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Preoperative rTMS Language Mapping in Speech-Eloquent Brain Lesions Resected Under General Anesthesia: A Pair-Matched Cohort Study
Accepted Manuscript Preoperative rTMS language mapping in speech eloquent brain lesions resected under general anesthesia: a pair-matched cohort study Philipp Hendrix, MD, Sebastian Senger, MD, Andreas Simgen, MD, Christoph J. Griessenauer, MD, Joachim Oertel, MD PII:
S1878-8750(17)30054-2
DOI:
10.1016/j.wneu.2017.01.041
Reference:
WNEU 5138
To appear in:
World Neurosurgery
Received Date: 10 November 2016 Revised Date:
9 January 2017
Accepted Date: 10 January 2017
Please cite this article as: Hendrix P, Senger S, Simgen A, Griessenauer CJ, Oertel J, Preoperative rTMS language mapping in speech eloquent brain lesions resected under general anesthesia: a pairmatched cohort study, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.01.041. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Preoperative rTMS language mapping in speech eloquent brain lesions resected under general anesthesia: a pair-matched cohort study
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Philipp Hendrix MD1, Sebastian Senger MD1, Andreas Simgen MD2, Christoph J. Griessenauer MD3, Joachim Oertel MD1
Department of Neurosurgery, Saarland University Medical Center and Saarland University Faculty
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of Medicine, Homburg/Saar, Germany
Department of Neuroradiology, Saarland University Medical Center and Saarland University Faculty
of Medicine, Homburg/Saar, Germany 3
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Department of Neurosurgery, Geisinger Health System, Danville, PA
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Key words: navigated repetitive transcranial magnetic stimulation, general anesthesia, preoperative language mapping
Philipp Hendrix, MD
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Corresponding author:
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Klinik für Neurochirurgie
Universität des Saarlandes
Kirrberger Straße 100, Gebäude 90.5 66421 Homburg/ Saar, Germany Phone: +49-6841-1624400 Fax: +49-6841-1624480 [email protected] 1
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Abstract
Objective: The value of preoperative rTMS language mapping for function preservation in surgery of
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speech eloquent lesions under general anesthesia remains to be determined.
Methods: The authors prospectively enrolled 20 consecutive right-handed patients with a malignant, left-sided perisylvian language eloquent brain tumor. All patients were subjected to surgical resection
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under general anesthesia guided by preoperative rTMS language mapping (rTMS group, 2014 – 2016). A matched-pair analysis with 20 patients that also underwent surgical resection under general
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anesthesia in the pre-rTMS era (pre-rTMS group, 2009 – 2013) was performed. Language performance status was ranked from grade 0 to grade 3 (none, mild, medium, severe). Results: Rates of gross total resection, of tumor residual, and of complications were equal in both groups. Duration of surgery (p = 0.039) and inpatient stay (p = 0.001) were significantly shorter in the
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rTMS group. Preoperatively, 14 patients in the rTMS and 13 patients in the pre-rTMS group suffered from language deficits (p = 0.380). One week after surgery, 8/14 patients (57.1 %) in the rTMS group but only 1/13 patients (7.7 %) in the pre-rTMS group experienced improvement of language
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performance status (p = 0.013). At six weeks follow-up, language performance status was significantly better in the rTMS group (p = 0.048). However, at three months follow-up, the rTMS-
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and pre-rTMS groups showed an equal language performance status. Conclusion: Implementation of preoperative rTMS language mapping seems to provide a favorable early language outcome in patients undergoing surgical resection of language eloquent lesions under general anesthesia.
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Introduction
Cortical language organization is diverse as evidenced by numerous studies using direct cortical 3,5
. Formerly,
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stimulation (DCS) for language mapping in patients undergoing awake brain surgery
DCS was performed through a large craniotomy and a widely exposed cortical surface. Language mapping was performed by assessing large areas of the diseased hemisphere and included positive 7,24
. A different approach was introduced by Sanai et al. in 2008 who
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language sites as controls
navigated lesion resection using negative cortical language sites without identification of positive
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sites as controls. They performed smaller, tailored craniotomies, and achieved a favorable language outcome 33. Awake craniotomy may be contraindicated in patients that do not consent, have decreased mental capacity, anxiety, and psychiatric disorders. Or awake craniotomy may fail due to restlessness, somnolence, and intractable seizures requiring conversion to general anesthesia
23
. To date, there is
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only one prospective, randomized controlled trial comparing awake craniotomy and surgery under general anesthesia for eloquent brain tumors. This study did not reveal significant differences with respect to efficacy of surgery in preventing development of new neurological deficits accompanied by 12
. However, widespread conclusions from this study can only be
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an increase in extent of resection
drawn with caution as the sample size was small and recent studies have reported excellent language
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outcome with awake craniotomy
14,26,32,33,38
. A novel technique to preoperatively identify cortical
language sites is the use of transcranial magnetic stimulation (TMS). Transcranial magnetic stimuli penetrate the skull and induce an electrical field on the cortical surface modulating neuronal activity adjacent to the stimulus. The optical tracking device allows for coregistration with the preoperative MRI obtained for intraoperative neuronavigation. This is referred to as navigated transcranial magnetic stimulation (nTMS). Application of repetitive transcranial magnetic stimuli (rTMS) leads to a temporarily lasting neuronal modulation capable of provoking naming errors on an object-naming 3
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task. Some studies have used preoperative rTMS to create language maps in brain tumor patients 16,28,37
. Recently, Ille et al. reported on four patients who underwent resection of a language eloquent
brain lesion based on rTMS language mapping
15
. In two patients awake craniotomy with
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intraoperative mapping had to be stopped due to complications. The other two patients were scheduled for resection under general anesthesia using the rTMS language map and represented the first report of favorable language outcome after surgery under general anesthesia guided by rTMS 15
. To assess the value of preoperative rTMS language mapping in patients
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language mapping
undergoing resection using general anesthesia, larger cohorts and a control group are warranted. The
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herein presented cohort is the first prospective collection of consecutive patients with a primary or secondary malignant, language eloquent brain tumor who underwent surgical resection under general anesthesia guided by preoperative rTMS language mapping. This cohort was compared to patients of the pre-rTMS era that also underwent surgery under general anesthesia. Each rTMS patient was
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matched pairwise to a retrospectively analyzed pre-rTMS patient.
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Methods
Patient enrollment, pair-matching, and surgical procedure
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Preoperative rTMS language mapping is established at our institution since January 2014. For the present study, the following inclusion criteria were defined: contrast-enhancing lesion on brain MRI in language eloquent areas (left perisylvian area, right-handed), preoperative rTMS language
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mapping, resection guided by the rTMS language map under general anesthesia, and histopathologically confirmed malignant brain tumor. A total of 20 consecutive patients were
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prospectively enrolled. Those patients were matched pairwise with historical controls treated in the pre-rTMS area before December 2013. Matching was based on the following criteria: tumor location according the cortical parcellation system (CPS) (Figure 1 and Table 1) 5, tumor and edema volume (spheric/ellipsoid equation 18); preoperative language deficits as assessed on history and neurological
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examination; and histopathology. Matching was independently performed by a consultant neuroradiologist (A. S.) and a neurosurgical resident (P. H.). Any discrepancies were resolved by discussion. Consent was obtained from all rTMS patients. The study was performed in accordance
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with the local ethics committee and the Declaration of Helsinki. In both groups each patient underwent surgical resection under general anesthesia by surgeons with equal neuro-oncological
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expertise. Surgical resection aimed for resection of the T1 contrast-enhancing lesion on MRI. The procedure was guided by intraoperative neuronavigation in all cases (rTMS and pre-rTMS). In the rTMS group, intraoperative neuronavigation was guided by the preoperatively acquired rTMS language map.
Clinical language assessment
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All patients underwent a detailed history and neurological examination prior rTMS language mapping and surgical resection. Postoperative neurological assessment was routinely performed on a daily basis until hospital discharge and continued on an outpatient basis. Language performance at
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postoperative day one (POD 1), one week after surgery (ranging from day 5 – 7; POD 7), six weeks after surgery (ranging from 4 – 6 weeks; POD 45) and at three months follow-up (ranging from 3 – 4 months; POD 90) were used for comparison. Language performance status was categorized into one
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of four grades (adjusted from 17,34): grade 0 – no language deficit; grade 1 – mild language deficit (i.e. slight deficits, however, adequate communication possible); grade 2 – medium deficit (i.e.
