XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
Acta Radiol OnlineFirst, published on December 19, 2014 as doi:10.1177/0284185114562992
Original Article Acta Radiologica 0(0) 1–8 ! The Foundation Acta Radiologica 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0284185114562992 acr.sagepub.com
Presurgical functional magnetic resonance imaging in patients with brain tumors Søren Ravn1,2, Mats Holmberg3, Preben Sørensen4, Jens B Frokjaer1,2 and Jesper Carl2,5
Abstract Background: Clinical functional magnetic resonance imaging (fMRI) is still an upcoming diagnostic tool because it is time-consuming to perform the post-scan calculations and interpretations. A standardized and easily used method for the clinical assessment of fMRI scans could decrease the workload and make fMRI more attractive for clinical use. Purpose: To evaluate a standardized clinical approach for distance measurement between benign brain tumors and eloquent cortex in terms of the ability to predict pre- and postoperative neurological deficits after intraoperative neuronavigation-assisted surgery. Material and Methods: A retrospective study of 34 patients. The fMRI data were reanalyzed using a standardized distance measurement procedure combining data from both fMRI and three-dimensional T1 MRI scans. The pre- and postoperative neurological status of each patient was obtained from hospital records. Data analysis was performed using logistic regression analysis to determine whether the distance measured between the tumor margin and fMRI activity could serve as a predictor for neurological deficits. Results: An odds ratio of 0.89 mm–1 (P ¼ 0.03) was found between the risk of preoperative neurological motor deficits and the tumor-fMRI distance. An odds ratio of 0.82 mm–1 (P ¼ 0.04) was found between the risk of additional postoperative neurological motor deficits and the tumor-fMRI distance. The tumor was radically removed in 10 cases; five patients experienced additional postoperative motor deficits (tumor-fMRI distance 18 mm) (P ¼ 0.008). Conclusion: This study indicates that the distance measured between the tumor margin and fMRI activation could serve as a valuable predictor of neurological motor deficits.
Keywords Functional magnetic resonance imaging (fMRI), CNS, brain, surgery Date received: 4 July 2014; accepted: 11 November 2014
Introduction Primary benign brain tumors (incidence, 13 in 100,000 per year), including low grade gliomas (34%), meningiomas (21–28%), neurinomas (8–12%), pituitary adenomas (8–12%), and others (14–16%), are associated with a wide range of comorbidities, such as epileptic seizures and neurological deficits (1–3). Each attempt at full or partial tumor removal is associated with a non-negligible risk of additional neurological deficit (4–6). Technical advancements, such as intraoperative neuronavigation systems and functional magnetic
resonance imaging (fMRI), have been developed over the past two decades, with the overall objective to remove as much tumor tissue as possible without 1
Department Department 3 Department 4 Department 5 Department 2
of of of of of
Radiology, Aalborg University Hospital, Denmark Clinical Medicine Aarhus University, Denmark Oncology, Aalborg University Hospital, Denmark Neurosurgery, Aalborg University Hospital, Denmark Medical Physics, Aalborg University Hospital, Denmark
Corresponding author: Søren Ravn, Las Poulsens Vej 13, 9000 Aalborg, Denmark. Email: [email protected]
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
2
Acta Radiologica 0(0)
damaging healthy tissue (4,7). fMRI is a non-invasive MRI technique that, based on the blood oxygenation level-dependent (BOLD) response, is able to connect activated brain regions to various tasks by detecting indirect effects of neuronal activity on local blood volume, flow, and oxygen saturation (8–11). fMRI enables the surgeon to perform a risk assessment based on the relationship between the tumor and eloquent cortex, to make therapeutic decisions, such as selecting patients for invasive intraoperative mapping (IOM), and to carefully advise the patient about the estimated risks and benefits of the procedure (7,12– 15). The surgeon is able to develop a resection plan and estimate the position and relationship between the abnormal tissue and the important functional tissue that should be preserved (7,14). Resection borders cannot be reliably determined only based on fMRI data. However, it has been suggested that a tumor can be safely resected at a distance of at least 10 mm from the fMRI activation without causing any decline in neurological function (13,16). The general idea is that the risk assessment of inducing neurological deficits can be achieved by identifying the distance between the tumor margin and the eloquent or essential functional areas. Thus far, different authors have used different methods to determine the threshold of the fMRI activation maps used for the distance measurements (12,13,16). Although the availability of high magnetic field scanners is increasing in the medical environment, clinical fMRI is seldom part of the standard preoperative imaging of brain tumor patients because it is time consuming to perform the post-scan calculations and interpretations. In this respect, clinical fMRI could be categorized as an upcoming diagnostic tool (17). A robust, standardized, and easily used distance measurement method that correlates with the risk of preand postoperative neurological deficits could diminish the workload and make fMRI more attractive for clinical use. The aim of the present study was to evaluate a new approach for distance measurement that was originally introduced in a smaller study of 14 patients (18), to combine both anatomical landmarks and fMRI, and to assess the method’s ability to predict pre- and postoperative neurological deficit outcomes before and after surgery (assisted by intraoperative neuronavigation).
Material and Methods Patients Between February 2008 and February 2011, the Department of Neurosurgery, Aalborg University Hospital, referred 34 patients for presurgical fMRI to facilitate the decision-making process in terms of tumor
operability and surgical approach. All patients were considered to have a primary benign supratentorial brain tumor near the eloquent motor and/or language cortex. There were 34 patients (17 men, 17 women; age range, 10–71 years; mean age, 41.1 years). Preoperative assessments were performed for all patients with no previous brain surgery or radiation therapy. Postoperative assessments were performed for all patients who, according to the preoperative assessments, had undergone surgery assisted only by intraoperative neuronavigation (i.e. no direct cortical stimulation before or during surgery). The operation involved radical excision. This retrospective study was approved by the National Danish Board of Health and the Danish Data Protection Agency.
MRI technique All patients were scanned with a 3 T MR scanner (Signa HDx, R14M5, GE Healthcare, Milwaukee, WI, USA) using an 8-channel receive-only head coil (8HRBRAIN, GE Healthcare). The entire brain was covered with a morphological axial T1-weighted (T1W) fast spoiled gradient echo images (FSPGR); repetition time (TR)/echo time (TE), 10.864/4.58 ms; slice thickness, 1.2 mm; interslice gab, 0 mm; field of view (FOV), 240 240 mm; matrix, 352 224). Axial BOLD fMRIs were obtained using a single shot gradient-recalled echo planar imaging pulse sequence (SS-GRE-EPI), with the following parameters: TR/TE, 3000/30 ms; flip angle, 90 ; NEX 1; matrix, 96 96; FOV, 240 240 mm; and slice/thickness/gap, 3.5/0 mm. Standardized 30-s block tasks (each with a total duration of 240 s) were used to visualize the eloquent motor and language cortical areas. The total baseline motor activity was measured at rest (the text in the goggles read ‘‘Relax. . .’’). There were four different motor tasks available in this setup: foot nodding, finger tapping, tongue nodding with closed mouth, and lip pouting. The language baseline activity was a visual input with no meaning (e.g.:?/((!). The language activity task consisted of written nouns (e.g. ship, car), for which the patient should think of a corresponding verb (e.g. sail, drive). The neurosurgeon and the neuroradiologist responsible for the patient decided how many and which tasks each patient was required to perform.
