Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev

Original article

Advantageous information provided by magnetoencephalography for patients with neocortical epilepsy Tomoshiro Ito a, Hiroshi Otsubo b,⇑, Hideaki Shiraishi a, Kazuyori Yagyu a, Yumi Takahashi a, Yuki Ueda a, Fumiya Takeuchi c, Kayoko Takahashi d, Shingo Nakane d, Shinobu Kohsaka a, Shinji Saitoh a,e b

a Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan Division of Neurology, Department of Pediatrics, The Hospital for Sick Children and The University of Toronto, Toronto, Canada c Faculty of Health Sciences, Hokkaido University Graduate School of Medicine, Sapporo, Japan d Division of Magnetoencephalography, Hokkaido University Hospital, Sapporo, Japan e Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

Received 4 October 2013; received in revised form 4 April 2014; accepted 8 April 2014

Abstract Purpose: We evaluated whether magnetoencephalography (MEG), in addition to surgery, was valuable for the diagnosis and management of epileptic syndromes in patients with neocortical epilepsy (NE). Methods: We studied MEG in 73 patients (29 females; aged 1–26 years; mean 10.3 years) for the clinical diagnosis of epilepsy and for preoperative evaluation. MEG data were recorded by 204-channel whole head gradiometers with a 600 Hz sampling rate. MEG spike sources were localized on magnetic resonance images (MRI) using a single dipole model to project equivalent current dipoles. Results: MEG localized an epileptic focus with single clustered dipoles in 24 (33%) of 73 NE patients: 16 (25%) of 64 symptomatic localization-related epilepsy (SLRE) patients and eight (89%) of nine idiopathic localization-related epilepsy (ILRE) patients. MEG provided advantageous information in 12 (50%) of 24 patients with clustered dipoles and confirmed the diagnosis in the remaining 12 (50%). Furthermore, the use of MEG resulted in changes to surgical treatments in nine (38%) patients and in medical management in eight (33%). MEG confirmed the diagnosis in eight (16%) of 49 patients with scattered dipoles. MRI identified a single lesion (28 patients, 38%), multiple lesions (5, 7%), and no lesion (40, 55%). MRI provided confirming information in 19 of 28 patients with a single lesion and 18 of them required surgical resections. MRI did not provide any supportive information in 54 (74%) patients with a single (9), multiple (5) and no lesion (40). Conclusion: Our study shows that MEG provides fundamental information to aid the choice of diagnostic and therapeutic procedures including changes in medication in addition to surgical treatments for NE. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Diagnosis and treatment; Equivalent current dipole; Symptomatic localization-related epilepsy; Idiopathic localization-related epilepsy; Tertiary care

1. Introduction ⇑ Corresponding author. Address: 555 University Avenue, Toronto,

Ontario M5G 1X8, Canada. Tel.: +1 416 813 6660; fax: +1 416 813 6334. E-mail address: [email protected] (H. Otsubo).

Magnetoencephalography (MEG) is a neurophysiological examination procedure that uses a superconducting quantum interference device (SQUID). The use of MEG has the advantage that it can obtain information

http://dx.doi.org/10.1016/j.braindev.2014.04.006 0387-7604/Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Ito T et al. Advantageous information provided by magnetoencephalography for patients with neocortical epilepsy.. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.04.006

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about brain function and epileptic discharges with higher spatial and temporal resolution than electroencephalography (EEG) [1–4]. MEG is performed using a non-invasive diagnostic device to detect and localize the source of epileptic foci in epilepsy patients [1,3,4]. Typically, epilepsy and epileptic syndromes have been diagnosed using the correlations found by analyzing brain development, seizure history, semiology, electrophysiological and neuroimaging findings [5]. MRI provides absolute values for surgical treatments in patients with lesional epilepsy, whereas MEG localizes epileptogenic foci for lesional epilepsies to enable resection of both the epileptogenic zone and lesions [6]. Patients with non-lesional epilepsy require additional specific information to enable the appropriate choice of medications for idiopathic localization-related epilepsy. In addition, these patients require surgical options for generalized epilepsy in which localization-related epilepsy can be identified [7–9]. In this study, we evaluated the clinical relevance of MEG information in comparison to MRI in both making a diagnosis and the choice of treatments for NE patients.

the hospital as a result of their epilepsy that was intractable to antiepileptic medications. 2.2. MEG MEG was performed in a magnetically shielded room using a 204-channel whole-head gradiometer (Vector View System, Elekta Co. Ltd., Stockholm, Sweden) with a 600 Hz sampling rate. 2.3. MEG analysis We analyzed equivalent current dipoles (ECDs) using Xfit software (Neuromag Oy, Helsinki, Finland). The ECD with a highest (>70%) goodness of fit (GOF) was selected as the representative ECD of the MEG spike. The electrical current moment was calculated to validate significant ECDs. The ECDs with a moment of 80–700 nAm were superimposed onto the patients’ three-dimensional-MRI. 2.4. ECD cluster ECDs were classified as “clustered” if more than 70% were located in neighboring Brodmann’s areas. ECDs that did not cluster were classified as “scattered” (Fig. 1).