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impairment of conversational speech and/or speech comprehension; aggravated communication); grade 3 – severe language deficits (i.e. severely disrupted ability to communicate).
Magnetic resonance imaging
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Pre- and postoperative MRI scans were performed on a 1.5 or 3 T scanner (Magnetom Skyra 3.0 T; Magnetom Symphony-TIM 1.5 T, Siemens, Erlangen, Germany). For nTMS and intraoperative neuronavigation, a contrast-enhanced T1-weighted MP RAGE in axial plane was obtained. Analysis
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of preoperative edema size and postoperative ischemia was conducted using T2 FLAIR and DWI, respectively. A postoperative CT-scan was routinely performed when leaving the intensive-care-unit
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at postoperative day 1 to screen for CSF obstruction, brain swelling, edema increase or hemorrhage. Craniotomy flap diameters in anteroposterior and lateral view were obtained from postoperative CTscans. All flaps were of ellipsoid shape. The size of the craniotomy bone flap was calculated via ellipsoid surface area equation. Postoperative MRI was routinely performed within 48 hours after surgical resection to assess resection rate and postoperative complications (e.g. ischemia or edema).
Preoperative rTMS language mapping 6
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Preoperative rTMS language mapping was performed using the eXimia NBS system 4.3 with NEXSPEECH®. Each mapping and each analysis were solely performed by the first and second authors (P. H., S. S.), both neurosurgical residents, trained and experienced with the NBS system 13.
language mapping reports
15,16,22,36,37
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Experimental settings were mainly employed according established protocols from recent rTMS . Briefly, language mapping is conducted through evaluation of
potential language errors elicited on an object-naming task that is performed with synchronous
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applications of rTMS impulses to the lesional hemisphere. First, baseline assessment of an objectnaming task is performed twice. A total of 150 objects are presented on a monitor to be named using
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one word as fast as possible (inter-picture interval 2500 ms, display time of presented object 700 – 1000 ms). Each object-presentation with response is recorded on a video camera. All objects that were named incorrectly, such as using more than one word or a delayed response, were discarded from the original object sample. Next, applications of rTMS impulses were integrated. The adjusted
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object sample was re-presented to the patient with synchronous application of rTMS impulses (picture to trigger interval 0 msec, 7 Hz/7 pulses with 110 % of the individual resting motor potential, derived from the abducens pollicis brevis muscle motor evoked potential obtained on the same
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hemisphere). As with the baseline assessment, this step was also video recorded. After each object presentation/rTMS impulse, the stimulation coil was randomly moved from one spot to another
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across the lesional hemisphere to cover the whole hemisphere. Finally, video sequences from the baseline assessment and rTMS language mapping sessions were compared and analyzed for errors. Errors were assigned no response, hesitation, phonological error, semantic error, neologism, or performance error. Each error from the rTMS language session (i.e. positive language map) was used for intraoperative neuronavigation.
Statistical analysis and data preparation 7
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Statistical analysis was conducted using the software package SPSS (SPSS version 23; SPSS, Inc., Chicago, IL). To compare groups, Fisher´s exact test, Chi-square test, unpaired t-test and Mann-
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Whitney U-test were used where appropriate. Level of statistical significance was set to p < 0.05.
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Results
Patient and tumor characteristics
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Age, gender, histology, and tumor characteristics were equally distributed between groups. In both groups, 8 lesions primarily affected anterior language areas: mPrG (2), mMFG (1), opIFG (2), pMFG (2), trIFG (1). The remaining 12 lesions primarily affected posterior language areas in both groups:
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AnG (1), aSMG (1), aSTG (1), mMTG (3), mPoG (1), mSTG (3), pMTG (1), pSTG (1) (Figure 1 and Table 1). History and neurological examination revealed comparable preoperative language deficits
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(Table 2).
Preoperative rTMS language mapping and impact on surgical strategy
Experimental settings and parameters for rTMS language mapping sessions are shown in Table 3.
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Each identified error was assigned to a distinct region of the CPS. Figure 2 displays frequency of errors of all sessions for a specific CPS region. To guide surgical resection in the rTMS group, the positive rTMS language map (i.e. all identified errors) was used for intraoperative neuronavigation.
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Surgical characteristics
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Resection was performed through language negative sites and language positive sites were avoided.
Repetitive TMS language mapping was associated with significantly shorter surgery duration and inpatient stay. Craniotomy flap sizes and complication rates were equivalent in both groups. In the rTMS group, three patients showed hemorrhage within the tumor cavity that exceeded expected postoperative findings. None of the patients experienced neurological deterioration. In group B, one patient suffered from an epidural hematoma, another from a subdural hematoma. Two other patients had small areas of ischemic events in vicinity of the surgical corridor. In one of those patients 9
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ischemia might have contributed to postoperative language deterioration. However, none of the patients required a reoperation due to surgery-related complications. In both groups, postoperative MRI revealed a gross total resection (GTR) in 13 patients. Seven patients had small tumor residuals
Exclusion of patients from postoperative language analysis
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in each group. Tumor residuals were equal in volume in both groups (Table 4 and Figure 3).
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For POD 45 and 90 analyses, patients that were lost to follow-up or had suffered from tumor recurrence accompanied by general health and neurological deterioration were excluded from
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analysis. This included four rTMS patients. Two were lost to follow-up after discharge from hospital (language performance at POD 7 for patients were grade 0 and grade 1, respectively) and two patients suffering from glioblastoma multiforme experienced tumor recurrence. Both suffered from significant neurological and general health deterioration. Gross total resection was achieved in one of those
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patients. Language performance on POD 7 for patients was grade 0 and grade 1, respectively. Two patients from the pre-rTMS era were lost to follow-up and therefore excluded from analysis (language performance at POD 7 for patients was grade 1 and grade 2, respectively).
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For POD 90 analysis, additional patients were excluded: one rTMS patient was excluded due to glioblastoma recurrence with significant neurological and general health deterioration despite gross
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total resection. Language performance on POD 45 was grade 0. Two patients from the pre-rTMS era were lost to follow-up (language performance at POD 45 was grade 0 and grade 2, respectively). Collectively, rTMS patients excluded (last language grades before exclusion: 0; 0; 0; 1; 1) had a better recent language performance than those excluded from the pre-rTMS era (last language grades before exclusion: 0; 1; 2; 2).
Postoperative language performance 10
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Preoperative language deficits were equally distributed. Language performance did not differ on POD 1 or POD 7. At POD 45, however, rTMS patients showed a significant better language performance status (Figure 4). Ninety days after surgery (POD 90), this difference was no longer significant (Table
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5 and Figure 4).
On POD 1, three patients in the rTMS but none in pre-rTMS era group experienced an improvement of language deficit grade (grade 2 to grade 1 twice, grade 1 to grade 0). A deterioration of language
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function was observed in one rTMS patient (grade 0 to grade 1) and two pre-rTMS patients (grade 1 to grade 2). Statistically, there was no difference. On POD 7, eight of 14 rTMS patients (57.1 %) with
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a preoperative language deficit improved. Of 13 pre-rTMS era, only one patient (7.7 %) improved (p = 0.013). The deficit in the rTMS patient resolved at six weeks follow-up. In the pre-rTMS group, one patient returned to his prior language performance on POD 7. The other patient had a persistent
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deficit at six week follow-up and was lost for three months follow-up.
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Discussion
This is the first comparative study on preoperative rTMS language mapping in patients with
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language-eloquent malignant brain tumors undergoing resection under general anesthesia.