Postprocessing of the fMRI data Each fMRI scan was analyzed using dedicated software located on the MRI scanner (BrainwavePA version
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
Ravn et al.
3
1.3.08130, GE Healthcare). The analysis included smoothing with a Gaussian spatial filter at a full width/half maximum (FWHM) of 8 8 8 mm. The measured BOLD signal was compared to the applied hemodynamic reference function on a voxel-wise basis using multiple regression analysis, which generated a ttest map with a threshold of P ¼ 0.05. The software automatically estimated the effective number of degrees of freedom to account for temporal autocorrelation caused by the smoothness of the hemodynamic response, which was used to convert the t-test map to an ‘‘activation’’ Z map. The activation Z map was then co-registered to the morphological images. For every fMRI task, the neuroradiologist generated functional maps for clinical use by raising the Z score, i.e. increasing the statistical threshold (P < 0.05) to a level that illustrated where each performed task was located in the cerebral cortex (Fig. 1). These maps were made assessable for the neurosurgeon as clinical fMRI maps for presurgical planning and intraoperative neuronavigation purposes. A standardized method for measuring the lesion-toactivation distance (LAD) was retrospectively applied. The method considers the morphology and fMRI activity. Project fMRI maps were made for each task (Fig. 2); the statistical threshold was at a level at which activity was only visible in one axial image plane that corresponded to the relevant morphological area. The relevant morphological area was identified using various anatomical landmarks (12,19). Using a MR workstation (GE-Reformat version 4.2, GE Healthcare), the distance between the high threshold
fMRI map and the tumor could then be directly obtained in the oblique three-dimensional (3D) window (Fig. 3). For each tumor, the volume was roughly estimated from the T1 morphological images using the formula for an ellipsoid, V ¼ 4pabc/6. After the LAD measurement of each fMRI task, the neurological statuses of the patients were obtained from the hospital records. In all cases, the neurological assessment was performed by a senior neurosurgeon. Based on the findings from the objective neurological examination, each patient was scored pre- and postoperatively for neurological deficits corresponding to the motor and or the language task with shortest LAD. Any relevant motor/language deficits were scored preoperatively as yes/no. Any additional relevant motor/language deficits postoperatively were scored yes/no. No standard protocol was used for neurological testing.
Data and statistical analysis The shortest measured LAD for both the motor and language tasks was compared to the corresponding motor or language deficits pre- and postoperatively. LAD versus neurological deficits was tested using logistical regression analysis (Stata/IC 11.2 for Windows, StataCorp LP, College Station, TX, USA). Tumor volume, compared with the pre- and postoperative neurological deficits, was also tested using logistical regression analysis. When comparing groups, the nonparametric Wilcoxon-Mann-Whitney test was used,
Fig. 1. Clinical fMRI, with active motor stimulation of the right hand in patient 10. The statistical threshold of the presurgical fMRI was determined by consensus between the neuroradiologist and the neurosurgeon. Activity is observed in the motor cortex, the sensor cortex, and the supplementary motor (SMA) cortex (corresponding to the right hand).
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
4
Acta Radiologica 0(0)
Fig. 2. Project fMRI, with active motor stimulation of the right hand in patient 10. The statistical threshold was adjusted according to the relevant anatomical landmarks, in this case the ‘‘hand knob’’ (a) in the axial images and ‘‘hand hook’’ (b) in the sagittal images. Therefore, the pixels with activity in the relevant morphological area were only visible in one axial image (a).
Fig. 3. Project fMRI, with active motor stimulation of the right hand in patient 10. The red dot in the ‘‘hand hook’’ area corresponds to the activity in the motor cortex, according to Fig. 2. The 10.5-mm distance between the tumor and fMRI activity was measured using the oblique 3D window on an MRI workstation.
and P 0.05 was considered to be statistically significant.
Results fMRI was successful in all patient sessions; all performed tasks clearly delineated the motor and/or language cortices in the hemisphere with the tumor. In the preoperative assessment, 27 of the 34 patients met the inclusion criteria. Among the 27 included patients, 26 underwent one or more motor fMRI scans, and one patient underwent only a language
fMRI scan (Table 1). There was a significant relationship between the preoperative neurological motor deficits and LAD (Table 2). Twelve patients underwent a preoperative language fMRI. Four of these patients had bilateral fMRI activation, and eight had unilateral activation (Table 1). In the unilateral group of language fMRI activation, the tumor was placed in the same hemisphere as the activation in all eight cases. Preoperative neurological language deficits tended to be associated with LAD, P ¼ 0.15 (Table 2). No significant relationship was found between tumor volume and preoperative neurological motor or language deficits (Table 2). Seventeen of the 27 patients from the preoperative assessment also met the inclusion criteria for the postoperative assessment. Among the 17 included patients, 16 underwent one or more motor fMRI scans (Table 3). There was a significant relationship between additional postoperative neurological motor deficits and the LAD (Table 2). Among the 16 patients with motor fMRIs, the tumor was radically removed in 10 patients, based on a 48-h postoperative MRI. Logistic regression analysis in this group of 10 patients suggested a perfect fit, with a cutoff LAD of 18 mm. Five patients with a LAD of less than 18 mm experienced additional postoperative neurological motor deficits, whereas five patients with a tumor-fMRI distance greater than 18 mm did not experience additional postoperative neurological motor deficits (P ¼ 0.008, Fisher’s exact test). Among the 17 included patients, eight underwent a language fMRI (Table 4). Six of these patients had unilateral fMRI activation in the same hemisphere as
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
Ravn et al.
5
Table 1. Patients included for preoperative assessment. LAD (mm) Age Patient (years)/ sex Tumor location no.
