorganization of cortical and The addition of nTMS-based DTI FT to nTMS language subcortical language-related structures as repeatedly re- 3,7,8,14,17,59 mapping, as presented in this study, enables the visualiza- ported for patients suffering from brain tumors. tion of subcortical language-related pathways. Although Hence, patients with tumor-induced plastic reshaping are the results of nTMS-based DTI FT of language-related unlikely to present highly language-eloquent structures only at sites known from the textbook; they rather pres- pathways have not yet been confirmed by subcortical DES due to the novelty of the approach, this method appears to ent with at least partial reallocation of sites within the 3,7,8,14,17,59 be helpful in guiding resection trajectories and resection tumor-affected or contralateral hemisphere. This per se. In the present study, 28.3% of patients initially reallocation can be mapped by DES during awake surgery, but further techniques are commonly used preoperatively harboring highly language-eloquent gliomas showed re- to assess plastic reshaping noninvasively and the spatial siduals according to postoperative evaluation. Preopera- relationship between language-related structures and the tive nTMS language mapping combined with nTMS-based tumor volume. This can help during resection planning DTI FT, incorporated into intraoperative neuronavigation, and intraoperative guidance. Among these techniques, may lead to an increased cond fi ence of the neurosurgeon 6 Neurosurg Focus Volume 44 • June 2018 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC N. Sollmann et al. 26,56,63 in identifying the individual functional anatomy of the to DES without distinct analyses of clinical outcome. patient, thus possibly leading to more radical resections. Third, nTMS language mapping has been shown to corre- Similar associations have already been suggested in terms late well with DES; nevertheless, it suffers from a compar- 5,9,60 of intraoperative techniques such as DES and IONM. atively low specic fi ity and positive predictive value, com - Concerning surgery-related language deterioration, bined with a high overall sensitivity and a high negative 31.7% of patients enrolled in this study suffered from predictive value. The high sensitivity may indicate that transient surgery-related language dec fi its, whereas 8.3% not all language-positive nTMS sites are essential or non- of patients suffered from permanent dec fi its; however, no resectable sites from a neurosurgical point of view but are patient suffered from a severe surgery-related permanent rather involved in language processing. Thus, negative dec fi it. In this context, various prior studies examined nTMS language mapping was shown to correlate well with short- and long-term outcome following DES in LGG and negative DES, which is actually sufc fi ient for neurosurgi - HGG. Immediate transient postoperative deterioration of cal clinical application, because even for awake surgery, language function has been shown to exist in 14%–50% some centers rely fully on mapped but language-negative 11,49,66 19,63 of patients. Permanent new surgery-related decline cortical areas. Nevertheless, further nTMS protocol op- of function can be observed in approximately 5%–20% of timizations may help to increase the positive correlation to 1,4,50,65 patients on average. DES. One previous study already showed the successful Of note, the selection of patients for awake surgery can stand-alone use of nTMS and nTMS-based DTI FT in very differ signic fi antly between centers and likewise plays a preselected patients who were unable to undergo awake highly relevant role regarding clinical outcome. During surgery. Yet, if awake surgery is possible, this should al- the time of enrollment for the present study, no patient was ways be the first choice. determined to harbor a nonresectable tumor, thus leading to the inclusion of a consecutive series of patients with Conclusions highly language-eloquent lesions. Inclusion of such pa- The present study combined nTMS language mapping tients with potentially high risks of surgery-related perma- with nTMS-based DTI FT to provide a comprehensive nent dec fi its due to tumor location can be obtained by de - preoperative approach for anatomico-functional language tailed preoperative information as outlined in this report, assessment among patients suffering from highly lan- which also helps to qualify more patients for a surgical guage-eloquent gliomas. It ree fl cts the first study to ana - approach. Thus, such valuable noninvasive data might lead lyze various clinical outcome parameters in the context not only to a considerably low rate of dec fi its but also to a of this novel approach. Our preoperative setup, combined higher number of patients undergoing surgery. with subsequent awake surgery including DES and IONM, resulted in good clinical outcome. 