Functional MRI and magnetoencephalography are being used for language research and have also been implemented in the preoperative neurosurgical work-up. However, accuracy, reliability, and
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overall value of these neuroimaging modalities for surgical decision making in brain tumor patients are under debate 9,11,25,30,31. Still, DCS mapping is the gold standard for the localization of functional 1,5–8,24
been shown to result in excellent language outcome surgery under general anesthesia
32
and is an attractive alternative to
14,23
, patient anxiety
29,41
, and lack of evidence of
over surgery under general anesthesia have to be considered. These limitations may
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6–8,14,26,33
. However, the complexity of the procedure, patient selection,
failure of awake craniotomy, complications superiority
. Using awake craniotomy with DCS has
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language areas and cortical language organization
explain why DCS and awake craniotomy has only been used for 17.9 – 21.8% of patients undergoing surgery for malignant glioma 4. Here, the authors aimed to address the question whether preoperative
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rTMS language mapping provides a valuable tool for the resection of language-eloquent malignant brain tumors resected using general anesthesia. One of the flaws of this study is the retrospective
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control group. Hence, not too strong conclusions can be drawn, however, the matching of the groups was done for a number of factors and substantial homogeneity was achieved.
Craniotomy flap size
Awake craniotomy with DCS requires the exposure of a large area of cortical surface
14,33,38
.
Sollmann et al. showed that preoperative rTMS language mapping significantly decreased the size of craniotomy for awake craniotomy with DCS, most likely due to decreased necessity to perform 12
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extensive intraoperative mapping 35. In contrast to awake craniotomy, craniotomy for the resection of brain tumors under general anesthesia generally encircles solely the extent of the tumor. Therefore, it is not expected that preoperative rTMS language mapping has an impact on craniotomy size. Our
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present study substantiates this hypothesis as craniotomy flap sizes did not differ between the rTMS and pre-rTMS groups.
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Surgery-related complications
Collectively, surgery-related complications in brain tumor surgery are rare. However, among
ischemia and swelling due to edema
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complications, more frequent complications encompass postoperative hemorrhage, csf obstruction, . Rates of complications for surgery under general anesthesia
and awake craniotomy with DCS have been reported to range in equal scopes
12,32
. Additional
preoperative rTMS language mapping did not alter complication rates in patients undergoing awake 35
. Likewise, preoperative rTMS language mapping did neither increase nor
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craniotomy with DCS
decrease rate of complication in our study. Therefore, neither selection of surgical procedure nor additional information on cortical language organization seems to influence the rate of surgery-related
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Duration of surgery
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complications.
In a recent study on patients undergoing awake craniontomy with DCS, additional preoperative rTMS language mapping also decreased duration of surgery. The authors attributed this effect to result from a restricted necessity to perform extensive intraoperative mapping
35
. We found that preoperative
rTMS language mapping potentially reduces average duration of surgery. It allows for preoperative development of the ideal surgical strategy and following of this strategy during the procedure guided by the rTMS language map. 13
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Gross total resection and residual tumor Both DCS and rTMS modulate neuronal function and can be used to map brain functions.
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Additionally, information from both modalities share the potential to positively influence GTR rates accompanied with favorable functional outcome in patients undergoing surgical resection for eloquent brain lesions 6,8,10,20. In our study, GTR rates were 65 % in both groups. This is comparable
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to previous studies that reported GTR rates of 64 – 69 % for awake craniotomy with DCS 19,33, 60 % for awake craniotomy with DCS and preoperative rTMS language mapping 35, and 63 % for surgery 12
. Preoperative rTMS language mapping did neither increase rate of
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under general anesthesia alone
GTR nor cause underresection. It yet remains to be determined to which extent preoperative rTMS language mapping might contribute to improving rates of GTR in patients with language eloquent
Inpatient stay
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lesions undergoing resection under general anesthesia.
Several aspects contribute to length of inpatient stay, including general health status, other medical
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issues requiring subsequent therapy and necessity of transfer to other disciplines. Length of hospital stay differs between the U.S. and Germany
2,39,40
. Total length of hospital stay in our cohort was
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comparable to reports of other major German academic medical centers
21,27,34
. In their prospective
randomized trial, Gupta et al. did not find differences in length of inpatient stay between awake craniotomy and surgery under general anesthesia 12. Others, however, found awake craniotomy to be associated with significant shorter inpatient stay
26,32
. Additional preoperative rTMS language
mapping in patients undergoing awake craniotomy did not alter length of hospital stay in a recent study by Sollmann et al. 35. We found implementation of preoperative rTMS language mapping to be associated with significant shorter inpatient stay in patients undergoing surgery under general 14
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anesthesia. However, various factors may influence length of inpatient stay. Hence, it remains uncertain whether preoperative rTMS language mapping contributes to the reduction of inpatient stay
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in these patients or if other unknown factors are responsible.
Language performance
Two important observations were made: first, significantly more patients in the rTMS group
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experienced an improvement of their language impairment within the first week after surgery. Second, after six weeks, the language performance status was significantly better in the rTMS group.
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Thus, preoperative rTMS language mapping might result in earlier language recovery while maintaining comparable rates of GTR. The difference in language performance was no longer evident at three months follow-up. Similar observations have been made by Sollmann et al. who compared awake craniotomy with DCS with and without preoperative rTMS language mapping
35
. Thus,
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preoperative rTMS language mapping potentially has its greatest value in the early phase after surgery regardless which kind of surgical procedure is followed.
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Strength and limitations
Even though not statistically significant, the number of glioblastoma and cerebral metastasis were not
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identical in both groups. This presents a limitation of the study as differences in the clinical courses of the underlying pathology may have an impact on surgical and functional outcomes. However, surgical strategy was the same for both pathologies, i.e. resection of the T1 contrast-enhancing lesion guided via neuronavigation. Various other relevant factors like tumor location and size, and the resultant local mass effect have significant impact on the neurological condition and were well matched. Thus, assessment of tumor and edema volumes was performed here rather than tumor diameter in 2D planes facilitating comparability of groups. We also paid attention to a history of 15
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recent speech disturbance, potentially not evident on admission and preoperative neurological examination. Recent disturbances may indicate that the language network is at a specific risk for further deterioration. Despite the complex requirement of obtaining comparable groups, the rTMS
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and the pre-rTMS group displayed significant homogeneity. Preoperative rTMS language mappings were exclusively performed and analyzed by two neurosurgical residents well-versed on the rTMS system with clinical experience of rTMS language mapping of more than 60 patients. Even though
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collection of rTMS group data was prospective, the study is limited by bias inherit to the retrospective analysis of the control group. A larger study, ideally a prospective randomized trial, should be
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performed to further elucidate potential benefits from preoperative rTMS language mapping. Besides sparing of cortical language eloquent areas, the integrity of subcortical language pathways is of importance for preservation of language function. Yet, it remains to be determined which modalities and protocols accurately display both cortical and subcortical speech eloquent networks. Future
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research on combining preoperative rTMS language mapping and diffusion tensor imaging fibertracking might provide additional insights into language organization and help illustrate essential
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language networks.
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Conclusions
Implementation of preoperative rTMS language mapping seems to provide a favorable early language
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anesthesia. Further research is required to substantiate these findings.
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outcome in patients undergoing surgical resection of language eloquent lesions under general
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Acknowledgements
We would like to thank our colleagues for their support during establishment of nTMS at our
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institution. Especially, Dr. Thomas Picht, Dept. of Neurosurgery, Charité Berlin and his team, and Dr. Sandro Krieg, Dept. of Neurosurgery, Klinikum rechts der Isar, Technische Universität München. We
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thank Nexstim Plc (Frankfurt, Germany) for technical support.
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Disclosure
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The authors declare that they have no conflict of interest.