Diagnosis
Tumor Language Volume lateralization Motor Language Dom/Nondom MDPr LDPr (cm3)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Astrocytoma Grade I-II Astrocytoma Grade I-II Metastasis Metastasis Astrocytoma Grade I-II Oligodendroglioma Cavsrnoma Oligod endroglioma Astrocytom grade III Astrocytoma grade I–II Glioblastoma Astrocytoma grade I–II Ganglioglioma Astrocytoma grade III Gliose Oligodendroglioma Astrocytoma grade I–II Glioblastoma Meningioma Astrocytoma grade I–II Pleomorft xanthoastrocytoma Oligodendroglioma Oligodendroglioma Astrocytoma grade I–II Oligodendroglioma Astrocytoma grade III Astrocytoma grade I–II
25.4 15.3 6.4 27.9 18.1 18.1 14.3 12.1 12.3 10.5 27.9 21.8 54 0 29.6 0 30.4 24.6 3.6 6.6 25.7 35 21.2 2.6 61.4 * 13.5
37/M 40/M 68/M 71/F 22/F 10/F 29/F 39/F 53/F 39/F 62/F 33/M 25/M 55/M 18/F 41/M 35/M 55/F 44/F 28/M 53/F 50/M 37/F 34/M 44/F 44/M 39/M
L temporal L frontoparietal L parietal R frontal R frontal L frontopariotemporal L frontal L frontal R frontal L frontal L frontal R temporal L temporal L frontal L frontal L frontotemporal L frontal L temporal R parietal R frontal L frontal R frontal R frontal R frontal L frontal L frontal L parietal
0 28.3 * * 33.7 * * 48.4 * * * 0 21.7 * 12.3 * 0 12 * * 31.2 * * 38.8 * 9.8 *
L L
R/L
L/R
L/R L L/R L L
L
R L
No No Yes Yes No Yes No Yes Yes Yes No No No Yes No Yes No No Yes No No No Yes No No No No
Yes No No Yes No Yes No Yes No No No No No No No No No Yes No No No No No No No Yes No
32.3 45.0 9.5 0.6 22.2 * 2.7 4.5 2.1 11.2 0.9 68.1 0.8 37.6 9.8 102.3 113.7 6.5 13.0 56.7 7.5 80.5 25.2 18.8 94.5 198.7 40.2
Patients listed in chronological order of fMRI. *Not performed. Dom, dominant hemisphere; L, left; LAD, lesion-to-activation distance; LDPr, language deficits preoperative; MDPr, motor deficits preoperative; Nondom, non-dominant hemisphere; R, right.
the tumor. No significant relationship was found between LAD and postoperative neurological language deficits, P ¼ 0.50 (Table 2). No significant relationship was found between tumor volume and additional postoperative neurological motor or language deficits (Table 2). The patients (Tables 3 and 4) selected for surgeryassisted (solely by intraoperative neuronavigation) radical tumor removal after the preoperative fMRI had an overall mean LAD of 18.8 mm in contrast to the non-operated patients, who had a mean LAD of 6.9 mm (P ¼ 0.02, non-parametric Wilcoxon-MannWhitney test).
Discussion The present study indicates that the applied standardized method for distance measurement between tumor and preoperative fMRI was able to predict postoperative outcomes in terms of neurological motor deficits following intraoperative neuronavigation surgery. Although the method differs from those of other investigators, the LAD cutoff of 18 mm, beyond which no neurological motor deficits were observed in radically operated patients, aligns with the methods used in similar studies (13,16). Considering the preoperative assessments, a statistically significant relationship (P ¼ 0.03)
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
6
Acta Radiologica 0(0) Table 2. Neurological deficits versus fMRI distance and tumor volume. Neurological Neurological deficits/ fMRI distance deficits Odds ratio (1/mm) CI (1/mm) P (n/ntotal) Preoperative assessment Motor fMRI 10/26 Unilateral language fMRI 4/8 Postoperative assessment Motor fMRI 7/16 Unilateral language fMRI 3/6
Neurological deficits/ Tumor volume Odds ratio (1/cm3)
CI (1/cm3)
P
0.89 0.88
0.81;0.99 0.75;1.05
0.03 0.15
0.99 1.01
0.96;1.01 0.99;1.03
0.32 0.40
0.82 1.06
0.67;0.99 0.89;1.26
0.04 0.50
0.99 0.93
0.96;1.02 0.80;1.09
0.56 0.41
CI, 95% confidence interval; n, number of patients with neurological deficits in the group; ntotal, total number of patients in the group.
Table 3. Patients included for postoperative motor fMRI assessment.
Table 4. Patients included for postoperative language fMRI assessment.
Patient LAD (mm) Tumor no. motor MDPr nMDPo volume (cm3) Resection*
Language Tumor Lateralization volume Patient LAD (mm) Dom/ LDPr nLDPo (cm3) Resection* no. Language Nondom
2 3 4 5 7 8 11 13 17 18 19 20 21 22 23 25
15.3 6.4 27.9 18.1 14.3 12.1 27.9 54 30.4 24.6 3.6 6.6 25.7 35 21.2 61.4
No Yes Yes No No Yes No No No No Yes No No No Yes No
Yes No No Yes Yes Yes No No No No Yes Yes No No Yes No
45.0 9.5 0.6 22.2 2.7 4.5 0.9 0.8 113.7 6.5 13.0 56.7 7.5 80.5 25.2 94.5
C – – C C C C C C P C P C C P P
Patients listed in chronological order of fMRI. *C ¼ complete; P ¼ partial. L, left; LAD, lesion-to-activation distance; MDPr, motor deficits preoperative; nMDPo, new motor deficits postoperative; R, right.
was found between preoperative neurological motor deficits and LAD, indicating involvement of the motor cortex. These findings indicate the usefulness of the applied LAD measurement in terms of risk assessment prior to surgery close to the motor cortex. The applied method was not able to predict postoperative outcomes in terms of neurological language deficits, although preoperative neurological deficits tended to be associated with LAD (P ¼ 0.15). This finding could be attributed to the limited number of
2 5 8 13 17 18 21 26
28.3 33.7 48.4 21.7 0 12 31.2 9.8
L R/L L/R L L L L L
No No Yes No No Yes No Yes
No No No Yes No Yes Yes No
45.0 22.2 4.5 0.8 113.7 6.5 7.5 198.7
C C C C C P C P
Patients listed in chronological order of fMRI. *C ¼ complete; P ¼ partial. Dom, dominant hemisphere; L, left; LAD, lesion-to-activation distance; LDPr, language deficits preoperative; nLDPo, new language deficits postoperative; Non-dom, non-dominant hemisphere; R, right.
patients who underwent preoperative language fMRI and the fact that only six patients had unilateral language activation. Another reason could be the involvement of the white matter tracts between the Broca’s and Wernicke’s areas, which could also explain why both patient 13 (LAD for language ¼21.7 mm) and patient 21 (LAD for language ¼31.2 mm) experienced additional postoperative language deficits. The use of a LAD measurement based only on the fMRI activation has met with some criticism because the LAD is highly determined by the accuracy of fMRI localization and technical factors, such as the statistical threshold (12,20). It is true that the accuracy of fMRI localization is low, but note that the fMRI BOLD signal only serves as a pseudo measure for neural activity. The BOLD contrast originates from hemodynamic changes in the vasculature and is slightly offset toward
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
Ravn et al.
