Epilepsia, 52(12):2233–2238, 2011 doi: 10.1111/j.1528-1167.2011.03265.x
FULL-LENGTH ORIGINAL RESEARCH
MEG in frontal lobe epilepsies: Localization and postoperative outcome *yHermann Stefan, *zXintong Wu, xMichael Buchfelder, *Stefan Rampp, *Burkhard Kasper, *Ru¨diger Hopfenga¨rtner, {Friedhelm Schmitt, **Arnd Do¨rfler, yyIngmar Blu¨mcke, zDong Zhou, and xDaniel Weigel *Neurological Clinic, University Hospital Erlangen, Erlangen, Germany; yInterdisciplinary Epilepsy Center, Neurological Clinic, University Hospital Giessen and Marburg, Marburg, Germany; zDepartment of Neurology, West China Hospital, Sichuan University, Chengdu, China; xClinic of Neurosurgery, University Hospital Erlangen, Erlangen, Germany; {Neurological Clinic, University Hospital Magdeburg, Magdeburg, Germany; **Department of Neuroradiology, University Erlangen-Nuremberg, Erlangen, Germany; and yyInstitute of Neuropathology, University Erlangen-Nuremberg, Erlangen, Germany
SUMMARY Purpose: This study aimed to analyze magnetoencephalography (MEG) localizations of epileptic clusters in different cortical regions of the frontal lobe and relate these findings to postoperative outcomes associated with frontal lobe epilepsy (FLE). Methods: Thirty-nine patients from the Epilepsy Center of Erlangen-Nuremberg University with or without lesions on their magnetic resonance imaging (MRI) scans underwent MEG measurements and operation and were then analyzed retrospectively. MEG data were obtained using systems with either 74 or 248 channels. Single dipole analysis assuming a spherical head model was performed for localization. Key Findings: Epileptic clusters were detected by MEG in 30 patients, corresponding to a sensitivity of 76.9%; there was a sensitivity of 66.7% (20 of 30) in patients with monofocal activity (70% had an Engel class 1 outcome)
Because frontal lobe cortex represents 40% of the total cortex and rapid propagation of epileptic activity occurs in large networks, localizing epileptic clusters in the frontal lobe is difficult, even with invasive video–electroencephalography (EEG) monitoring. Therefore, in addition to EEG, magnetoencephalography (MEG) investigations may be useful for localizing the sources of focal epileptic activity. MEG localization of extratemporal lobe epileptic clusters was found to be favorable compared with EEG (Nakasato et al., 1994; Knowlton et al., 1997; Merlet et al., 1997; Shiraishi et al., 2001; Pataraia et al., 2002;
and 33.3% (10 of 30) in patients with multifocal activity (20% had an Engel class 1 outcome). Of the patients who had isolated clusters, the distance between the MEG localizations and the respective lesions was equal to or 3 cm in 10% (2 of 20) of patients (one of them had an Engel class 1 outcome). A statistical difference was found between the outcomes of patients with a single focus and with multiple foci (p < 0.05). Significance: Patients with a single focus had better postoperative outcomes compared with patients with multiple foci. MEG localizations close to the lesion marked the lesion or its surrounding network as epileptogenic. Therefore, source localization can provide important information for the presurgical evaluation of patients with FLE. KEY WORDS: Magnetoencephalography, Network, Surgery, Compartment.
Yoshinaga et al., 2002; Stefan et al., 2003; Barkley, 2004; Baumgartner, 2004; Park et al., 2004). One study found that MEG is superior to EEG in screening for frontal lobe epilepsy (FLE) (Ossenblok et al., 2007). In the present study, we aimed to analyze noninvasive MEG localization in different regions of frontal lobe cortex and relate these findings to postoperative outcomes. We hypothesize that MEG localizes clinically relevant epileptic networks in FLE.