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16. Ille S, Sollmann N, Hauck T, Maurer S, Tanigawa N, Obermueller T, et al: Combined noninvasive language mapping by navigated transcranial magnetic stimulation and functional MRI and its comparison with direct cortical stimulation. J Neurosurg 123:212–225, 2015 17. Ille S, Sollmann N, Hauck T, Maurer S, Tanigawa N, Obermueller T, et al: Impairment of preoperative language mapping by lesion location: a functional magnetic resonance imaging, navigated transcranial magnetic stimulation, and direct cortical stimulation study. J Neurosurg 123:314–324, 2015 18. Karpagam S, Gowri S: Brain tumour growth and volume detection by ellipsoid-diameter technique using MRI data. Int J Comp Sci 9:6, 2012 19. Kim SS, McCutcheon IE, Suki D, Weinberg JS, Sawaya R, Lang FF, et al: Awake craniotomy for brain tumors near eloquent cortex: correlation of intraoperative cortical mapping with neurological outcomes in 309 consecutive patients. Neurosurgery 64:836–846, 2009 20. Krieg SM, Sabih J, Bulubasova L, Obermueller T, Negwer C, Janssen I, et al: Preoperative motor mapping by navigated transcranial magnetic brain stimulation improves outcome for motor eloquent lesions. Neuro-Oncol 16:1274–1282, 2014 21. Krieg SM, Sollmann N, Obermueller T, Sabih J, Bulubas L, Negwer C, et al: Changing the clinical course of glioma patients by preoperative motor mapping with navigated transcranial magnetic brain stimulation. BMC Cancer 15:2015 Available: http://www.biomedcentral.com/1471-2407/15/231. Accessed 15 May 2016 22. Krieg SM, Tarapore PE, Picht T, Tanigawa N, Houde J, Sollmann N, et al: Optimal timing of pulse onset for language mapping with navigated repetitive transcranial magnetic stimulation. NeuroImage 100:219–236, 2014 23. Nossek E, Matot I, Shahar T, Barzilai O, Rapoport Y, Gonen T, et al: Failed awake craniotomy: a retrospective analysis in 424 patients undergoing craniotomy for brain tumor: Clinical article. J Neurosurg 118:243–249, 2013 24. Ojemann G, Ojemann J, Lettich E, Berger M: Cortical language localization in left, dominant hemisphere: an electrical stimulation mapping investigation in 117 patients. J Neurosurg 71:316–326, 1989 25. Papanicolaou AC, Simos PG, Breier JI, Zouridakis G, Willmore LJ, Wheless JW, et al: Magnetoencephalographic mapping of the language-specific cortex. J Neurosurg 90:85–93, 1999 26. Peruzzi P, Bergese SD, Viloria A, Puente EG, Abdel-Rasoul M, Chiocca EA: A retrospective cohort-matched comparison of conscious sedation versus general anesthesia for supratentorial glioma resection. Clinical article. J Neurosurg 114:633–639, 2011 27. Picht T, Frey D, Thieme S, Kliesch S, Vajkoczy P: Presurgical navigated TMS motor cortex mapping improves outcome in glioblastoma surgery: a controlled observational study. J Neurooncol 126:535–543, 2016 28. Picht T, Krieg SM, Sollmann N, Rösler J, Niraula B, Neuvonen T, et al: A Comparison of Language Mapping by Preoperative Navigated Transcranial Magnetic Stimulation and Direct Cortical Stimulation During Awake Surgery: Neurosurgery 72:808–819, 2013 29. Quick-Weller J, Konczalla J, Duetzmann S, Franz-Jaeger C, Strouhal U, Brawanski N, et al: General anesthesia versus local anesthesia in stereotactic biopsies of brain lesions - a prospective randomized study. World Neurosurg:2016 30. Roux F-E, Boulanouar K, Lotterie J-A, Mejdoubi M, LeSage JP, Berry I: Language functional magnetic resonance imaging in preoperative assessment of language areas: correlation with direct cortical stimulation. Neurosurgery 52:1335-45-1347, 2003 20
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31. Rutten G-J, Ramsey NF: The role of functional magnetic resonance imaging in brain surgery. Neurosurg Focus 28:E4, 2010 32. Sacko O, Lauwers-Cances V, Brauge D, Sesay M, Brenner A, Roux F-E: Awake craniotomy vs surgery under general anesthesia for resection of supratentorial lesions. Neurosurgery 68:11928-1199, 2011 33. Sanai N, Mirzadeh Z, Berger MS: Functional outcome after language mapping for glioma resection. N Engl J Med 358:18–27, 2008 34. Sollmann N, Ille S, Hauck T, Maurer S, Negwer C, Zimmer C, et al: The impact of preoperative language mapping by repetitive navigated transcranial magnetic stimulation on the clinical course of brain tumor patients. BMC Cancer 15:261, 2015 35. Sollmann N, Ille S, Hauck T, Maurer S, Negwer C, Zimmer C, et al: The impact of preoperative language mapping by repetitive navigated transcranial magnetic stimulation on the clinical course of brain tumor patients. BMC Cancer 15:2015 Available: http://www.biomedcentral.com/1471-2407/15/261. Accessed 8 August 2016 36. Sollmann N, Kubitscheck A, Maurer S, Ille S, Hauck T, Kirschke JS, et al: Preoperative language mapping by repetitive navigated transcranial magnetic stimulation and diffusion tensor imaging fiber tracking and their comparison to intraoperative stimulation. Neuroradiology:2016 37. Tarapore PE, Findlay AM, Honma SM, Mizuiri D, Houde JF, Berger MS, et al: Language mapping with navigated repetitive TMS: proof of technique and validation. NeuroImage 82:260–272, 2013 38. Taylor MD, Bernstein M: Awake craniotomy with brain mapping as the routine surgical approach to treating patients with supratentorial intraaxial tumors: a prospective trial of 200 cases. J Neurosurg 90:35–41, 1999 39. Trinh VT, Davies JM, Berger MS: Surgery for primary supratentorial brain tumors in the United States, 2000-2009: effect of provider and hospital caseload on complication rates. J Neurosurg 122:280–296, 2015 40. White PF: Ambulatory anesthesia advances into the new millennium. Anesth Analg 90:1234– 1235, 2000 41. Wrede KH, Stieglitz LH, Fiferna A, Karst M, Gerganov VM, Samii M, et al: Patient acceptance of awake craniotomy. Clin Neurol Neurosurg 113:880–884, 2011
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Figure legends Figure 1. The cortical parcellation system (CPS) according Corina et al.
Figure 3. Duration of surgery and inpatient stay
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Figure 2. Error rates from all mappings allocated to CPS
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Figure 4. Clinical course of language performance status. Preoperatively (PRE), postoperative day 7 (POD7) and day 45 (POD45).