7
the venous compartment and, thus, does not precisely localize the electrically active neurons (12). However, it has been shown that there is a high reproducibility of the fMRI localization within the human motor and sensory cortex (21,22) when using methods without threshold adjustment (22) and when different methods of threshold adjustments of the fMRI map were used (21). Therefore, using fMRI for preoperative risk assessment seems feasible, as long as there is a good correlation between the preoperative fMRI LAD measurements and postoperative outcomes. To address criticism regarding the determination of the statistical threshold, the applied standardized method combines both the data from the fMRI and the morphological images of the T1 3D FSPGR sequence to set the statistical threshold used for the LAD measurement. The inter-observer coefficient of reproducibility was reported in a previous study to be 2.4 mm for the LAD (18). The inter-observer difference included both the differences in outlining of the high threshold fMRI activation and in outlining the tumor. The presented method for LAD measurement should only be applied in the preoperative risk assessment to determine whether to operate solely supported by a neuronavigation system. In this study, the cutoff value was 18 mm for the distance between the tumor and eloquent motor cortex (i.e. the distance that did not result in any postoperative transient or permanent neurological deficits in patients for whom the tumor was concluded to have been radically excised). Other distance measurement studies have differentiated between transient and permanent neurological deficits (13,16). These studies show that a distance between 0 and 10 mm (between the fMRI-activation and tumor) results in a greater risk of permanent neurological deficits. In the present study, for 10 of the 27 patients, the neurosurgeons choose not to operate solely by neuronavigation. These 10 patients had a mean LAD of 6.9 mm. This group, in which one would expect a high risk of permanent neurological deficits after neuronavigation assisted surgery, was actually recommended for another surgical approach. The assignment was based on the morphological MRIs, the clinical fMRIs (Fig. 1) and the clinical experiences of the neurosurgeons. This result indicates that the presented standardized and easy-to-use method for LAD measurement could serve as a more objective clinical management method. Together with the distance measurement, the clinical fMRI could assist neurosurgeons in assessing the feasibility of radical surgical resection in low-grade tumors. If radical surgical resection is believed to be feasible, three key stages could be proposed for surgical planning: (i) motor LAD 18 mm, an operation solely assisted by intraoperative neuronavigation, with minimal risk of postoperative
neurological deficits; (ii) motor LAD < 18 mm, an fMRI-guided operation assisted by IOM; and (iii) inconclusive motor fMRI, with an operation assisted solely by IOM. It is important to consider how one should present the distance measurement results. If the results are presented as a combination of Figs. 2 and 3, then there is a considerable risk of misinterpretation. As discussed earlier, the fMRI activity is only a pseudo measurement of neuronal activity. A combination of Figs. 2 and 3 could lead the surgeon to the conclusion that the high threshold fMRI activity in motor cortex would correspond to the exact same point if he/she had used IOM. However, the relationship between the presented method for distance measurement and IOM needs further investigation. Meanwhile, the distance measurement could be presented with the clinical fMRI images (Fig. 1). One limitation of this study is the small sample size, which can limit the generalization of the results. A larger patient cohort is needed in future research. Another limitation is the retrospective study design. Further prospective studies are needed to evaluate the value of this method for motor, language, and sensor areas. In conclusion, the presented easy-to-use approach for lesion-to-activation distance (LAD) measurement combines both anatomical landmarks and fMRI using clinically approved software, and it was able to predict the presence of preoperative neurological motor deficits, as well as the occurrence of additional postoperative neurological motor deficits, assisted by intraoperative neuronavigation. Acknowledgments This study was supported by CIRRO – the Lundbeck Foundation Center for Interventional Research in Radiation Oncology and the Danish Council for Strategic Research.
Conflict of interest None declared.
Ethical approval The study was approved as a retrospective study by the National Danish Board of Health (no. 7-604-04-2/220/ HKR) and the Danish Data Protection Agency (no. 200941-3464).
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Buckner JC, Brown PD, O’Neill BP, et al. Central nervous system tumors. Mayo Clin Proc 2007;82:1271–1286.
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
8
Acta Radiologica 0(0)
2. Weller M, Stupp R, Wick W. Epilepsy meets cancer: when, why, and what to do about it? Lancet Oncol 2012;13:375–382. 3. Wrensch M, Minn Y, Chew T, et al. Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro Oncol 2002;4:278–299. 4. Duffau H. Lessons from brain mapping in surgery for low-grade glioma: insights into associations between tumour and brain plasticity. Lancet Neurol 2005;4: 476–486. 5. Fadul C, Wood J, Thaler H, et al. Morbidity and mortality of craniotomy for excision of supratentorial gliomas. Neurology 1988;38:1374–1379. 6. Ojemann JG, Miller JW, Silbergeld DL. Preserved function in brain invaded by tumor. Neurosurgery 1996;39: 253–258. 7. Tronnier VM. Functional neuronavigation. In: Stippich C (ed.) Clinical Functional MRI – Presurgical Functional Neuroimaging. Stuttgart: Springer, 2007, pp.149–166. 8. Ogawa S, Tank DW, Menon R, et al. Intrinsic signal changes accompanying sensory stimulation: functional brain mapping with magnetic resonance imaging. Proc Natl Acad Sci U S A 1992;89:5951–5955. 9. Stippich C, Mohammed J, Kress B, et al. Robust localization and lateralization of human language function: an optimized clinical functional magnetic resonance imaging protocol. Neurosci Lett 2003;346:109–113. 10. Kwong KK, Belliveau JW, Chesler DA, et al. Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc Natl Acad Sci U S A 1992;89:5675–5679. 11. Bandettini PA, Wong EC, Hinks RS, et al. Time course EPI of human brain function during task activation. Magn Reson Med 1992;25:390–397. 12. Sunaert S. Presurgical planning for tumor resectioning. J Magn Reson Imaging 2006;23:887–905. 13. Krishnan R, Raabe A, Hattingen E, et al. Functional magnetic resonance imaging-integrated neuronavigation:
14.
15.
16.
17.
18.
19.
20.
21.
22.
correlation between lesion-to-motor cortex distance and outcome. Neurosurgery 2004;55:904–914. Duffau H. New concepts in surgery of WHO grade II gliomas: functional brain mapping, connectionism and plasticity–a review. J Neurooncol 2006;79:77–115. Stippich C, Rapps N, Dreyhaupt J, et al. Localizing and lateralizing language in patients with brain tumors: feasibility of routine preoperative functional MR imaging in 81 consecutive patients. Radiology 2007;243:828–836. Haberg A, Kvistad KA, Unsgard G, et al. Preoperative blood oxygen level-dependent functional magnetic resonance imaging in patients with primary brain tumors: clinical application and outcome. Neurosurgery 2004;54: 902–914. Blatow M, Reinhardt J, Riffel K, et al. Clinical functional MRI of sensorimotor cortex using passive motor and sensory stimulation at 3 Tesla. J Magn Reson Imaging 2011;34:429–437. Laustsen SR, Sorensen P, Frund T, et al. [Preoperative functional magnetic resonance imaging in patients with brain tumors]. Ugeskr Laeger 2010;172:2370–2376. Naidich TN, Yousry TA. Functional neuroanatomy. In: Stippich C (ed.) Clinical Functional MRI – Presurgical Functional Neuroimaging. Stuttgart: Springer, 2007, pp.53–85. Wengenroth M, Blatow M, Guenther J, et al. Diagnostic benefits of presurgical fMRI in patients with brain tumours in the primary sensorimotor cortex. Eur Radiol 2011;21:1517–1525. Vidyasagar R, Parkes LM. Reproducibility of functional MRI localization within the human somatosensory cortex. J Magn Reson Imaging 2011;34:1439–1444. Voyvodic JT, Petrella JR, Friedman AH. fMRI activation mapping as a percentage of local excitation: consistent presurgical motor maps without threshold adjustment. J Magn Reson Imaging 2009;29:751–759.