Methods Accepted July 31, 2011; Early View publication September 20, 2011. Address correspondence to Hermann Stefan, Neurological Clinic, University Hospital Erlangen, Schwabachanlage 10, 91054 Erlangen, Germany. E-mail:
[email protected] Wiley Periodicals, Inc. ª 2011 International League Against Epilepsy
Patients Patients meeting the following criteria were recruited retrospectively from the Epilepsy Center of NurembergErlangen University Hospital: (1) patients had refractory FLE; (2) patients underwent MEG as one of the presur-
2233
2234 H. Stefan et al. gical evaluation techniques; and (3) patients subsequently underwent epileptic operations. Therefore, 39 patients were selected and analyzed. Magnetic resonance imaging (MRI) detected lesions in 34 patients, and 5 patients had no detectable lesion. The clinical characteristics of the pharmacoresistant patients are shown in Table 1. Postoperative follow-up was carried out from 6 months to 11 years (mean 4.1 € 3.3 years). MRI All recruited patients underwent high-resolution MRI at the Department of Neuroradiology at Erlangen University Hospital in Germany. The machines used were either the 3T Magnetom Trio or the 1.5 T Magnetom Sonata (both proTable 1. The clinical characteristics of all the patients No
ID
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17a 18 19 20 21 22 23 24 25 26 27 28 29a 30 31b 32a,b 33a,b 34b 35b 36b 37a,b 38b 39b
Ab.A M.C W.M K-S.D L.R W.O G.E G.J F.K S.S H.G Z.S T.E St.C S.M S.A P.R L.B K.B L.P G.A L.M S.K B.J H.S K.F J.M S.J Si.C W.J D.H G.U M.H M.A Au.A M.B K.A S.N W.H
Age Gender 27 45 42 33 38 30 44 15 30 23 64 32 60 39 30 44 37 43 30 43 29 45 43 32 34 47 40 43 39 42 51 54 44 45 37 40 43 29 67
M F M F M M F F M M M F F F M F F M M M F F F M M F M M M M M M M M M F F F M
OP-date 26.08.2008 14.10.2008 14.01.2010 25.06.2009 18.12.2007 10.07.2000 29.10.2001 07.02.2008 17.02.2000 19.04.2007 25.06.2007 17.02.2003 18.05.2000 10.04.1997 15.07.2004 20.02.1997 18.12.1995 19.07.1995 02.11.1995 21.07.1997 27.11.2006 22.05.1995 08.11.1994 12.07.2005 06.11.1991 08.08.1991 18.02.2002 18.12.1991 28.07.1994 29.09.1997 07.03.1994 17.11.1994 02.05.1994 30.11.1998 18.04.1996 04.02.2003 28.03.1991 19.08.1999 03.12.2001
OP-site Outcome Follow-up R L L R L L R L L L R L L L L R R R L R L L R L R L R L L R R L R R R L L L L
1a 1a 1a 1a 1a 1a 1c 1a 4a 1d 2b 2b 2b 2b 3a 1a 4b 1d 3a 3a 1b 1b 2b 3a 3a 1a 4a 1a 1a 3a 1a 2b 1a 1c 4b 4a 2d 1a 1a
6M 6M 6M 18 M 3Y 5Y 5Y 6M 5Y 6M 2Y 7Y 5Y 5Y 1Y 7Y 2Y 5Y 1Y 5Y 2Y 5Y 5Y 1Y 2Y 2Y 1Y 5Y 11 Y 1Y 11 Y 11 Y 11 Y 10 Y 5Y 1Y 3Y 5Y 5Y
M, male; F, female; OP, operation; L, left; R, right; Y, years; M, months. a With negative-MRI. b No clusters in MEG.