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Number (Fig. 1) Abbreviation 1 polSFG polar part of superior frontal gyrus 2 aSFG anterior superior frontal gyrus 3 mSFG middle superior frontal gyrus 4 pSFG posterior superior frontal gyrus 5 polmFG polar part of middle frontal gyrus 6 aMFG anterior middle frontal gyrus 7 mMFG middle party of middle frontal gyrus 8 pMFG posterior middle frontal gyrus 9 polIFG polar part of inferior frontal gyrus 10 orIFG orbital party of inferior frontal gyrus 11 trIFG triangluar part of inferior frontal gyrus 12 opIFG opercular part of inferior frontal gyrus 13 vPrG ventral precentral gyrus 14 mPrG middle precentral gyrus 15 dPrG dorsal precentral gyrus 16 dPoG dorsal postcentral gyrus 17 mPoG middle postcentral gyrus 18 vPoG ventral postcentral gyrus 19 aSMG anterior supramarginal gyrus 20 pSMG posterior supramarginal gyrus 21 ANG angular gyrus 22 polSTG polar part of superior temporal gyrus 23 aSTG anterior superior temporal gyrus 24 mSTG middle superior temporal gyrus 25 pSTG posterior superior temporal gyrus 26 polMTG polar part of middle temporal gyrus 27 aMTG anterior middle temporal gyrus 28 mMTG middle part of middle temporal gyrus 29 pMTG posterior middle temporal gyrus 30 polITG polar part of inferior temporal gyrus 31 aITG anterior inferior temporal gyrus 32 mITG middle inferior temporal gyrus 33 pITG posterior inferior temporal gyrus 34 SPL superior parietal lobule 35 dLOG dorsolateral part of occipital gyrus 36 vLOG ventrolateral part of occipital gyrus 37 polLOG polar-lateral part of occipital gyrus
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Age (mean in years) Female
rTMS
pre-rTMS
p-value
61.1 ± 9.9
64.7 ± 9.2
0.243
10 (50.0%) 12 (60.0%)
Gender
0.525 10 (50.0%)
Glioblastoma
10 (50.0%) 14 (70.0%)
Histology
0.197
Metastasis
10 (50.0%)
6 (30.0%)
Tumor diameter (cm)
2.9 ± 1.4
3.4 ± 1.1
Tumor volume (cm³)
18.1 ± 25.7
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Tumor characteristics
0.786
Edema volume (cm³) 76.4 ± 62.2 72.1 ± 37.6
0.792
grade 0 grade 1 grade 2
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3 (15.0%)
2 (10.0%)
13 (65.0%) 17 (85.0%) 4 (20.0%)
1 (5.0%)
0 (0%)
0 (0%)
grade 0
6 (30.0%)
7 (35.0%)
grade 1
10 (50.0%) 12 (60.0%)
grade 2
4 (20.0%)
1 (5.0%)
grade 3
0 (0%)
0 (0%)
grade 3
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Preoperative language
0.251
16.4 ±13.4
(Mean)
0.532
Neurological exam
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deficits
8 (40.0%)
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Male
0.380
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rTMS applications 221 ± 70 per session Errors per session 12 ± 5 Error rate per session (%) 5±7 Peeling depth (mm) 22 ± 3 Stimulator intensity 36 ± 9 Electrical field ranges (V/m) 60 ± 18 – 83 ± 23 Inter-picture interval (ms) 2500 – 2800 Display time (ms) 700 – 1000 Picture to trigger interval (ms) 0 Stimulus frequency/number of pulses 7 Hz / 7 Mapping intensity 110% of RMT
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Table 3. Stimulation parameters of rTMS language mappings
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103.5 ± 36.0 135.4 ± 56.4 16.2 ± 7.4 10 % 10 % 0% 0% 65 %
1.000
1.2 ± 1.1
0.8 ± 1.0
0.506
9.9 ± 3.0
15.3 ± 6.3
0.001
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0.039
15.2 ± 4.8 15 % 0% 0% 0% 65 %
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Gross total resection rate (MRI evaluation) Residual tumor volume on MRI (cm³) Inpatient stay (mean in days)
p-value
0.601 1.000
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Bleeding Ischemia CSF obstruction Increasing edema
Complication rate (MRI evaluation)
pre-rTMS
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rTMS pre-rTMS p-value 6 7 grade 0 10 12 Preoperative grade 1 0.380 grade 2 4 1 0 0 grade 3 grade 0 6 7 POD 1 grade 1 12 10 (day 1) 0.952 grade 2 2 3 grade 3 0 0 9 8 grade 0 11 10 POD 7 grade 1 0.520 (day 5 – 7) grade 2 0 2 0 0 grade 3 grade 0 16 14 POD 45$ grade 1 0 3 0.048 (4 – 6 weeks) grade 2 0 1 grade 3 0 0 grade 0 15 14 POD 90§ grade 1 0 2 0.551 (3 – 4 months) grade 2 0 0 0 0 grade 3 $ four patients of rTMS and two patients of pre-rTMS group were excluded from analysis. § in addition to the excluded patients from $, one patient of rTMS and two patients of prerTMS group were excluded from analysis.
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ACCEPTED MANUSCRIPT * In the rTMS group, significantly more patients experienced improvement of their language performance within the first week after surgery compared to the pre-rTMS group. * At six weeks follow-up, language performance status was significantly better in the rTMS
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group compared to the pre-rTMS group. * Duration of surgery and inpatient stay may be reduced by the implementation of
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preoperative rTMS language mapping.
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direct cortical stimulation (DCS) gross total resection (GTR) navigated transcranial magnetic stimulation (nTMS) postoperative day (POD)
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repetitive transcranial magnetic stimuli (rTMS)
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cortical parcellation system (CPS)
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Abbreviations:
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transcranial magnetic stimulation (TMS)
S1878-8750(17)30054-2
DOI:
10.1016/j.wneu.2017.01.041
Reference:
WNEU 5138
To appear in:
World Neurosurgery
Received Date: 10 November 2016 Revised Date:
9 January 2017
Accepted Date: 10 January 2017
Please cite this article as: Hendrix P, Senger S, Simgen A, Griessenauer CJ, Oertel J, Preoperative rTMS language mapping in speech eloquent brain lesions resected under general anesthesia: a pairmatched cohort study, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.01.041. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Preoperative rTMS language mapping in speech eloquent brain lesions resected under general anesthesia: a pair-matched cohort study
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Philipp Hendrix MD1, Sebastian Senger MD1, Andreas Simgen MD2, Christoph J. Griessenauer MD3, Joachim Oertel MD1
Department of Neurosurgery, Saarland University Medical Center and Saarland University Faculty
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1
of Medicine, Homburg/Saar, Germany
Department of Neuroradiology, Saarland University Medical Center and Saarland University Faculty
of Medicine, Homburg/Saar, Germany 3
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Department of Neurosurgery, Geisinger Health System, Danville, PA
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Key words: navigated repetitive transcranial magnetic stimulation, general anesthesia, preoperative language mapping
Philipp Hendrix, MD
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Corresponding author:
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Klinik für Neurochirurgie
Universität des Saarlandes
Kirrberger Straße 100, Gebäude 90.5 66421 Homburg/ Saar, Germany Phone: +49-6841-1624400 Fax: +49-6841-1624480 [email protected] 1
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Abstract
Objective: The value of preoperative rTMS language mapping for function preservation in surgery of
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speech eloquent lesions under general anesthesia remains to be determined.
Methods: The authors prospectively enrolled 20 consecutive right-handed patients with a malignant, left-sided perisylvian language eloquent brain tumor. All patients were subjected to surgical resection
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under general anesthesia guided by preoperative rTMS language mapping (rTMS group, 2014 – 2016). A matched-pair analysis with 20 patients that also underwent surgical resection under general
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anesthesia in the pre-rTMS era (pre-rTMS group, 2009 – 2013) was performed. Language performance status was ranked from grade 0 to grade 3 (none, mild, medium, severe). Results: Rates of gross total resection, of tumor residual, and of complications were equal in both groups. Duration of surgery (p = 0.039) and inpatient stay (p = 0.001) were significantly shorter in the
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rTMS group. Preoperatively, 14 patients in the rTMS and 13 patients in the pre-rTMS group suffered from language deficits (p = 0.380). One week after surgery, 8/14 patients (57.1 %) in the rTMS group but only 1/13 patients (7.7 %) in the pre-rTMS group experienced improvement of language
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performance status (p = 0.013). At six weeks follow-up, language performance status was significantly better in the rTMS group (p = 0.048). However, at three months follow-up, the rTMS-
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and pre-rTMS groups showed an equal language performance status. Conclusion: Implementation of preoperative rTMS language mapping seems to provide a favorable early language outcome in patients undergoing surgical resection of language eloquent lesions under general anesthesia.
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Introduction
Cortical language organization is diverse as evidenced by numerous studies using direct cortical 3,5
. Formerly,
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stimulation (DCS) for language mapping in patients undergoing awake brain surgery
DCS was performed through a large craniotomy and a widely exposed cortical surface. Language mapping was performed by assessing large areas of the diseased hemisphere and included positive 7,24
. A different approach was introduced by Sanai et al. in 2008 who
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language sites as controls
navigated lesion resection using negative cortical language sites without identification of positive
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sites as controls. They performed smaller, tailored craniotomies, and achieved a favorable language outcome 33. Awake craniotomy may be contraindicated in patients that do not consent, have decreased mental capacity, anxiety, and psychiatric disorders. Or awake craniotomy may fail due to restlessness, somnolence, and intractable seizures requiring conversion to general anesthesia
23
. To date, there is
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only one prospective, randomized controlled trial comparing awake craniotomy and surgery under general anesthesia for eloquent brain tumors. This study did not reveal significant differences with respect to efficacy of surgery in preventing development of new neurological deficits accompanied by 12
. However, widespread conclusions from this study can only be
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an increase in extent of resection
drawn with caution as the sample size was small and recent studies have reported excellent language
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outcome with awake craniotomy
14,26,32,33,38
. A novel technique to preoperatively identify cortical
language sites is the use of transcranial magnetic stimulation (TMS). Transcranial magnetic stimuli penetrate the skull and induce an electrical field on the cortical surface modulating neuronal activity adjacent to the stimulus. The optical tracking device allows for coregistration with the preoperative MRI obtained for intraoperative neuronavigation. This is referred to as navigated transcranial magnetic stimulation (nTMS). Application of repetitive transcranial magnetic stimuli (rTMS) leads to a temporarily lasting neuronal modulation capable of provoking naming errors on an object-naming 3
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task. Some studies have used preoperative rTMS to create language maps in brain tumor patients 16,28,37
. Recently, Ille et al. reported on four patients who underwent resection of a language eloquent
brain lesion based on rTMS language mapping
15
. In two patients awake craniotomy with
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intraoperative mapping had to be stopped due to complications. The other two patients were scheduled for resection under general anesthesia using the rTMS language map and represented the first report of favorable language outcome after surgery under general anesthesia guided by rTMS 15
. To assess the value of preoperative rTMS language mapping in patients
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language mapping
undergoing resection using general anesthesia, larger cohorts and a control group are warranted. The
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herein presented cohort is the first prospective collection of consecutive patients with a primary or secondary malignant, language eloquent brain tumor who underwent surgical resection under general anesthesia guided by preoperative rTMS language mapping. This cohort was compared to patients of the pre-rTMS era that also underwent surgery under general anesthesia. Each rTMS patient was
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matched pairwise to a retrospectively analyzed pre-rTMS patient.