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
(ACR)
[1–8] [PREPRINTER stage]
Acta Radiol OnlineFirst, published on December 19, 2014 as doi:10.1177/0284185114562992
Original Article Acta Radiologica 0(0) 1–8 ! The Foundation Acta Radiologica 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0284185114562992 acr.sagepub.com
Presurgical functional magnetic resonance imaging in patients with brain tumors Søren Ravn1,2, Mats Holmberg3, Preben Sørensen4, Jens B Frokjaer1,2 and Jesper Carl2,5
Abstract Background: Clinical functional magnetic resonance imaging (fMRI) is still an upcoming diagnostic tool because it is time-consuming to perform the post-scan calculations and interpretations. A standardized and easily used method for the clinical assessment of fMRI scans could decrease the workload and make fMRI more attractive for clinical use. Purpose: To evaluate a standardized clinical approach for distance measurement between benign brain tumors and eloquent cortex in terms of the ability to predict pre- and postoperative neurological deficits after intraoperative neuronavigation-assisted surgery. Material and Methods: A retrospective study of 34 patients. The fMRI data were reanalyzed using a standardized distance measurement procedure combining data from both fMRI and three-dimensional T1 MRI scans. The pre- and postoperative neurological status of each patient was obtained from hospital records. Data analysis was performed using logistic regression analysis to determine whether the distance measured between the tumor margin and fMRI activity could serve as a predictor for neurological deficits. Results: An odds ratio of 0.89 mm–1 (P ¼ 0.03) was found between the risk of preoperative neurological motor deficits and the tumor-fMRI distance. An odds ratio of 0.82 mm–1 (P ¼ 0.04) was found between the risk of additional postoperative neurological motor deficits and the tumor-fMRI distance. The tumor was radically removed in 10 cases; five patients experienced additional postoperative motor deficits (tumor-fMRI distance 18 mm) (P ¼ 0.008). Conclusion: This study indicates that the distance measured between the tumor margin and fMRI activation could serve as a valuable predictor of neurological motor deficits.
Keywords Functional magnetic resonance imaging (fMRI), CNS, brain, surgery Date received: 4 July 2014; accepted: 11 November 2014
Introduction Primary benign brain tumors (incidence, 13 in 100,000 per year), including low grade gliomas (34%), meningiomas (21–28%), neurinomas (8–12%), pituitary adenomas (8–12%), and others (14–16%), are associated with a wide range of comorbidities, such as epileptic seizures and neurological deficits (1–3). Each attempt at full or partial tumor removal is associated with a non-negligible risk of additional neurological deficit (4–6). Technical advancements, such as intraoperative neuronavigation systems and functional magnetic
resonance imaging (fMRI), have been developed over the past two decades, with the overall objective to remove as much tumor tissue as possible without 1
Department Department 3 Department 4 Department 5 Department 2
of of of of of
Radiology, Aalborg University Hospital, Denmark Clinical Medicine Aarhus University, Denmark Oncology, Aalborg University Hospital, Denmark Neurosurgery, Aalborg University Hospital, Denmark Medical Physics, Aalborg University Hospital, Denmark
Corresponding author: Søren Ravn, Las Poulsens Vej 13, 9000 Aalborg, Denmark. Email: [email protected]
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
2
Acta Radiologica 0(0)
damaging healthy tissue (4,7). fMRI is a non-invasive MRI technique that, based on the blood oxygenation level-dependent (BOLD) response, is able to connect activated brain regions to various tasks by detecting indirect effects of neuronal activity on local blood volume, flow, and oxygen saturation (8–11). fMRI enables the surgeon to perform a risk assessment based on the relationship between the tumor and eloquent cortex, to make therapeutic decisions, such as selecting patients for invasive intraoperative mapping (IOM), and to carefully advise the patient about the estimated risks and benefits of the procedure (7,12– 15). The surgeon is able to develop a resection plan and estimate the position and relationship between the abnormal tissue and the important functional tissue that should be preserved (7,14). Resection borders cannot be reliably determined only based on fMRI data. However, it has been suggested that a tumor can be safely resected at a distance of at least 10 mm from the fMRI activation without causing any decline in neurological function (13,16). The general idea is that the risk assessment of inducing neurological deficits can be achieved by identifying the distance between the tumor margin and the eloquent or essential functional areas. Thus far, different authors have used different methods to determine the threshold of the fMRI activation maps used for the distance measurements (12,13,16). Although the availability of high magnetic field scanners is increasing in the medical environment, clinical fMRI is seldom part of the standard preoperative imaging of brain tumor patients because it is time consuming to perform the post-scan calculations and interpretations. In this respect, clinical fMRI could be categorized as an upcoming diagnostic tool (17). A robust, standardized, and easily used distance measurement method that correlates with the risk of preand postoperative neurological deficits could diminish the workload and make fMRI more attractive for clinical use. The aim of the present study was to evaluate a new approach for distance measurement that was originally introduced in a smaller study of 14 patients (18), to combine both anatomical landmarks and fMRI, and to assess the method’s ability to predict pre- and postoperative neurological deficit outcomes before and after surgery (assisted by intraoperative neuronavigation).
Material and Methods Patients Between February 2008 and February 2011, the Department of Neurosurgery, Aalborg University Hospital, referred 34 patients for presurgical fMRI to facilitate the decision-making process in terms of tumor
operability and surgical approach. All patients were considered to have a primary benign supratentorial brain tumor near the eloquent motor and/or language cortex. There were 34 patients (17 men, 17 women; age range, 10–71 years; mean age, 41.1 years). Preoperative assessments were performed for all patients with no previous brain surgery or radiation therapy. Postoperative assessments were performed for all patients who, according to the preoperative assessments, had undergone surgery assisted only by intraoperative neuronavigation (i.e. no direct cortical stimulation before or during surgery). The operation involved radical excision. This retrospective study was approved by the National Danish Board of Health and the Danish Data Protection Agency.
MRI technique All patients were scanned with a 3 T MR scanner (Signa HDx, R14M5, GE Healthcare, Milwaukee, WI, USA) using an 8-channel receive-only head coil (8HRBRAIN, GE Healthcare). The entire brain was covered with a morphological axial T1-weighted (T1W) fast spoiled gradient echo images (FSPGR); repetition time (TR)/echo time (TE), 10.864/4.58 ms; slice thickness, 1.2 mm; interslice gab, 0 mm; field of view (FOV), 240 240 mm; matrix, 352 224). Axial BOLD fMRIs were obtained using a single shot gradient-recalled echo planar imaging pulse sequence (SS-GRE-EPI), with the following parameters: TR/TE, 3000/30 ms; flip angle, 90 ; NEX 1; matrix, 96 96; FOV, 240 240 mm; and slice/thickness/gap, 3.5/0 mm. Standardized 30-s block tasks (each with a total duration of 240 s) were used to visualize the eloquent motor and language cortical areas. The total baseline motor activity was measured at rest (the text in the goggles read ‘‘Relax. . .’’). There were four different motor tasks available in this setup: foot nodding, finger tapping, tongue nodding with closed mouth, and lip pouting. The language baseline activity was a visual input with no meaning (e.g.:?/((!). The language activity task consisted of written nouns (e.g. ship, car), for which the patient should think of a corresponding verb (e.g. sail, drive). The neurosurgeon and the neuroradiologist responsible for the patient decided how many and which tasks each patient was required to perform.