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Sawaya R, Hammoud M, Schoppa D, Hess KR, Wu SZ, Shi supratentorial intraaxial tumors: a prospective trial of 200 WM, et al: Neurosurgical outcomes in a modern series of cases. J Neurosurg 90:35–41, 1999 400 craniotomies for treatment of parenchymal tumors. Neu- 66. Wilson SM, Lam D, Babiak MC, Perry DW, Shih T, Hess CP, rosurgery 42:1044–1056, 1998 et al: Transient aphasias after left hemisphere resective sur- gery. J Neurosurg 123:581–593, 2015 51. Schreiber A, Hubbe U, Ziyeh S, Hennig J: The inu fl ence of gliomas and nonglial space-occupying lesions on blood- oxygen-level-dependent contrast enhancement. AJNR Am J Neuroradiol 21:1055–1063, 2000 52. Sollmann N, Giglhuber K, Tussis L, Meyer B, Ringel F, Krieg Disclosures SM: nTMS-based DTI fiber tracking for language pathways Dr. Krieg is a consultant for BrainLAB AG and Nexstim Plc. Drs. correlates with language function and aphasia – a case report. Ringel and Meyer are consultants for BrainLAB AG. Clin Neurol Neurosurg 136:25–28, 2015 53. Sollmann N, Ille S, Hauck T, Maurer S, Negwer C, Zimmer Author Contributions C, et al: The impact of preoperative language mapping by repetitive navigated transcranial magnetic stimulation on the Conception and design: Krieg, Sollmann. Acquisition of data: clinical course of brain tumor patients. BMC Cancer 15:261, Krieg, Sollmann, Kelm, Ille, Schröder, Ringel, Meyer. Analysis and interpretation of data: Krieg, Sollmann, Kelm, Ille, Schröder. 54. Sollmann N, Meyer B, Krieg SM: Implementing functional Drafting the article: Krieg, Sollmann. Critically revising the preoperative mapping in the clinical routine of a neurosurgi- article: Krieg. Reviewed submitted version of manuscript: Krieg, cal department: technical note. World Neurosurg 103:94– Kelm, Ille, Schröder, Zimmer, Ringel, Meyer. Approved the final 105, 2017 version of the manuscript on behalf of all authors: Krieg. Statisti- 55. Sollmann N, Negwer C, Ille S, Maurer S, Hauck T, Kirschke cal analysis: Sollmann. Administrative/technical/material support: JS, et al: Feasibility of nTMS-based DTI fiber tracking of Krieg, Zimmer, Ringel, Meyer. Study supervision: Krieg, Ringel, language pathways in neurosurgical patients using a frac- Meyer. tional anisotropy threshold. J Neurosci Methods 267:45–54, Supplemental Information 56. Sollmann N, Picht T, Mäkelä JP, Meyer B, Ringel F, Krieg Current Affiliation SM: Navigated transcranial magnetic stimulation for preop- Dr. Ringel: Department of Neurosurgery, Universitätsmedizin erative language mapping in a patient with a left frontooper- Mainz, Germany. cular glioblastoma. J Neurosurg 118:175–179, 2013 57. Sollmann N, Tanigawa N, Ringel F, Zimmer C, Meyer B, Correspondence Krieg SM: Language and its right-hemispheric distribution in healthy brains: an investigation by repetitive transcranial Sandro M. Krieg: Klinikum rechts der Isar, Technische Univer- magnetic stimulation. Neuroimage 102:776–788, 2014 sität München, Germany. [email protected]. Neurosurg Focus Volume 44 • June 2018 9 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgical Focus Unpaywall

Setup presentation and clinical outcome analysis of treating highly language-eloquent gliomas via preoperative navigated transcranial magnetic stimulation and tractography

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Abstract

NEUROSURGICAL FOCUS Neurosurg Focus 44 (6):E2, 2018 Setup presentation and clinical outcome analysis of treating highly language-eloquent gliomas via preoperative navigated transcranial magnetic stimulation and tractography 1–3 2,3 2,3 2 Nico Sollmann, MD, PhD, Anna Kelm, Sebastian Ille, MD, Axel Schröder, 1,3 2 2 2,3 Claus Zimmer, MD, Florian Ringel, MD, Bernhard Meyer, MD, and Sandro M. Krieg, MD, MBA 1 2 3 Department of Diagnostic and Interventional Neuroradiology, Department of Neurosurgery, and TUM-Neuroimaging Center, Klinikum rechts der Isar, Technische Universität München, Germany OBJECTIVE Awake surgery combined with intraoperative direct electrical stimulation (DES) and intraoperative neuro- monitoring (IONM) is considered the gold standard for the resection of highly language-eloquent brain tumors. Different modalities, such as functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG), are commonly added as adjuncts for preoperative language mapping but have been shown to have relevant limitations. Thus, this study presents a novel multimodal setup consisting of preoperative navigated transcranial magnetic stimulation (nTMS) and nTMS-based diffusion tensor imaging fiber tracking (DTI FT) as an adjunct to awake surgery. METHODS Sixty consecutive patients (63.3% men, mean age 47.6 ± 13.3 years) suffering from highly language-elo- quent left-hemispheric low- or high-grade glioma underwent preoperative nTMS language mapping and nTMS-based DTI FT, followed by awake surgery for tumor resection. Both nTMS language mapping and DTI FT data were available for resection planning and intraoperative guidance. Clinical outcome parameters, including craniotomy size, extent of resec- tion (EOR), language deficits at different time points, Karnofsky Performance Scale (KPS) score, duration of surgery, and inpatient stay, were assessed. RESULTS According to postoperative evaluation, 28.3% of patients showed tumor residuals, whereas new surgery-re- lated permanent language deficits occurred in 8.3% of patients. KPS scores remained unchanged (median preoperative score 