Epilepsia, 52(12):2233–2238, 2011 doi: 10.1111/j.1528-1167.2011.03265.x
duced by Siemens Medical Solutions, Erlangen, Germany) with 8- and 32-channel head array coils, respectively. MEG Spontaneous magnetic activity was recorded continuously for the purpose of focus assessment using a 74channel, two-sensor system (Magnes II; 4-D Neuroimaging, San Diego, CA, U.S.A.) in a magnetically shielded room (Vakuumschmelze, Hanau, Germany). Each MEG sensor consisted of 37 first-order gradiometers with a 5-cm baseline and an average distance between channels of 2.8 cm. Only one patient was measured using the whole-head magnetometer MEG system (Magnes WHS 3600; 4-D Neuroimaging). The patients usually lay down on their side between the sensor units. They sat upright or reclined halfway during recordings of activity from central and midline regions. Previous clinical findings were used to position the MEG sensors, and control areas were also covered. The recording duration depended on the amount of epileptic discharge; if no or few epileptic discharges were seen on the online display, each position was recorded for a total of 30 min. On average, MEG was recorded at two to four different sensor positions for 20–30 min each. The MEG signal was processed with an analog bandpass filter (1–120 Hz) and digitized with a sampling rate of 520.8 Hz. Afterward, MEG recordings were digitally bandpass filtered (3–70 Hz, notch filter 50 Hz). These settings were based on the in-house standard for clinical routine investigations. No forced antiepileptic drug (AED) withdrawal was performed. Epileptic spikes were identified visually during the inspection of the complete recording period. A minimum of five spikes was required for a localization result. Single dipole analysis assuming a spherical head model was performed using magnetic source imaging (MSI) software (4-D Neuroimaging). A single dipole solution was considered valid if it had a correlation coefficient of at least 0.97 and a confidence volume below 3 cm3. Since 2001, source localization by CURRY software (Version 4.6; Compumedics Neuroscan, El Paso, TX, U.S.A.) with three spherical shells or a boundary element method volume conductor has been available for EEG analysis, as well as for MEG crossvalidation. Dipoles calculated with MSI or CURRY were visualized on coregistered individual MRI data. After localization, the distance between MEG and MRI localizations was defined as the average length from the center of a cluster localized by MEG to the border zone of the epileptogenic lesion localized by MRI. A distance of equal to or 3 cm in 2 (10%) of 20 patients. Comparisons with postoperative outcomes showed that 13 (72.2%) of 18 patients with a distance of 3 cm) had a resective operation and then multiple subpial transections (MSTs), resulting in a postoperative outcome of Engel class IVb; case 29 had monofocal epileptic activity (£3 cm) detected by MEG and an Engel class Ia outcome. Among the 30 patients with MEG findings, 14 (46.7%) had MEG findings that influenced their intracranial EEG procedures; in four patients (cases 6, 12, 21, and 30), invasive EEG recording was not used because of the MEG results. In two patients, the positions of intraoperative electrocorticography (ECoG) electrodes were guided by the MEG localizations. In eight patients, invasive EEG was guided by MEG. Three patients (cases 11, 17, and 20) had both resective operations and MST. The remaining three patients had only palliative operations: two underwent MST (cases 16 and 22) and one (case 3) underwent corpus callosotomy. Fifteen of the 20 patients (75%) with monofocal activity had isolated localizations specifically in one of the FLE areas defined above (FB 20%, FL 20%, FP 10%, FM 10%, FPr 10%, and FC 5%), whereas 5 patients (25%) had MEGlocalized clusters that covered a large area in the frontal Table 2. The data of monofocal and multifocal localizations by MEG
Outcome (Engel classification) 1a 1b 1c 1d IIb IIIa IVa IVb Total
Monofocal (n = 20)
Multifocal (n = 10)
n (£3 cm)
%
n (>3 cm)
%
n
%
9 2 0 2 2 2 1 0 18
45 10 0 10 10 10 5 0 90
1 0 0 0 0 0 0 1 2
5 0 0 0 0 0 0 5 10
1 0 1 0 3 4 1 0 10
10 0 10 0 30 40 10 0 100
Epilepsia, 52(12):2233–2238, 2011 doi: 10.1111/j.1528-1167.2011.03265.x
2236 H. Stefan et al. Table 3. The histologic result and postoperative outcome in different localizations of FLE Monofocal (n = 20) Localization
Focal lesion (n = 15)
FB (4)
Scar Trauma FCD (Typ IIa) CM FCD (Typ IIb) Scar (2nd OP) Cyst (2nd OP) CM Unspecific changes DNET FCD (Typ IIb) DNET mMCD (Typ II) Ganglioglioma Scar (2nd OP)
FL (4)
FP (2) FM (2) FPr (2) FC (1)
Outcome 1a 1d 1d 1aa 1a 1a IVa IIIa 1a IIIa 1a 1ab IIb 1a 1b
Localization
Multifocal (n = 10) Large-areal lesion (n = 5)
FM + FPr FL + FPr FB + FP + FL FB + FL + FC
Cavernoma Cavernoma DNET FCD (Typ IIb) Scar (2nd OP)
Outcome
Lesion
Outcome
1a IVba,b 1b 1a IIb
Trauma Cavernoma CM Scar FCD (Typ I) Glioneural hamartoma Trauma Unspecific changes Ependymoma Inflammation
1a 1c IIb IIb IIIa IIb IIIa IIIa IVa IIIa
FB, frontal basal; FL, frontal lateral; FP, frontal polar; FM, frontal mesial; FPr, frontal precentral; FC, frontal central; DNET, dysembryoplastic neuroepithelial tumour; FCD, focal cortical dysplasia; mMCD, mild malformation of cortical development; CM, cortical malformation; FLE, frontal lobe epilepsy; OP, operation; 2nd, second; Typ, type. a Negative-MRI. b >3 cm.