Postprocessing of the fMRI data Each fMRI scan was analyzed using dedicated software located on the MRI scanner (BrainwavePA version
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
Ravn et al.
3
1.3.08130, GE Healthcare). The analysis included smoothing with a Gaussian spatial filter at a full width/half maximum (FWHM) of 8 8 8 mm. The measured BOLD signal was compared to the applied hemodynamic reference function on a voxel-wise basis using multiple regression analysis, which generated a ttest map with a threshold of P ¼ 0.05. The software automatically estimated the effective number of degrees of freedom to account for temporal autocorrelation caused by the smoothness of the hemodynamic response, which was used to convert the t-test map to an ‘‘activation’’ Z map. The activation Z map was then co-registered to the morphological images. For every fMRI task, the neuroradiologist generated functional maps for clinical use by raising the Z score, i.e. increasing the statistical threshold (P < 0.05) to a level that illustrated where each performed task was located in the cerebral cortex (Fig. 1). These maps were made assessable for the neurosurgeon as clinical fMRI maps for presurgical planning and intraoperative neuronavigation purposes. A standardized method for measuring the lesion-toactivation distance (LAD) was retrospectively applied. The method considers the morphology and fMRI activity. Project fMRI maps were made for each task (Fig. 2); the statistical threshold was at a level at which activity was only visible in one axial image plane that corresponded to the relevant morphological area. The relevant morphological area was identified using various anatomical landmarks (12,19). Using a MR workstation (GE-Reformat version 4.2, GE Healthcare), the distance between the high threshold
fMRI map and the tumor could then be directly obtained in the oblique three-dimensional (3D) window (Fig. 3). For each tumor, the volume was roughly estimated from the T1 morphological images using the formula for an ellipsoid, V ¼ 4pabc/6. After the LAD measurement of each fMRI task, the neurological statuses of the patients were obtained from the hospital records. In all cases, the neurological assessment was performed by a senior neurosurgeon. Based on the findings from the objective neurological examination, each patient was scored pre- and postoperatively for neurological deficits corresponding to the motor and or the language task with shortest LAD. Any relevant motor/language deficits were scored preoperatively as yes/no. Any additional relevant motor/language deficits postoperatively were scored yes/no. No standard protocol was used for neurological testing.
Data and statistical analysis The shortest measured LAD for both the motor and language tasks was compared to the corresponding motor or language deficits pre- and postoperatively. LAD versus neurological deficits was tested using logistical regression analysis (Stata/IC 11.2 for Windows, StataCorp LP, College Station, TX, USA). Tumor volume, compared with the pre- and postoperative neurological deficits, was also tested using logistical regression analysis. When comparing groups, the nonparametric Wilcoxon-Mann-Whitney test was used,
Fig. 1. Clinical fMRI, with active motor stimulation of the right hand in patient 10. The statistical threshold of the presurgical fMRI was determined by consensus between the neuroradiologist and the neurosurgeon. Activity is observed in the motor cortex, the sensor cortex, and the supplementary motor (SMA) cortex (corresponding to the right hand).
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
4
Acta Radiologica 0(0)
Fig. 2. Project fMRI, with active motor stimulation of the right hand in patient 10. The statistical threshold was adjusted according to the relevant anatomical landmarks, in this case the ‘‘hand knob’’ (a) in the axial images and ‘‘hand hook’’ (b) in the sagittal images. Therefore, the pixels with activity in the relevant morphological area were only visible in one axial image (a).
Fig. 3. Project fMRI, with active motor stimulation of the right hand in patient 10. The red dot in the ‘‘hand hook’’ area corresponds to the activity in the motor cortex, according to Fig. 2. The 10.5-mm distance between the tumor and fMRI activity was measured using the oblique 3D window on an MRI workstation.
and P 0.05 was considered to be statistically significant.
Results fMRI was successful in all patient sessions; all performed tasks clearly delineated the motor and/or language cortices in the hemisphere with the tumor. In the preoperative assessment, 27 of the 34 patients met the inclusion criteria. Among the 27 included patients, 26 underwent one or more motor fMRI scans, and one patient underwent only a language
fMRI scan (Table 1). There was a significant relationship between the preoperative neurological motor deficits and LAD (Table 2). Twelve patients underwent a preoperative language fMRI. Four of these patients had bilateral fMRI activation, and eight had unilateral activation (Table 1). In the unilateral group of language fMRI activation, the tumor was placed in the same hemisphere as the activation in all eight cases. Preoperative neurological language deficits tended to be associated with LAD, P ¼ 0.15 (Table 2). No significant relationship was found between tumor volume and preoperative neurological motor or language deficits (Table 2). Seventeen of the 27 patients from the preoperative assessment also met the inclusion criteria for the postoperative assessment. Among the 17 included patients, 16 underwent one or more motor fMRI scans (Table 3). There was a significant relationship between additional postoperative neurological motor deficits and the LAD (Table 2). Among the 16 patients with motor fMRIs, the tumor was radically removed in 10 patients, based on a 48-h postoperative MRI. Logistic regression analysis in this group of 10 patients suggested a perfect fit, with a cutoff LAD of 18 mm. Five patients with a LAD of less than 18 mm experienced additional postoperative neurological motor deficits, whereas five patients with a tumor-fMRI distance greater than 18 mm did not experience additional postoperative neurological motor deficits (P ¼ 0.008, Fisher’s exact test). Among the 17 included patients, eight underwent a language fMRI (Table 4). Six of these patients had unilateral fMRI activation in the same hemisphere as
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
Ravn et al.
5
Table 1. Patients included for preoperative assessment. LAD (mm) Age Patient (years)/ sex Tumor location no.
Diagnosis
Tumor Language Volume lateralization Motor Language Dom/Nondom MDPr LDPr (cm3)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Astrocytoma Grade I-II Astrocytoma Grade I-II Metastasis Metastasis Astrocytoma Grade I-II Oligodendroglioma Cavsrnoma Oligod endroglioma Astrocytom grade III Astrocytoma grade I–II Glioblastoma Astrocytoma grade I–II Ganglioglioma Astrocytoma grade III Gliose Oligodendroglioma Astrocytoma grade I–II Glioblastoma Meningioma Astrocytoma grade I–II Pleomorft xanthoastrocytoma Oligodendroglioma Oligodendroglioma Astrocytoma grade I–II Oligodendroglioma Astrocytoma grade III Astrocytoma grade I–II
25.4 15.3 6.4 27.9 18.1 18.1 14.3 12.1 12.3 10.5 27.9 21.8 54 0 29.6 0 30.4 24.6 3.6 6.6 25.7 35 21.2 2.6 61.4 * 13.5
37/M 40/M 68/M 71/F 22/F 10/F 29/F 39/F 53/F 39/F 62/F 33/M 25/M 55/M 18/F 41/M 35/M 55/F 44/F 28/M 53/F 50/M 37/F 34/M 44/F 44/M 39/M
L temporal L frontoparietal L parietal R frontal R frontal L frontopariotemporal L frontal L frontal R frontal L frontal L frontal R temporal L temporal L frontal L frontal L frontotemporal L frontal L temporal R parietal R frontal L frontal R frontal R frontal R frontal L frontal L frontal L parietal
0 28.3 * * 33.7 * * 48.4 * * * 0 21.7 * 12.3 * 0 12 * * 31.2 * * 38.8 * 9.8 *
L L
R/L
L/R
L/R L L/R L L
L
R L
No No Yes Yes No Yes No Yes Yes Yes No No No Yes No Yes No No Yes No No No Yes No No No No
Yes No No Yes No Yes No Yes No No No No No No No No No Yes No No No No No No No Yes No
32.3 45.0 9.5 0.6 22.2 * 2.7 4.5 2.1 11.2 0.9 68.1 0.8 37.6 9.8 102.3 113.7 6.5 13.0 56.7 7.5 80.5 25.2 18.8 94.5 198.7 40.2
Patients listed in chronological order of fMRI. *Not performed. Dom, dominant hemisphere; L, left; LAD, lesion-to-activation distance; LDPr, language deficits preoperative; MDPr, motor deficits preoperative; Nondom, non-dominant hemisphere; R, right.