90, median follow-up score 90). CONCLUSIONS This is the first study to present a clinical outcome analysis of this very modern approach, which is increasingly applied in neurooncological centers worldwide. Although human language function is a highly complex and dynamic cortico-subcortical network, the presented approach offers excellent functional and oncological outcomes in patients undergoing surgery of lesions affecting this network. https://thejns.org/doi/abs/10.3171/2018.3.FOCUS1838 KEYWORDS awake surgery; brain tumor; direct electrical stimulation; language mapping; navigated transcranial magnetic stimulation n modern neurooncology, awake surgery combined language mapping during surgery, which aims to detect with intraoperative direct electrical stimulation (DES) and spatially enclose language-related cortical and subcor- I and intraoperative neuromonitoring (IONM) ree fl cts tical structures as an efc fi ient way to reduce postoperative 6,46 the standard for resection of language-eloquent brain tu- language dec fi its. Within the context of the so-called 19,46,48,61,62 mors. This approach is favored over resection oncofunctional balance, a minimum rate of postoperative under general anesthesia due to the fact that it allows for dec fi its should be achieved in combination with maximum ABBREVIATIONS AP = anterior-posterior; BOLD = blood oxygenation level–dependent; DES = direct electrical stimulation; DTI = diffusion tensor imaging; DTI FT = DTI fiber tracking; EOR = extent of resection; fMRI = functional MRI; GTR = gross-total resection; HGG = high-grade glioma; IONM = intraoperative neuromonitoring; KPS = Karnofsky Performance Scale; LGG = low-grade glioma; MEG = magnetoencephalography; nTMS = navigated transcranial magnetic stimulation; rMT = resting motor threshold; STR = subtotal resection. SUBMITTED January 27, 2018. ACCEPTED March 19, 2018. INCLUDE WHEN CITING DOI: 10.3171/2018.3.FOCUS1838. ©AANS 2018, except where prohibited by US copyright law Neurosurg Focus Volume 44 • June 2018 1 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC N. Sollmann et al. tumor resection, thus ideally leading to optimal postoper- Only patients who were diagnosed with a left-hemispheric 2,10,36,47 ative quality of life and prolonged patient survival. perisylvian brain tumor (according to preoperative imag- However, the gold standard of awake surgery with ing) that was postoperatively confirmed to be a low-grade DES and IONM can be supported by various preopera- glioma (LGG) or high-grade glioma (HGG) according to tive adjuncts that allow for mapping of language func- histopathological examination were included for this post tion prior to tumor resection, which enables the treating hoc analysis of our prospectively collected cohort data. The enrolled patients underwent preoperative nTMS lan- neurosurgeon to assess functionally critical cortical and subcortical structures in advance. Among the most com- guage mapping (and nTMS-based DTI FT) in addition to mon options in clinical routine, functional MRI (fMRI) consecutive awake surgery for tumor resection, including and magnetoencephalography (MEG) have been applied DES and IONM. Exclusion criteria were age less than 18 16,35,39,40,43,44 successfully. In addition, navigated transcra- years, metallic implants (e.g., cochlear implant, cardiac pacemaker, or deep brain stimulation electrodes) as con- nial magnetic stimulation (nTMS) has been introduced traindications for nTMS language mapping, and preopera- recently as a novel technique for preoperative language 42,56,63 tive aphasia to a degree that would not allow preoperative mapping in patients with brain tumors. By using a magnetic coil, magnetic pulses can be delivered over pre- or intraoperative language testing. selected areas of the scalp of a patient, and these pulses can be spatially related to the respective patient’s individ- Clinical Examinations ual cortical anatomy, thanks to an integrated neuronavi- Prior to surgery, each patient underwent standardized 45,54 gation unit. The pulses develop into an electric e fi ld clinical examinations, which covered testing of sensory that is then capable of stimulating nervous tissue of the function, coordination, muscle strength, and cranial nerve brain and can result in transient language disturbances of function. Furthermore, the patient’s Karnofsky Perfor- different kinds when language-related structures are af- mance Scale (KPS) score was assessed. Language abil- 18,34,63 fected by the induced electric e fi ld. Because this ap- ity was evaluated by neuropsychologists using the Aachen proach primarily allows one to parcellate the stimulated Aphasia Test, which was supplemented by further den fi i - 23,24,29,31,53 cortex into language-positive and language-negative sites, tions of aphasia grades: 1) no dec fi it (grade 0); 2) nTMS language mapping has been combined with diffu- mild dec fi it (grade 1; normal speech comprehension and/ sion tensor imaging b fi er tracking (DTI FT) to allow the or conversational speech with slight amnesic aphasia, ad- neurosurgeon to also gain information about subcortical equate communication ability); 3) medium dec fi it (grade 38,52,55 language-related structures. 