lobe. The relationship between localizations in different parts of the frontal lobe and outcomes is shown in Table 3.
Discussion The epileptogenic area of FLE is often difficult to localize by means of noninvasive EEG or even invasive recordings. Improvements in noninvasive localization could allow for better counseling of patients before invasive recordings or surgery. This noninvasive information could optimize and reduce invasive implantations and provide additional information for predicting the postoperative outcome. Our study shows that MEG has remarkable sensitivity (76.9%) in the localization of epileptic focal activity in the frontal lobe. In this respect, our study confirms the previous results of Ossenblok et al. (2007), in which MEG was used for screening, but no comparison with postoperative outcomes was performed. MEG recordings not only yield remarkable sensitivity in localizing monofocal activity in FLE, but can also predict the postoperative outcome. We found that postoperative outcomes were better in patients with isolated, focal MEG localizations than in patients with multiple foci (p < 0.05). The involvement of extensive networks in multifocal frontal lobe epilepsies might affect decision making and performance during operations, as well as surgical outcomes. All patients except for two with single foci had MEG localizations close to the epileptogenic lesions. Concerning the resection volume and the completeness of the removal of epileptic tissue indicated by MEG and MRI, more studies with larger sample sizes should be conducted to verify the correspondence between these techniques in localizing epileptic activity, and their Epilepsia, 52(12):2233–2238, 2011 doi: 10.1111/j.1528-1167.2011.03265.x
ability to predict patient outcomes. As shown in Fig. 1, case 4 had a close spatial proximity between epileptic activity and the focal cortical dysplasia (FCD). The extent of resection was predominantly guided by the decision to perform an extended lesionectomy. This included the predominant interictal MEG localization surrounding the lesion. From animal and human research studies, the close proximity between focal epileptic activity and FCD or its surrounding tissue can be expected (Widjaja et al., 2009; Blumcke & Spreafico, 2011). Concerning etiology, five patients (cases 3, 4, 5, 18, and 29) with an Engel class I outcome and MEG localizations that were close to the respective lesions had cortical malformations revealed histologically. FCD may play a special role in patients with a favorable outcome due to monofocal activity (£3 cm). Some patients (cases 9, 12, 13, 20, and 30) having monofocal localizations with a distance of £3 cm had less favorable outcomes (Engel class II–IV). Two of these patients (cases 9 and 12) had a reoperation after a tumor or angioma excision. It has been shown that the outcome after a second epilepsy surgery can be unfavorable (Wyler et al., 1989; Siegel et al., 2004; Gonzalez-Martinez et al., 2007), especially if a tumor or angioma cannot be removed completely. In the other three cases (cases 13, 20, and 30), resective operations were limited to preserve the function of eloquent cortex. Incompletely resecting epileptogenic tissue may be one reason for unfavorable outcomes. Our results demonstrate that MEG is useful for delineating the relationship between structural abnormalities and the relevant epileptogenic network. Comparisons between MEG localizations and lesion types showed that the predominant epileptic activity localized by MEG may be
2237 MEG in Frontal Lobe Epilepsy Operation within the lesion, surrounding the whole lesion, or partly overlapping the lesion. Future research is necessary to decide whether resecting the complete lesion or parts of the lesion, including the MEG cluster, is preferable for seizure control. In patients without lesions detected by MRI, MEG can point to epileptogenic cortical areas where microscopic lesions are later found in the operated tissue through neuropathologic investigations, for example, in case 29. In this case, further preoperative or intraoperative invasive recordings were used to confirm the noninvasive MEG localizations. Unexpectedly, 70% of patients had