the tumor. No significant relationship was found between LAD and postoperative neurological language deficits, P ¼ 0.50 (Table 2). No significant relationship was found between tumor volume and additional postoperative neurological motor or language deficits (Table 2). The patients (Tables 3 and 4) selected for surgeryassisted (solely by intraoperative neuronavigation) radical tumor removal after the preoperative fMRI had an overall mean LAD of 18.8 mm in contrast to the non-operated patients, who had a mean LAD of 6.9 mm (P ¼ 0.02, non-parametric Wilcoxon-MannWhitney test).
Discussion The present study indicates that the applied standardized method for distance measurement between tumor and preoperative fMRI was able to predict postoperative outcomes in terms of neurological motor deficits following intraoperative neuronavigation surgery. Although the method differs from those of other investigators, the LAD cutoff of 18 mm, beyond which no neurological motor deficits were observed in radically operated patients, aligns with the methods used in similar studies (13,16). Considering the preoperative assessments, a statistically significant relationship (P ¼ 0.03)
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
6
Acta Radiologica 0(0) Table 2. Neurological deficits versus fMRI distance and tumor volume. Neurological Neurological deficits/ fMRI distance deficits Odds ratio (1/mm) CI (1/mm) P (n/ntotal) Preoperative assessment Motor fMRI 10/26 Unilateral language fMRI 4/8 Postoperative assessment Motor fMRI 7/16 Unilateral language fMRI 3/6
Neurological deficits/ Tumor volume Odds ratio (1/cm3)
CI (1/cm3)
P
0.89 0.88
0.81;0.99 0.75;1.05
0.03 0.15
0.99 1.01
0.96;1.01 0.99;1.03
0.32 0.40
0.82 1.06
0.67;0.99 0.89;1.26
0.04 0.50
0.99 0.93
0.96;1.02 0.80;1.09
0.56 0.41
CI, 95% confidence interval; n, number of patients with neurological deficits in the group; ntotal, total number of patients in the group.
Table 3. Patients included for postoperative motor fMRI assessment.
Table 4. Patients included for postoperative language fMRI assessment.
Patient LAD (mm) Tumor no. motor MDPr nMDPo volume (cm3) Resection*
Language Tumor Lateralization volume Patient LAD (mm) Dom/ LDPr nLDPo (cm3) Resection* no. Language Nondom
2 3 4 5 7 8 11 13 17 18 19 20 21 22 23 25
15.3 6.4 27.9 18.1 14.3 12.1 27.9 54 30.4 24.6 3.6 6.6 25.7 35 21.2 61.4
No Yes Yes No No Yes No No No No Yes No No No Yes No
Yes No No Yes Yes Yes No No No No Yes Yes No No Yes No
45.0 9.5 0.6 22.2 2.7 4.5 0.9 0.8 113.7 6.5 13.0 56.7 7.5 80.5 25.2 94.5
C – – C C C C C C P C P C C P P
Patients listed in chronological order of fMRI. *C ¼ complete; P ¼ partial. L, left; LAD, lesion-to-activation distance; MDPr, motor deficits preoperative; nMDPo, new motor deficits postoperative; R, right.
was found between preoperative neurological motor deficits and LAD, indicating involvement of the motor cortex. These findings indicate the usefulness of the applied LAD measurement in terms of risk assessment prior to surgery close to the motor cortex. The applied method was not able to predict postoperative outcomes in terms of neurological language deficits, although preoperative neurological deficits tended to be associated with LAD (P ¼ 0.15). This finding could be attributed to the limited number of
2 5 8 13 17 18 21 26
28.3 33.7 48.4 21.7 0 12 31.2 9.8
L R/L L/R L L L L L
No No Yes No No Yes No Yes
No No No Yes No Yes Yes No
45.0 22.2 4.5 0.8 113.7 6.5 7.5 198.7
C C C C C P C P
Patients listed in chronological order of fMRI. *C ¼ complete; P ¼ partial. Dom, dominant hemisphere; L, left; LAD, lesion-to-activation distance; LDPr, language deficits preoperative; nLDPo, new language deficits postoperative; Non-dom, non-dominant hemisphere; R, right.
patients who underwent preoperative language fMRI and the fact that only six patients had unilateral language activation. Another reason could be the involvement of the white matter tracts between the Broca’s and Wernicke’s areas, which could also explain why both patient 13 (LAD for language ¼21.7 mm) and patient 21 (LAD for language ¼31.2 mm) experienced additional postoperative language deficits. The use of a LAD measurement based only on the fMRI activation has met with some criticism because the LAD is highly determined by the accuracy of fMRI localization and technical factors, such as the statistical threshold (12,20). It is true that the accuracy of fMRI localization is low, but note that the fMRI BOLD signal only serves as a pseudo measure for neural activity. The BOLD contrast originates from hemodynamic changes in the vasculature and is slightly offset toward
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
Ravn et al.