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Methods
Patient enrollment, pair-matching, and surgical procedure
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Preoperative rTMS language mapping is established at our institution since January 2014. For the present study, the following inclusion criteria were defined: contrast-enhancing lesion on brain MRI in language eloquent areas (left perisylvian area, right-handed), preoperative rTMS language
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mapping, resection guided by the rTMS language map under general anesthesia, and histopathologically confirmed malignant brain tumor. A total of 20 consecutive patients were
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prospectively enrolled. Those patients were matched pairwise with historical controls treated in the pre-rTMS area before December 2013. Matching was based on the following criteria: tumor location according the cortical parcellation system (CPS) (Figure 1 and Table 1) 5, tumor and edema volume (spheric/ellipsoid equation 18); preoperative language deficits as assessed on history and neurological
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examination; and histopathology. Matching was independently performed by a consultant neuroradiologist (A. S.) and a neurosurgical resident (P. H.). Any discrepancies were resolved by discussion. Consent was obtained from all rTMS patients. The study was performed in accordance
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with the local ethics committee and the Declaration of Helsinki. In both groups each patient underwent surgical resection under general anesthesia by surgeons with equal neuro-oncological
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expertise. Surgical resection aimed for resection of the T1 contrast-enhancing lesion on MRI. The procedure was guided by intraoperative neuronavigation in all cases (rTMS and pre-rTMS). In the rTMS group, intraoperative neuronavigation was guided by the preoperatively acquired rTMS language map.
Clinical language assessment
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All patients underwent a detailed history and neurological examination prior rTMS language mapping and surgical resection. Postoperative neurological assessment was routinely performed on a daily basis until hospital discharge and continued on an outpatient basis. Language performance at
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postoperative day one (POD 1), one week after surgery (ranging from day 5 – 7; POD 7), six weeks after surgery (ranging from 4 – 6 weeks; POD 45) and at three months follow-up (ranging from 3 – 4 months; POD 90) were used for comparison. Language performance status was categorized into one
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of four grades (adjusted from 17,34): grade 0 – no language deficit; grade 1 – mild language deficit (i.e. slight deficits, however, adequate communication possible); grade 2 – medium deficit (i.e.
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impairment of conversational speech and/or speech comprehension; aggravated communication); grade 3 – severe language deficits (i.e. severely disrupted ability to communicate).
Magnetic resonance imaging
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Pre- and postoperative MRI scans were performed on a 1.5 or 3 T scanner (Magnetom Skyra 3.0 T; Magnetom Symphony-TIM 1.5 T, Siemens, Erlangen, Germany). For nTMS and intraoperative neuronavigation, a contrast-enhanced T1-weighted MP RAGE in axial plane was obtained. Analysis
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of preoperative edema size and postoperative ischemia was conducted using T2 FLAIR and DWI, respectively. A postoperative CT-scan was routinely performed when leaving the intensive-care-unit
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at postoperative day 1 to screen for CSF obstruction, brain swelling, edema increase or hemorrhage. Craniotomy flap diameters in anteroposterior and lateral view were obtained from postoperative CTscans. All flaps were of ellipsoid shape. The size of the craniotomy bone flap was calculated via ellipsoid surface area equation. Postoperative MRI was routinely performed within 48 hours after surgical resection to assess resection rate and postoperative complications (e.g. ischemia or edema).
Preoperative rTMS language mapping 6
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Preoperative rTMS language mapping was performed using the eXimia NBS system 4.3 with NEXSPEECH®. Each mapping and each analysis were solely performed by the first and second authors (P. H., S. S.), both neurosurgical residents, trained and experienced with the NBS system 13.
language mapping reports
15,16,22,36,37
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Experimental settings were mainly employed according established protocols from recent rTMS . Briefly, language mapping is conducted through evaluation of
potential language errors elicited on an object-naming task that is performed with synchronous
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applications of rTMS impulses to the lesional hemisphere. First, baseline assessment of an objectnaming task is performed twice. A total of 150 objects are presented on a monitor to be named using
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one word as fast as possible (inter-picture interval 2500 ms, display time of presented object 700 – 1000 ms). Each object-presentation with response is recorded on a video camera. All objects that were named incorrectly, such as using more than one word or a delayed response, were discarded from the original object sample. Next, applications of rTMS impulses were integrated. The adjusted
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object sample was re-presented to the patient with synchronous application of rTMS impulses (picture to trigger interval 0 msec, 7 Hz/7 pulses with 110 % of the individual resting motor potential, derived from the abducens pollicis brevis muscle motor evoked potential obtained on the same
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hemisphere). As with the baseline assessment, this step was also video recorded. After each object presentation/rTMS impulse, the stimulation coil was randomly moved from one spot to another
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across the lesional hemisphere to cover the whole hemisphere. Finally, video sequences from the baseline assessment and rTMS language mapping sessions were compared and analyzed for errors. Errors were assigned no response, hesitation, phonological error, semantic error, neologism, or performance error. Each error from the rTMS language session (i.e. positive language map) was used for intraoperative neuronavigation.
Statistical analysis and data preparation 7
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Statistical analysis was conducted using the software package SPSS (SPSS version 23; SPSS, Inc., Chicago, IL). To compare groups, Fisher´s exact test, Chi-square test, unpaired t-test and Mann-
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Whitney U-test were used where appropriate. Level of statistical significance was set to p < 0.05.
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Results
Patient and tumor characteristics
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Age, gender, histology, and tumor characteristics were equally distributed between groups. In both groups, 8 lesions primarily affected anterior language areas: mPrG (2), mMFG (1), opIFG (2), pMFG (2), trIFG (1). The remaining 12 lesions primarily affected posterior language areas in both groups:
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AnG (1), aSMG (1), aSTG (1), mMTG (3), mPoG (1), mSTG (3), pMTG (1), pSTG (1) (Figure 1 and Table 1). History and neurological examination revealed comparable preoperative language deficits
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(Table 2).
Preoperative rTMS language mapping and impact on surgical strategy
Experimental settings and parameters for rTMS language mapping sessions are shown in Table 3.
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Each identified error was assigned to a distinct region of the CPS. Figure 2 displays frequency of errors of all sessions for a specific CPS region. To guide surgical resection in the rTMS group, the positive rTMS language map (i.e. all identified errors) was used for intraoperative neuronavigation.
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Surgical characteristics
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Resection was performed through language negative sites and language positive sites were avoided.
Repetitive TMS language mapping was associated with significantly shorter surgery duration and inpatient stay. Craniotomy flap sizes and complication rates were equivalent in both groups. In the rTMS group, three patients showed hemorrhage within the tumor cavity that exceeded expected postoperative findings. None of the patients experienced neurological deterioration. In group B, one patient suffered from an epidural hematoma, another from a subdural hematoma. Two other patients had small areas of ischemic events in vicinity of the surgical corridor. In one of those patients 9
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ischemia might have contributed to postoperative language deterioration. However, none of the patients required a reoperation due to surgery-related complications. In both groups, postoperative MRI revealed a gross total resection (GTR) in 13 patients. Seven patients had small tumor residuals
Exclusion of patients from postoperative language analysis
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in each group. Tumor residuals were equal in volume in both groups (Table 4 and Figure 3).