monofocal localizations of epileptic activity in our study. Concepts of epileptic networks consider so-called ‘‘small world’’ connections in which certain neuronal clusters represent important connectivity points for the long-distance transmission of information (Watts & Strogatz, 1998). Especially active communicative clusters are called ‘‘hubs,’’ which may mediate local excessive excitation and rapid distribution in a global network of epileptic activities. Therefore, the source localizations in our patients may be interpreted as perilesional hubs, suggested by stable cluster localizations. In lesional FLE (e.g., low-grade glioma, cavernoma, trauma, FCD, and so on) with constant leading hubs within or close to the lesion, MEG localization can guide epilepsy surgery. The resection of tissue containing hubs may eliminate focal epileptic activity or disconnect net propagation from epileptogenic hubs. FLE may also be more or less focal, regional, or extended in both hemispheres, with a varying dominance of network excitation. Noninvasive source localization (e.g., MEG) improves the clinical localization of predominant epileptic networks in patients with FLE. Up to now there has been no definitive anatomic categorization of FLE. Previous studies discussed a subdivision of FLE into different compartments: precentral, premotor, and prefrontal cortex, as well as limbic and paralimbic areas (Bartolomei & Chauvel, 2000). However, this differentiation is not generally included in the current categorization of FLE. In our study, six anatomic compartments were subdivided based on MEG localizations. Fifteen patients had MEG localizations in different compartments (Table 3), and an Engel class I outcome was associated with localizations in the following compartments: FB (n = 4), FL (n = 2), FP (n = 1), FM (n = 2), FPr (n = 1), and FC (n = 1). Therefore, the Engel class I outcome was associated with localizations in each compartment. There were no significant differences in outcomes associated with localizations in the different compartments, possibly due to the small sample size. Further studies with a larger number of patients should investigate this issue. Future studies should also explore whether the localizations are due to the compartmental network organization or the location and nature of the lesions, as well as determine the connectivity of network compartments and the influence of surgery on connectivity.
Invasive video-EEG monitoring is required for preoperative evaluation in some intractable FLE cases (Chauvel et al., 1992). MEG has also been used to guide invasive EEG recording during procedures and operations, especially during preoperative or intraoperative invasive electrode placement, which may be helpful for detecting previously masked or subtle lesions (Stefan et al., 2003; Knowlton, 2008; Sutherling et al., 2008). In our retrospective study, four patients avoided invasive EEG recordings due to MEG findings, and the intracranial EEG procedures of 10 patients were influenced by the MEG findings. In addition, MEG may be able to provide important clinical contributions to the presurgical evaluation of pharmacoresistant FLE. In some cases, MEG can even replace invasive EEG, thereby preventing patient suffering from extraoperative damage and leading to satisfactory postsurgical outcomes.
Conclusion MEG localizations close to lesions marked the lesions or their surrounding networks as epileptogenic. Monofocal epileptic activity detected by MEG may be a predictor of favorable postoperative outcomes compared with multifocal activities in FLE. Source localization with MEG provides important information for the presurgical evaluation of FLE patients. Future approaches using connectivity analysis should be considered in multifocal FLE for the determination of epileptic networks.
Acknowledgments This study was supported by the Deutsche Forschungsgemeinschaft (DFG, STE-380/13-1) and the Erlangen ELAN-Programm (09.05.30.1). We would like to thank all colleagues who took part in this study. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Disclosure The authors have no conflicts of interest to disclose.
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