7
the venous compartment and, thus, does not precisely localize the electrically active neurons (12). However, it has been shown that there is a high reproducibility of the fMRI localization within the human motor and sensory cortex (21,22) when using methods without threshold adjustment (22) and when different methods of threshold adjustments of the fMRI map were used (21). Therefore, using fMRI for preoperative risk assessment seems feasible, as long as there is a good correlation between the preoperative fMRI LAD measurements and postoperative outcomes. To address criticism regarding the determination of the statistical threshold, the applied standardized method combines both the data from the fMRI and the morphological images of the T1 3D FSPGR sequence to set the statistical threshold used for the LAD measurement. The inter-observer coefficient of reproducibility was reported in a previous study to be 2.4 mm for the LAD (18). The inter-observer difference included both the differences in outlining of the high threshold fMRI activation and in outlining the tumor. The presented method for LAD measurement should only be applied in the preoperative risk assessment to determine whether to operate solely supported by a neuronavigation system. In this study, the cutoff value was 18 mm for the distance between the tumor and eloquent motor cortex (i.e. the distance that did not result in any postoperative transient or permanent neurological deficits in patients for whom the tumor was concluded to have been radically excised). Other distance measurement studies have differentiated between transient and permanent neurological deficits (13,16). These studies show that a distance between 0 and 10 mm (between the fMRI-activation and tumor) results in a greater risk of permanent neurological deficits. In the present study, for 10 of the 27 patients, the neurosurgeons choose not to operate solely by neuronavigation. These 10 patients had a mean LAD of 6.9 mm. This group, in which one would expect a high risk of permanent neurological deficits after neuronavigation assisted surgery, was actually recommended for another surgical approach. The assignment was based on the morphological MRIs, the clinical fMRIs (Fig. 1) and the clinical experiences of the neurosurgeons. This result indicates that the presented standardized and easy-to-use method for LAD measurement could serve as a more objective clinical management method. Together with the distance measurement, the clinical fMRI could assist neurosurgeons in assessing the feasibility of radical surgical resection in low-grade tumors. If radical surgical resection is believed to be feasible, three key stages could be proposed for surgical planning: (i) motor LAD 18 mm, an operation solely assisted by intraoperative neuronavigation, with minimal risk of postoperative
neurological deficits; (ii) motor LAD < 18 mm, an fMRI-guided operation assisted by IOM; and (iii) inconclusive motor fMRI, with an operation assisted solely by IOM. It is important to consider how one should present the distance measurement results. If the results are presented as a combination of Figs. 2 and 3, then there is a considerable risk of misinterpretation. As discussed earlier, the fMRI activity is only a pseudo measurement of neuronal activity. A combination of Figs. 2 and 3 could lead the surgeon to the conclusion that the high threshold fMRI activity in motor cortex would correspond to the exact same point if he/she had used IOM. However, the relationship between the presented method for distance measurement and IOM needs further investigation. Meanwhile, the distance measurement could be presented with the clinical fMRI images (Fig. 1). One limitation of this study is the small sample size, which can limit the generalization of the results. A larger patient cohort is needed in future research. Another limitation is the retrospective study design. Further prospective studies are needed to evaluate the value of this method for motor, language, and sensor areas. In conclusion, the presented easy-to-use approach for lesion-to-activation distance (LAD) measurement combines both anatomical landmarks and fMRI using clinically approved software, and it was able to predict the presence of preoperative neurological motor deficits, as well as the occurrence of additional postoperative neurological motor deficits, assisted by intraoperative neuronavigation. Acknowledgments This study was supported by CIRRO – the Lundbeck Foundation Center for Interventional Research in Radiation Oncology and the Danish Council for Strategic Research.
Conflict of interest None declared.
Ethical approval The study was approved as a retrospective study by the National Danish Board of Health (no. 7-604-04-2/220/ HKR) and the Danish Data Protection Agency (no. 200941-3464).
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Buckner JC, Brown PD, O’Neill BP, et al. Central nervous system tumors. Mayo Clin Proc 2007;82:1271–1286.
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
XML Template (2014) [11.12.2014–2:08pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ACRJ/Vol00000/140218/APPFile/SG-ACRJ140218.3d
(ACR)
[1–8] [PREPRINTER stage]
8
Acta Radiologica 0(0)
2. Weller M, Stupp R, Wick W. Epilepsy meets cancer: when, why, and what to do about it? Lancet Oncol 2012;13:375–382. 3. Wrensch M, Minn Y, Chew T, et al. Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro Oncol 2002;4:278–299. 4. Duffau H. Lessons from brain mapping in surgery for low-grade glioma: insights into associations between tumour and brain plasticity. Lancet Neurol 2005;4: 476–486. 5. Fadul C, Wood J, Thaler H, et al. Morbidity and mortality of craniotomy for excision of supratentorial gliomas. Neurology 1988;38:1374–1379. 6. Ojemann JG, Miller JW, Silbergeld DL. Preserved function in brain invaded by tumor. Neurosurgery 1996;39: 253–258. 7. Tronnier VM. Functional neuronavigation. In: Stippich C (ed.) Clinical Functional MRI – Presurgical Functional Neuroimaging. Stuttgart: Springer, 2007, pp.149–166. 8. Ogawa S, Tank DW, Menon R, et al. Intrinsic signal changes accompanying sensory stimulation: functional brain mapping with magnetic resonance imaging. Proc Natl Acad Sci U S A 1992;89:5951–5955. 9. Stippich C, Mohammed J, Kress B, et al. Robust localization and lateralization of human language function: an optimized clinical functional magnetic resonance imaging protocol. Neurosci Lett 2003;346:109–113. 10. Kwong KK, Belliveau JW, Chesler DA, et al. Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc Natl Acad Sci U S A 1992;89:5675–5679. 11. Bandettini PA, Wong EC, Hinks RS, et al. Time course EPI of human brain function during task activation. Magn Reson Med 1992;25:390–397. 12. Sunaert S. Presurgical planning for tumor resectioning. J Magn Reson Imaging 2006;23:887–905. 13. Krishnan R, Raabe A, Hattingen E, et al. Functional magnetic resonance imaging-integrated neuronavigation:
14.
15.
16.
17.
18.
19.
20.
21.
22.
correlation between lesion-to-motor cortex distance and outcome. Neurosurgery 2004;55:904–914. Duffau H. New concepts in surgery of WHO grade II gliomas: functional brain mapping, connectionism and plasticity–a review. J Neurooncol 2006;79:77–115. Stippich C, Rapps N, Dreyhaupt J, et al. Localizing and lateralizing language in patients with brain tumors: feasibility of routine preoperative functional MR imaging in 81 consecutive patients. Radiology 2007;243:828–836. Haberg A, Kvistad KA, Unsgard G, et al. Preoperative blood oxygen level-dependent functional magnetic resonance imaging in patients with primary brain tumors: clinical application and outcome. Neurosurgery 2004;54: 902–914. Blatow M, Reinhardt J, Riffel K, et al. Clinical functional MRI of sensorimotor cortex using passive motor and sensory stimulation at 3 Tesla. J Magn Reson Imaging 2011;34:429–437. Laustsen SR, Sorensen P, Frund T, et al. [Preoperative functional magnetic resonance imaging in patients with brain tumors]. Ugeskr Laeger 2010;172:2370–2376. Naidich TN, Yousry TA. Functional neuroanatomy. In: Stippich C (ed.) Clinical Functional MRI – Presurgical Functional Neuroimaging. Stuttgart: Springer, 2007, pp.53–85. Wengenroth M, Blatow M, Guenther J, et al. Diagnostic benefits of presurgical fMRI in patients with brain tumours in the primary sensorimotor cortex. Eur Radiol 2011;21:1517–1525. Vidyasagar R, Parkes LM. Reproducibility of functional MRI localization within the human somatosensory cortex. J Magn Reson Imaging 2011;34:1439–1444. Voyvodic JT, Petrella JR, Friedman AH. fMRI activation mapping as a percentage of local excitation: consistent presurgical motor maps without threshold adjustment. J Magn Reson Imaging 2009;29:751–759.
Downloaded from acr.sagepub.com at University of British Columbia Library on July 2, 2015