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For POD 45 and 90 analyses, patients that were lost to follow-up or had suffered from tumor recurrence accompanied by general health and neurological deterioration were excluded from
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analysis. This included four rTMS patients. Two were lost to follow-up after discharge from hospital (language performance at POD 7 for patients were grade 0 and grade 1, respectively) and two patients suffering from glioblastoma multiforme experienced tumor recurrence. Both suffered from significant neurological and general health deterioration. Gross total resection was achieved in one of those
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patients. Language performance on POD 7 for patients was grade 0 and grade 1, respectively. Two patients from the pre-rTMS era were lost to follow-up and therefore excluded from analysis (language performance at POD 7 for patients was grade 1 and grade 2, respectively).
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For POD 90 analysis, additional patients were excluded: one rTMS patient was excluded due to glioblastoma recurrence with significant neurological and general health deterioration despite gross
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total resection. Language performance on POD 45 was grade 0. Two patients from the pre-rTMS era were lost to follow-up (language performance at POD 45 was grade 0 and grade 2, respectively). Collectively, rTMS patients excluded (last language grades before exclusion: 0; 0; 0; 1; 1) had a better recent language performance than those excluded from the pre-rTMS era (last language grades before exclusion: 0; 1; 2; 2).
Postoperative language performance 10
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Preoperative language deficits were equally distributed. Language performance did not differ on POD 1 or POD 7. At POD 45, however, rTMS patients showed a significant better language performance status (Figure 4). Ninety days after surgery (POD 90), this difference was no longer significant (Table
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On POD 1, three patients in the rTMS but none in pre-rTMS era group experienced an improvement of language deficit grade (grade 2 to grade 1 twice, grade 1 to grade 0). A deterioration of language
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function was observed in one rTMS patient (grade 0 to grade 1) and two pre-rTMS patients (grade 1 to grade 2). Statistically, there was no difference. On POD 7, eight of 14 rTMS patients (57.1 %) with
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a preoperative language deficit improved. Of 13 pre-rTMS era, only one patient (7.7 %) improved (p = 0.013). The deficit in the rTMS patient resolved at six weeks follow-up. In the pre-rTMS group, one patient returned to his prior language performance on POD 7. The other patient had a persistent
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deficit at six week follow-up and was lost for three months follow-up.
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Discussion
This is the first comparative study on preoperative rTMS language mapping in patients with
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language-eloquent malignant brain tumors undergoing resection under general anesthesia.
Functional MRI and magnetoencephalography are being used for language research and have also been implemented in the preoperative neurosurgical work-up. However, accuracy, reliability, and
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overall value of these neuroimaging modalities for surgical decision making in brain tumor patients are under debate 9,11,25,30,31. Still, DCS mapping is the gold standard for the localization of functional 1,5–8,24
been shown to result in excellent language outcome surgery under general anesthesia
32
and is an attractive alternative to
14,23
, patient anxiety
29,41
, and lack of evidence of
over surgery under general anesthesia have to be considered. These limitations may
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6–8,14,26,33
. However, the complexity of the procedure, patient selection,
failure of awake craniotomy, complications superiority
. Using awake craniotomy with DCS has
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language areas and cortical language organization
explain why DCS and awake craniotomy has only been used for 17.9 – 21.8% of patients undergoing surgery for malignant glioma 4. Here, the authors aimed to address the question whether preoperative
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rTMS language mapping provides a valuable tool for the resection of language-eloquent malignant brain tumors resected using general anesthesia. One of the flaws of this study is the retrospective
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control group. Hence, not too strong conclusions can be drawn, however, the matching of the groups was done for a number of factors and substantial homogeneity was achieved.
Craniotomy flap size
Awake craniotomy with DCS requires the exposure of a large area of cortical surface
14,33,38
.
Sollmann et al. showed that preoperative rTMS language mapping significantly decreased the size of craniotomy for awake craniotomy with DCS, most likely due to decreased necessity to perform 12
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extensive intraoperative mapping 35. In contrast to awake craniotomy, craniotomy for the resection of brain tumors under general anesthesia generally encircles solely the extent of the tumor. Therefore, it is not expected that preoperative rTMS language mapping has an impact on craniotomy size. Our
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present study substantiates this hypothesis as craniotomy flap sizes did not differ between the rTMS and pre-rTMS groups.
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Surgery-related complications
Collectively, surgery-related complications in brain tumor surgery are rare. However, among
ischemia and swelling due to edema
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complications, more frequent complications encompass postoperative hemorrhage, csf obstruction, . Rates of complications for surgery under general anesthesia
and awake craniotomy with DCS have been reported to range in equal scopes
12,32
. Additional
preoperative rTMS language mapping did not alter complication rates in patients undergoing awake 35
. Likewise, preoperative rTMS language mapping did neither increase nor
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craniotomy with DCS
decrease rate of complication in our study. Therefore, neither selection of surgical procedure nor additional information on cortical language organization seems to influence the rate of surgery-related
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Duration of surgery
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complications.
In a recent study on patients undergoing awake craniontomy with DCS, additional preoperative rTMS language mapping also decreased duration of surgery. The authors attributed this effect to result from a restricted necessity to perform extensive intraoperative mapping
35
. We found that preoperative
rTMS language mapping potentially reduces average duration of surgery. It allows for preoperative development of the ideal surgical strategy and following of this strategy during the procedure guided by the rTMS language map. 13
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Gross total resection and residual tumor Both DCS and rTMS modulate neuronal function and can be used to map brain functions.
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Additionally, information from both modalities share the potential to positively influence GTR rates accompanied with favorable functional outcome in patients undergoing surgical resection for eloquent brain lesions 6,8,10,20. In our study, GTR rates were 65 % in both groups. This is comparable
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to previous studies that reported GTR rates of 64 – 69 % for awake craniotomy with DCS 19,33, 60 % for awake craniotomy with DCS and preoperative rTMS language mapping 35, and 63 % for surgery 12
. Preoperative rTMS language mapping did neither increase rate of
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under general anesthesia alone
GTR nor cause underresection. It yet remains to be determined to which extent preoperative rTMS language mapping might contribute to improving rates of GTR in patients with language eloquent
Inpatient stay
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lesions undergoing resection under general anesthesia.
Several aspects contribute to length of inpatient stay, including general health status, other medical
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issues requiring subsequent therapy and necessity of transfer to other disciplines. Length of hospital stay differs between the U.S. and Germany
2,39,40
. Total length of hospital stay in our cohort was
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comparable to reports of other major German academic medical centers
21,27,34
. In their prospective
randomized trial, Gupta et al. did not find differences in length of inpatient stay between awake craniotomy and surgery under general anesthesia 12. Others, however, found awake craniotomy to be associated with significant shorter inpatient stay
26,32
. Additional preoperative rTMS language
mapping in patients undergoing awake craniotomy did not alter length of hospital stay in a recent study by Sollmann et al. 35. We found implementation of preoperative rTMS language mapping to be associated with significant shorter inpatient stay in patients undergoing surgery under general 14
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anesthesia. However, various factors may influence length of inpatient stay. Hence, it remains uncertain whether preoperative rTMS language mapping contributes to the reduction of inpatient stay
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in these patients or if other unknown factors are responsible.
Language performance
Two important observations were made: first, significantly more patients in the rTMS group
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experienced an improvement of their language impairment within the first week after surgery. Second, after six weeks, the language performance status was significantly better in the rTMS group.
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Thus, preoperative rTMS language mapping might result in earlier language recovery while maintaining comparable rates of GTR. The difference in language performance was no longer evident at three months follow-up. Similar observations have been made by Sollmann et al. who compared awake craniotomy with DCS with and without preoperative rTMS language mapping
35
. Thus,
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preoperative rTMS language mapping potentially has its greatest value in the early phase after surgery regardless which kind of surgical procedure is followed.