2; minor disruption of speech comprehension and/or con- The novel approach of nTMS language mapping and versational speech, adequate communication ability); and nTMS-based DTI FT is increasingly used in specialized 4) severe dec fi it (grade 3; major disruption of speech com - neurooncological centers, and standardized mapping pro- prehension and/or conversational speech, clear impair- 30,54 tocols and clinical worko fl w have been established. ment of communication ability). However, the distinct impact of nTMS language mapping The clinical examinations were repeated postoperative- on clinical treatment and outcome has only been analyzed ly during the inpatient stay and during follow-up examina- in 1 previous study, which did not routinely apply nTMS- tions in the outpatient clinic. This ear- based DTI FT in addition to cortical mapping. lier study investigated different types of brain tumors but Magnetic Resonance Imaging showed that postoperative language dec fi its were signifi - Imaging was performed on a 3-T MRI scanner (Achie- cantly less frequent in patients who underwent preopera- va, Philips Medical Systems, or Verio, Siemens Health- tive nTMS language mapping when compared to a control care). Our standard minimum preoperative and follow-up group without preoperative nTMS language mapping, and protocol in patients harboring brain tumors includes a a trend toward fewer unexpected tumor residuals was ob- FLAIR sequence, a 3D T1-weighted gradient echo se- served. quence with and without application of a contrast agent Against this background, this study presents the first (gadopentetate dimeglumine; Magnograf, Marotrast detailed analysis of using preoperative functional data GmbH), and DTI sequences with 6, 15, or 32 orthogonal derived from both nTMS language mapping and nTMS- diffusion directions. Immediate postoperative imaging based DTI FT as an adjunct to awake surgery. The study was performed within the first 48 hours subsequent to sur - evaluates the impact of this approach on functional and gery, again using FLAIR and T1-weighted sequences as neurooncological outcome measures among patients suf- well as diffusion-weighted and T2*-weighted imaging to fering from highly language-eloquent gliomas. search for ischemic events or intracranial bleeding. Methods Preoperative nTMS Patients and Enrollment nTMS Language Mapping Written informed consent was obtained from all pa- Language mapping was performed prior to surgery by tients. The study protocol was approved by the local ethics nTMS (eXimia NBS system; version 3.2.2 or 4.3, Nexstim committee and was followed in accordance with the Dec- Plc.). The 3D T1-weighted sequence of the respective pa- laration of Helsinki. tient was uploaded to the nTMS system and used during 42,45,54,63 All enrolled patients were treated at our neurosurgi- stimulation for neuronavigation purposes (Fig. 1). cal department between January 2011 and October 2017. After the resting motor threshold (rMT) was determined, 2 Neurosurg Focus Volume 44 • June 2018 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC N. Sollmann et al. tive surgical planning and for intraoperative application during tumor removal. Awake Surgery All patients underwent awake surgery for tumor remov- al within the scope of an asleep-awake-asleep approach 19,37,61,62 using DES and IONM as previously published. The saved data set, including nTMS results of the respec- tive patient, was available on intraoperative navigational screens during the whole procedure (BrainLAB Curve, BrainLAB AG; Fig. 2). Bupivacaine was applied for anesthesia of the galea and dura, and sedation was achieved by infusion of remifent- anil and propofol. The sedation was stopped approximate- ly 20 minutes prior to DES, which was applied during performance of an object-naming, verb-generation, and action-naming task, with the task performance evaluated by a neuropsychologist. DES used both bipolar (corti- cal stimulation) and monopolar (cortical and subcortical stimulation) electrodes (Inomed Medizintechnik GmbH) and was guided by the results of the preoperative data provided by nTMS and nTMS-based DTI FT (Fig. 2). A surface electroencephalogram was recorded to detect in- FIG. 1. Preoperative nTMS. This figure depicts nTMS language mapping traoperative seizures. Cortical sites adjacent to the ongo- with a 3D T1-weighted MRI sequence for neuronavigation purposes. 