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Strength and limitations
Even though not statistically significant, the number of glioblastoma and cerebral metastasis were not
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identical in both groups. This presents a limitation of the study as differences in the clinical courses of the underlying pathology may have an impact on surgical and functional outcomes. However, surgical strategy was the same for both pathologies, i.e. resection of the T1 contrast-enhancing lesion guided via neuronavigation. Various other relevant factors like tumor location and size, and the resultant local mass effect have significant impact on the neurological condition and were well matched. Thus, assessment of tumor and edema volumes was performed here rather than tumor diameter in 2D planes facilitating comparability of groups. We also paid attention to a history of 15
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recent speech disturbance, potentially not evident on admission and preoperative neurological examination. Recent disturbances may indicate that the language network is at a specific risk for further deterioration. Despite the complex requirement of obtaining comparable groups, the rTMS
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and the pre-rTMS group displayed significant homogeneity. Preoperative rTMS language mappings were exclusively performed and analyzed by two neurosurgical residents well-versed on the rTMS system with clinical experience of rTMS language mapping of more than 60 patients. Even though
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collection of rTMS group data was prospective, the study is limited by bias inherit to the retrospective analysis of the control group. A larger study, ideally a prospective randomized trial, should be
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performed to further elucidate potential benefits from preoperative rTMS language mapping. Besides sparing of cortical language eloquent areas, the integrity of subcortical language pathways is of importance for preservation of language function. Yet, it remains to be determined which modalities and protocols accurately display both cortical and subcortical speech eloquent networks. Future
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research on combining preoperative rTMS language mapping and diffusion tensor imaging fibertracking might provide additional insights into language organization and help illustrate essential
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language networks.
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Conclusions
Implementation of preoperative rTMS language mapping seems to provide a favorable early language
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anesthesia. Further research is required to substantiate these findings.
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outcome in patients undergoing surgical resection of language eloquent lesions under general
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Acknowledgements
We would like to thank our colleagues for their support during establishment of nTMS at our
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institution. Especially, Dr. Thomas Picht, Dept. of Neurosurgery, Charité Berlin and his team, and Dr. Sandro Krieg, Dept. of Neurosurgery, Klinikum rechts der Isar, Technische Universität München. We
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thank Nexstim Plc (Frankfurt, Germany) for technical support.
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Disclosure
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The authors declare that they have no conflict of interest.
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Figure legends Figure 1. The cortical parcellation system (CPS) according Corina et al.
Figure 3. Duration of surgery and inpatient stay
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Figure 2. Error rates from all mappings allocated to CPS
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Figure 4. Clinical course of language performance status. Preoperatively (PRE), postoperative day 7 (POD7) and day 45 (POD45).
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Number (Fig. 1) Abbreviation 1 polSFG polar part of superior frontal gyrus 2 aSFG anterior superior frontal gyrus 3 mSFG middle superior frontal gyrus 4 pSFG posterior superior frontal gyrus 5 polmFG polar part of middle frontal gyrus 6 aMFG anterior middle frontal gyrus 7 mMFG middle party of middle frontal gyrus 8 pMFG posterior middle frontal gyrus 9 polIFG polar part of inferior frontal gyrus 10 orIFG orbital party of inferior frontal gyrus 11 trIFG triangluar part of inferior frontal gyrus 12 opIFG opercular part of inferior frontal gyrus 13 vPrG ventral precentral gyrus 14 mPrG middle precentral gyrus 15 dPrG dorsal precentral gyrus 16 dPoG dorsal postcentral gyrus 17 mPoG middle postcentral gyrus 18 vPoG ventral postcentral gyrus 19 aSMG anterior supramarginal gyrus 20 pSMG posterior supramarginal gyrus 21 ANG angular gyrus 22 polSTG polar part of superior temporal gyrus 23 aSTG anterior superior temporal gyrus 24 mSTG middle superior temporal gyrus 25 pSTG posterior superior temporal gyrus 26 polMTG polar part of middle temporal gyrus 27 aMTG anterior middle temporal gyrus 28 mMTG middle part of middle temporal gyrus 29 pMTG posterior middle temporal gyrus 30 polITG polar part of inferior temporal gyrus 31 aITG anterior inferior temporal gyrus 32 mITG middle inferior temporal gyrus 33 pITG posterior inferior temporal gyrus 34 SPL superior parietal lobule 35 dLOG dorsolateral part of occipital gyrus 36 vLOG ventrolateral part of occipital gyrus 37 polLOG polar-lateral part of occipital gyrus
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Age (mean in years) Female
rTMS
pre-rTMS
p-value
61.1 ± 9.9
64.7 ± 9.2
0.243
10 (50.0%) 12 (60.0%)
Gender
0.525 10 (50.0%)
Glioblastoma
10 (50.0%) 14 (70.0%)
Histology
0.197
Metastasis
10 (50.0%)
6 (30.0%)
Tumor diameter (cm)
2.9 ± 1.4
3.4 ± 1.1
Tumor volume (cm³)
18.1 ± 25.7
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0.786
Edema volume (cm³) 76.4 ± 62.2 72.1 ± 37.6
0.792
grade 0 grade 1 grade 2
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3 (15.0%)
2 (10.0%)
13 (65.0%) 17 (85.0%) 4 (20.0%)
1 (5.0%)
0 (0%)
0 (0%)
grade 0
6 (30.0%)
7 (35.0%)
grade 1
10 (50.0%) 12 (60.0%)
grade 2
4 (20.0%)
1 (5.0%)
grade 3
0 (0%)
0 (0%)
grade 3
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0.251
16.4 ±13.4
(Mean)
0.532
Neurological exam
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deficits
8 (40.0%)
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Male
0.380
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rTMS applications 221 ± 70 per session Errors per session 12 ± 5 Error rate per session (%) 5±7 Peeling depth (mm) 22 ± 3 Stimulator intensity 36 ± 9 Electrical field ranges (V/m) 60 ± 18 – 83 ± 23 Inter-picture interval (ms) 2500 – 2800 Display time (ms) 700 – 1000 Picture to trigger interval (ms) 0 Stimulus frequency/number of pulses 7 Hz / 7 Mapping intensity 110% of RMT
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Table 3. Stimulation parameters of rTMS language mappings
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103.5 ± 36.0 135.4 ± 56.4 16.2 ± 7.4 10 % 10 % 0% 0% 65 %
1.000
1.2 ± 1.1
0.8 ± 1.0
0.506
9.9 ± 3.0
15.3 ± 6.3
0.001
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0.039
15.2 ± 4.8 15 % 0% 0% 0% 65 %
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Gross total resection rate (MRI evaluation) Residual tumor volume on MRI (cm³) Inpatient stay (mean in days)
p-value
0.601 1.000
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Bleeding Ischemia CSF obstruction Increasing edema
Complication rate (MRI evaluation)
pre-rTMS
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rTMS pre-rTMS p-value 6 7 grade 0 10 12 Preoperative grade 1 0.380 grade 2 4 1 0 0 grade 3 grade 0 6 7 POD 1 grade 1 12 10 (day 1) 0.952 grade 2 2 3 grade 3 0 0 9 8 grade 0 11 10 POD 7 grade 1 0.520 (day 5 – 7) grade 2 0 2 0 0 grade 3 grade 0 16 14 POD 45$ grade 1 0 3 0.048 (4 – 6 weeks) grade 2 0 1 grade 3 0 0 grade 0 15 14 POD 90§ grade 1 0 2 0.551 (3 – 4 months) grade 2 0 0 0 0 grade 3 $ four patients of rTMS and two patients of pre-rTMS group were excluded from analysis. § in addition to the excluded patients from $, one patient of rTMS and two patients of prerTMS group were excluded from analysis.
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ACCEPTED MANUSCRIPT * In the rTMS group, significantly more patients experienced improvement of their language performance within the first week after surgery compared to the pre-rTMS group. * At six weeks follow-up, language performance status was significantly better in the rTMS
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group compared to the pre-rTMS group. * Duration of surgery and inpatient stay may be reduced by the implementation of
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preoperative rTMS language mapping.
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direct cortical stimulation (DCS) gross total resection (GTR) navigated transcranial magnetic stimulation (nTMS) postoperative day (POD)
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repetitive transcranial magnetic stimuli (rTMS)
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cortical parcellation system (CPS)
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Abbreviations:
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transcranial magnetic stimulation (TMS)