26,27 ing resection were stimulated at least 3 times. Criteria Both language-negative nTMS sites (gray) and language-positive nTMS for limiting the extent of resection (EOR) during surgery sites (white) are displayed. The colored arrow indicates the currently were strictly based on functional borders rather than on selected stimulation point and visualizes the localization and angula- anatomical imaging to achieve the most optimal EOR. tion of the induced electric field as chosen during pulse application. Only language-positive nTMS sites (white) were exported and used for subsequent nTMS-based DTI FT and during awake surgery. The figure Analysis of Clinical Outcome is derived from nTMS language mapping in a patient harboring a large The following parameters were assessed to evaluate the left-hemispheric HGG affecting the supramarginal and angular gyrus. clinical outcome. Craniotomy Size The craniotomy size was measured in anterior-poste- language mapping was performed with 80%–120% of the rior (AP) and lateral directions based on postoperative individual rMT and 5–7 Hz according to a standardized 30,32,42,57 MRI. The overall size was then calculated. protocol using an object-naming task. Subsequent to nTMS language mapping, the video and Duration of Surgery and Inpatient Stay audio data were analyzed with the aim of detecting nam- The data on duration of the surgical procedure and in- ing errors of the following categories: no responses, per- patient stay were extracted from the patient charts. formance errors, neologisms, phonological paraphasias, 30,32,34,42,57 and semantic paraphasias. Hesitation errors were Extent of Resection not routinely taken into account. Stimulation sites that The EOR was assessed macroscopically by the surgi- showed naming errors of the above-mentioned categories cal team intraoperatively and by postoperative evaluation. were den fi ed as language-positive, whereas all other stim - ulation sites were classie fi d as language-negative. Postoperative evaluation included postoperative and fol- low-up MRI and PET, if available. We differentiated be- nTMS-Based DTI FT tween gross-total resection (GTR; no residual tumor pres- ent macroscopically at the end of surgery, in MRI, and All language-positive sites were transferred to an ex- in PET) and subtotal resection (STR). Any tumor residual ternal server for deterministic nTMS-based DTI FT that was confirmed by postoperative evaluation but was (BrainLAB iPlan Net server, version 3.0.1; BrainLAB not expected by the neurosurgeons was den fi ed as “unex - AG). The group of language-positive sites was first fused pected residual.” with the preoperatively acquired MRI sequences. Then, these sites were den fi ed as a region of interest, and trac- Language Deficit tography was conducted with a minimum b fi er length of 100 mm and a preden fi ed fractional anisotropy of 0.1 or Language function was assessed preoperatively, post- 0.15, enabling visualization of language-related subcor- operatively (on postoperative day 5), and during follow-up 38,52,54,55 tical tracts. The resulting data set—consisting of examinations (with the first regular follow-up 3 months preoperative MRI sequences, language-positive sites, and after surgery) according to the above-mentioned grades nTMS-based tractography—was then saved for preopera- (see Clinical Examinations above). Transient aphasia was Neurosurg Focus Volume 44 • June 2018 3 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC N. Sollmann et al. FIG. 2. Neuronavigation during awake surgery. This figure illustrates the integration of language mapping data by nTMS including nTMS-based DTI FT into neuronavigation during surgery. MRI fused with language-positive nTMS sites (purple) and nTMS-based DTI FT of language-related pathways (purple) was available on intraoperative navigational screens during the entire surgical pro- cedure. In addition to data derived from nTMS language mapping and tractography, motor-positive nTMS sites (green) and nTMS- based DTI FT of the corticospinal tract (yellow) are shown in this illustrative case of a patient suffering from a left-hemispheric HGG affecting the supramarginal and angular gyrus. den fi ed as any new or worsened dec fi it due to surgery that Prism, which was also used for the generation of graphs resolved within the regular follow-up interval. Permanent (version 7.0, GraphPad Software Inc.). aphasia was den fi ed as any new or aggravated dec fi it due to surgery that did not resolve to the preoperative status Results within the regular follow-up interval. Study Population KPS Score Overall, 60 patients suffering from left-hemispheric LGG or HGG full fi led the inclusion criteria and were en - The KPS score was determined preoperatively, post- rolled in the present study. All included patients under- operatively (on postoperative day 5), and during follow-up went preoperative nTMS language mapping followed by examinations (with the first regular follow-up 3 months af - awake surgery at our neurosurgical department. Forty-v fi e ter surgery). The preoperative scores were then compared patients (75%) also underwent preoperative nTMS-based against the scores registered during these later examina- DTI FT (nTMS-based tractography was not routinely per- tions. formed in patients during the years 2011–2013). Table 1 shows relevant patient-related characteristics. Statistical Analysis The parameters assessed in this study are presented as Craniotomy Size means ± standard deviations, medians, ranges, or abso- lute/relative frequencies. Results are shown either for all The AP extent of the craniotomy was 7.5 ± 1.4 cm patients together or separately for patients suffering from (range 4.1–10.4 cm). Furthermore, the lateral extent mea- LGG or HGG. Values were calculated using GraphPad sured 5.0 ± 2.1 cm (range 1.5–8.9 cm). The resulting over- 4 Neurosurg Focus Volume 44 • June 2018 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC N. Sollmann et al. TABLE 1. Patient-related characteristics Variable Value Age (yrs) Mean ± SD 47.6 ± 13.3 Range 23.9–73.9 Sex (%) Male 63.3 Female 36.7 WHO tumor grade (% of patients)* I 1.7 II 21.7 III 30.0 IV 46.6 Max tumor diameter (cm)† Mean ± SD 3.7 ± 1.4 FIG. 3. Extent of resection. This bar chart shows the percentage of Range 1.4–7.4 patients in whom GTR or STR was achieved according to postoperative evaluation, including evaluation of imaging. The fractions were calcu- Time to follow-up (mos) lated in relation to the total number of patients enrolled suffering from Mean ± SD 21.3 ± 16.0 either an LGG (n = 14 patients) or HGG (n = 46 patients). Range 3.0–63.6 Overall, 60 patients were enrolled, who suffered from either LGG (n = 14 patients) or HGG (n = 46 patients). was also recorded in terms of the postoperative (range * According to postoperative histopathological evaluation. 50–100; LGG: median 90, range 70–100; HGG: median † According to measurements during preoperative imaging. 85, range 50–100) and follow-up states (range 50–100; LGG: median 90, range 80–100; HGG: median 90, range all area of the craniotomy accounted for 37.6 ± 17.6 cm (range 10.1–80.1 cm ). TABLE 2. Language deficits % of Patients Extent of Resection Deficit LGG HGG According to intraoperative macroscopic evaluation of Preop the EOR by the surgical team, tumor residuals were pres- ent in 11 patients (18.3%; LGG, 5 patients, 35.7%; HGG, 6 Grade 0 85.7 41.3 patients, 13.0%) at the end of the surgical procedure. Ac- Grade 1 14.3 23.9 cording to postoperative evaluation including evaluation Grade 2 0.0 32.6 of imaging, 17 patients (28.3%; LGG, 6 patients, 42.9%; Grade 3 0.0 2.2 HGG, 11 patients, 23.9%) showed tumor residuals. Unex- Postop pected tumor residuals were found in 6 patients (10.0%; Grade 0 42.9 26.1 LGG, 1 patient, 7.1%; HGG, 5 patients, 10.9%). Figure 3 shows the fractions of GTR or STR according to postop- Grade 1 35.7 32.6 erative evaluation. Grade 2 21.4 28.3 Grade 3 0.0 13.0 Language Deficits Follow-up Transient language dec fi its were found in 19 patients Grade 0 78.6 47.8 (31.7%; LGG, 7 patients, 50.0%; HGG, 12 patients, 26.1%). Grade 1 21.4 26.1 Furthermore, 5 patients (8.3%; LGG, 1 patient, 7.1%; Grade 2 0.0 23.9 HGG, 4 patients, 8.7%) suffered from a new surgery-relat- ed permanent worsening of language function. However, Grade 3 0.0 2.2 none of the patients with surgery-related permanent defi - Surgery-related cits presented with an aphasia grade 3 at the first regular Transient 50.0 26.1 follow-up. Table 2 and Fig. 4 provide a detailed overview Permanent 7.1 8.7 of the language status at different time points. This table shows the relative frequencies of patients who suffered from dif- ferent grades of language deficits (grade 0 = no deficit, grade 1 = mild deficit, Karnofsky Performance Scale Score grade 2 = medium deficit, grade 3 = severe deficit) according to preoperative, The median preoperative KPS score was 90 (range 60– postoperative (on postoperative day 5), and follow-up examinations, with the 100; LGG: median 95, range 80–100; HGG: median 90, first regular follow-up occurring 3 months after surgery. Furthermore, data on range 60–100), and the same overall median KPS score surgery-related transient or permanent language deficits are provided. Neurosurg Focus Volume 44 • June 2018 5 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC N. Sollmann et al. fMRI and MEG are most frequently applied. However, both have been shown to harbor relevant limitations when considering mapping of tumor-affected brains. Concern- ing fMRI, it has been demonstrated that the blood oxy- genation level–dependent (BOLD) contrast lacks accuracy in patients with changed intracranial oxygen levels, which are regularly present in the vicinity of gliomas due to their glucose and oxygen consumption from surrounding brain 13,15,22,51 tissue. In contrast to BOLD fMRI, preoperative MEG in patients harboring brain tumors is not reported to severely suffer from altered oxygen levels. However, MEG represents a more expensive alternative that is not widely available. Furthermore, preoperative MEG has primarily been applied to assess language lateralization without dis- tinct detection of specic fi language-related sites because it identie fi s regions of cortical activity without testing of 12,28,41,63 single areas, as DES does. Another limitation is re- lated to analysis algorithms: a dipole analysis is commonly FIG. 4. Language deficits. This bar chart illustrates the percentage of used, which is known to be sensitive to noise and the se- patients who showed improved, unchanged, or worse language per- formance when comparing the preoperative to the follow-up results of lection of model parameters. More robust methods are clinical examination. The fractions were calculated in relation to the currently developed for preoperative MEG applications; total number of patients enrolled suffering from either an LGG (n = 14 however, the goal of any analysis mostly remains to deter- patients) or HGG (n = 46 patients). mine language lateralization without gaining explicit data 20,21 about single language-related sites. Due to the shortcomings reported for fMRI and MEG, 50–100). The median difference in KPS scores when com - nTMS has been recently introduced as an alternative for paring the preoperative to the follow-up state was 0 (range language mapping in patients harboring perisylvian brain -30 to 20; LGG: median 0, range -20 to 10, HGG: median 42,56,63 tumors. The approach uses noninvasive but targeted 0, range -30 to 20). stimulation of the brain with the aim of eliciting language disturbances during performance of a task; thus, the tech- Duration of Surgery and Inpatient Stay nique is principally comparable to DES during awake sur- For all enrolled patients combined, the duration of the gery, which ree fl cts the current gold standard in functional entire awake procedure from the skin incision to the su- 60–62 brain mapping. The noninvasive nature of nTMS en- ture at the end of surgery was 256.5 ± 52.7 minutes (range ables its preoperative application as a neurosurgical tool for 156.0–405.0 minutes). The median inpatient stay was 9.0 resection planning and guidance, which has been shown to days (range 4.0–34.0 days). be safe and well tolerated. Moreover, preoperative nTMS language mapping has already been compared to preoper- Discussion ative fMRI and MEG in combination with DES, with the result that nTMS correlates well with DES for neurosurgi- Preoperative Language Mapping 26,56,63 cal applications. In this context, preoperative nTMS This study presented the combination of preopera- detected language-related cortical sites in the vicinity of tive nTMS language mapping with nTMS-based DTI FT an HGG that correlated well with DES, whereas fMRI and awake surgery for the resection of highly language- failed to demonstrate the same sites and wrongly indicated eloquent brain tumors as a modern setup. It furthermore language dominance within the unaffected hemisphere. analyzed a variety of clinical outcome parameters of this Furthermore, nTMS language maps were shown to corre- novel approach, which has not yet been undertaken for this late well with those generated by DES, while MEG lacked combination. the same level of correlation in a cohort consisting of 12 The need for individual language mapping is based on patients suffering from language-eloquent tumors. the high potential of plastic reorganization of cortical and The addition of nTMS-based DTI FT to nTMS language subcortical language-related structures as repeatedly re- 3,7,8,14,17,59 mapping, as presented in this study, enables the visualiza- ported for patients suffering from brain tumors. tion of subcortical language-related pathways. Although Hence, patients with tumor-induced plastic reshaping are the results of nTMS-based DTI FT of language-related unlikely to present highly language-eloquent structures only at sites known from the textbook; they rather pres- pathways have not yet been confirmed by subcortical DES due to the novelty of the approach, this method appears to ent with at least partial reallocation of sites within the 3,7,8,14,17,59 be helpful in guiding resection trajectories and resection tumor-affected or contralateral hemisphere. This per se. In the present study, 28.3% of patients initially reallocation can be mapped by DES during awake surgery, but further techniques are commonly used preoperatively harboring highly language-eloquent gliomas showed re- to assess plastic reshaping noninvasively and the spatial siduals according to postoperative evaluation. Preopera- relationship between language-related structures and the tive nTMS language mapping combined with nTMS-based tumor volume. This can help during resection planning DTI FT, incorporated into intraoperative neuronavigation, and intraoperative guidance. Among these techniques, may lead to an increased cond fi ence of the neurosurgeon 6 Neurosurg Focus Volume 44 • June 2018 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC N. Sollmann et al. 26,56,63 in identifying the individual functional anatomy of the to DES without distinct analyses of clinical outcome. patient, thus possibly leading to more radical resections. Third, nTMS language mapping has been shown to corre- Similar associations have already been suggested in terms late well with DES; nevertheless, it suffers from a compar- 5,9,60 of intraoperative techniques such as DES and IONM. atively low specic fi ity and positive predictive value, com - Concerning surgery-related language deterioration, bined with a high overall sensitivity and a high negative 31.7% of patients enrolled in this study suffered from predictive value. The high sensitivity may indicate that transient surgery-related language dec fi its, whereas 8.3% not all language-positive nTMS sites are essential or non- of patients suffered from permanent dec fi its; however, no resectable sites from a neurosurgical point of view but are patient suffered from a severe surgery-related permanent rather involved in language processing. Thus, negative dec fi it. In this context, various prior studies examined nTMS language mapping was shown to correlate well with short- and long-term outcome following DES in LGG and negative DES, which is actually sufc fi ient for neurosurgi - HGG. Immediate transient postoperative deterioration of cal clinical application, because even for awake surgery, language function has been shown to exist in 14%–50% some centers rely fully on mapped but language-negative 11,49,66 19,63 of patients. Permanent new surgery-related decline cortical areas. Nevertheless, further nTMS protocol op- of function can be observed in approximately 5%–20% of timizations may help to increase the positive correlation to 1,4,50,65 patients on average. DES. One previous study already showed the successful Of note, the selection of patients for awake surgery can stand-alone use of nTMS and nTMS-based DTI FT in very differ signic fi antly between centers and likewise plays a preselected patients who were unable to undergo awake highly relevant role regarding clinical outcome. During surgery. Yet, if awake surgery is possible, this should al- the time of enrollment for the present study, no patient was ways be the first choice. determined to harbor a nonresectable tumor, thus leading to the inclusion of a consecutive series of patients with Conclusions highly language-eloquent lesions. Inclusion of such pa- The present study combined nTMS language mapping tients with potentially high risks of surgery-related perma- with nTMS-based DTI FT to provide a comprehensive nent dec fi its due to tumor location can be obtained by de - preoperative approach for anatomico-functional language tailed preoperative information as outlined in this report, assessment among patients suffering from highly lan- which also helps to qualify more patients for a surgical guage-eloquent gliomas. It ree fl cts the first study to ana - approach. Thus, such valuable noninvasive data might lead lyze various clinical outcome parameters in the context not only to a considerably low rate of dec fi its but also to a of this novel approach. Our preoperative setup, combined higher number of patients undergoing surgery. with subsequent awake surgery including DES and IONM, resulted in good clinical outcome. 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Sawaya R, Hammoud M, Schoppa D, Hess KR, Wu SZ, Shi supratentorial intraaxial tumors: a prospective trial of 200 WM, et al: Neurosurgical outcomes in a modern series of cases. J Neurosurg 90:35–41, 1999 400 craniotomies for treatment of parenchymal tumors. Neu- 66. Wilson SM, Lam D, Babiak MC, Perry DW, Shih T, Hess CP, rosurgery 42:1044–1056, 1998 et al: Transient aphasias after left hemisphere resective sur- gery. J Neurosurg 123:581–593, 2015 51. Schreiber A, Hubbe U, Ziyeh S, Hennig J: The inu fl ence of gliomas and nonglial space-occupying lesions on blood- oxygen-level-dependent contrast enhancement. AJNR Am J Neuroradiol 21:1055–1063, 2000 52. Sollmann N, Giglhuber K, Tussis L, Meyer B, Ringel F, Krieg Disclosures SM: nTMS-based DTI fiber tracking for language pathways Dr. Krieg is a consultant for BrainLAB AG and Nexstim Plc. Drs. correlates with language function and aphasia – a case report. Ringel and Meyer are consultants for BrainLAB AG. Clin Neurol Neurosurg 136:25–28, 2015 53. Sollmann N, Ille S, Hauck T, Maurer S, Negwer C, Zimmer Author Contributions C, et al: The impact of preoperative language mapping by repetitive navigated transcranial magnetic stimulation on the Conception and design: Krieg, Sollmann. Acquisition of data: clinical course of brain tumor patients. BMC Cancer 15:261, Krieg, Sollmann, Kelm, Ille, Schröder, Ringel, Meyer. Analysis and interpretation of data: Krieg, Sollmann, Kelm, Ille, Schröder. 54. Sollmann N, Meyer B, Krieg SM: Implementing functional Drafting the article: Krieg, Sollmann. Critically revising the preoperative mapping in the clinical routine of a neurosurgi- article: Krieg. Reviewed submitted version of manuscript: Krieg, cal department: technical note. World Neurosurg 103:94– Kelm, Ille, Schröder, Zimmer, Ringel, Meyer. Approved the final 105, 2017 version of the manuscript on behalf of all authors: Krieg. Statisti- 55. Sollmann N, Negwer C, Ille S, Maurer S, Hauck T, Kirschke cal analysis: Sollmann. Administrative/technical/material support: JS, et al: Feasibility of nTMS-based DTI fiber tracking of Krieg, Zimmer, Ringel, Meyer. Study supervision: Krieg, Ringel, language pathways in neurosurgical patients using a frac- Meyer. tional anisotropy threshold. J Neurosci Methods 267:45–54, Supplemental Information 56. Sollmann N, Picht T, Mäkelä JP, Meyer B, Ringel F, Krieg Current Affiliation SM: Navigated transcranial magnetic stimulation for preop- Dr. Ringel: Department of Neurosurgery, Universitätsmedizin erative language mapping in a patient with a left frontooper- Mainz, Germany. cular glioblastoma. J Neurosurg 118:175–179, 2013 57. Sollmann N, Tanigawa N, Ringel F, Zimmer C, Meyer B, Correspondence Krieg SM: Language and its right-hemispheric distribution in healthy brains: an investigation by repetitive transcranial Sandro M. Krieg: Klinikum rechts der Isar, Technische Univer- magnetic stimulation. Neuroimage 102:776–788, 2014 sität München, Germany. [email protected]. Neurosurg Focus Volume 44 • June 2018 9 Unauthenticated | Downloaded 11/11/21 09:08 PM UTC

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