2. Methods 2.5. EEG 2.1. Patients This study included consecutive 73 patients (male:female, 44:29; age, 1–26 years; mean age, 10.3 years) who were diagnosed with NE at the Hokkaido University Hospital between July 2003 and December 2008. Hokkaido University Hospital is one of the tertiary care centers for epileptic patients in Hokkaido prefecture (population, 5.6 million). We selected and analyzed MEG and MRI data for patients who were referred to

EEG was simultaneously recorded using 20 scalp electrodes, placed according to the international 10–20 system. 2.6. Magnetic resonance imaging (MRI) High resolution MRI was performed using 1.5 Tesla (Magnetom VISION; Siemens AG, Erlangen, Germany) for both MEG analysis and diagnostic purposes.

Fig. 1. MEG spike dipoles. (A) Three-dimensional MRI shows ”clustered dipoles” with 80% of MEG spike dipoles accumulated in the two neighboring Brodmann’s areas. (B) Three-dimensional MRI shows “scattered dipoles” with 40% of MEG spike dipoles accumulated in the two neighboring Brodmann’s areas.

Please cite this article in press as: Ito T et al. Advantageous information provided by magnetoencephalography for patients with neocortical epilepsy.. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.04.006

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2.7. Diagnosis and treatment after MEG and MRI The information from MEG and MRI was categorized into three groups: “advantageous information”, which identified focal abnormalities that were not known before; “confirming information”, which validated previous diagnoses and treatments; and “non-supportive information”, which did not provide any valuable information regarding patients’ epilepsies and epileptic syndromes.

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patients. Seven out of eight patients with ILRE were diagnosed with atypical benign partial epilepsy (ABPE), which was initially defined by Aicardi and Chevrie in 1982 [10]. In the seven patients with ABPE, two were treated as benign partial epilepsy in childhood with centro-temporal spikes (BECCT) and five were suspected as ABPE but not treated appropriately prior to MEG analysis. The MEG showed clustered and randomly oriented dipoles around the Rolandic-sylvian regions, which was different from BECCT (Fig. 2). These seven patients

3. Results 3.1. MEG MEG showed clustered dipoles in 24 (33%) patients and scattered dipoles in 49 (67%) patients (Table 1). As a result of the MEG study, 64 patients were diagnosed with symptomatic localization-related epilepsy (SLRE) and nine patients with idiopathic localizationrelated epilepsy (ILRE). The 64 SLRE patients comprised 21 with frontal lobe epilepsy (FLE), four with parietal lobe epilepsy (PLE), one with lateral temporal lobe epilepsy (TLE), seven with occipital lobe epilepsy (OLE), and 31 with multilobe or suspected foci. In the 24 patients with clustered dipoles, 16 were diagnosed as SLRE and eight were diagnosed as ILRE. The clustered dipole group had 12 (50%) patients with advantageous information and 12 (50%) with confirming information. The MEG information resulted in five patients undergoing surgery, four patients becoming surgical candidates, and eight patients undergoing a change of medication. A total of five patients did not change treatment as a result of the advantageous information. MEG identified focal abnormalities that provided advantageous information for SLRE, which resulted in their on-going medications producing improved seizure control. MEG provided advantageous information in three ILRE patients, and confirming information in five ILRE

Fig. 2. MEG spike dipoles in a patient with atypical benign partial epilepsy (ABPE). Axial and sagittal MRIs show two clustered dipoles in bilateral Rolandic-sylvian regions. MEG spike dipoles are oriented parallel in the right hemisphere and slightly randomly in the left hemisphere. Note that the locations of MEG spike dipoles are lower than benign partial epilepsy in childhood with centro-temporal spikes (BECCT).

Table 1 MEG and MRI findings.

SLRE, symptomatic localization related epilepsy; ILRE, idiopathic localization-related epilepsy (# of patients who underwent surgery/# of patients who are candidate of surgery).

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achieved seizure control after their medications were altered to include additional ethosuximide for the treatment of ABPE. The one other patient with clustered dipoles and identically oriented dipoles, who was previously suspected as ABPE, had their treatment was changed to that of BECCT and had no subsequent seizures. The remaining one patient with ILRE showed scattered MEG dipoles. Although MEG did not support a diagnosis of ABPE, the patient was successfully treated for ABPE because of typical clinical and EEG features of ABPE. Eight patients out of the 49 patients with scattered dipoles and SLRE had confirming information. The scattered dipoles correlated with the location of seizure foci. Two patients underwent surgery and five patients were considered for surgical treatment. The remaining 41 patients with scattered dipoles consisted of 40 patients with SLRE and one patient with ILRE who did not receive any supportive information. Three patients with scattered dipoles underwent surgery because of epilepsy secondary to brain tumors in two patients and cortical dysplasia in one patient. 3.2. MRI MRI showed abnormal lesions in 33 (45%) patients, consisting of 28 (38%) with a single lesion and five (7%) with multiple lesions (Table 1). In 28 (38%) patients with a single lesion, 19 (26%) had confirming information for their SLRE from MRI of the lesion. Nine (12%) patients did not receive any supportive information from MRI abnormalities because the single lesion did not relate to the seizure focus. MRI provided a confirming diagnosis in 19 (26%) patients with the single lesion, and 18 received or were planned for surgical resections. Five patients with multiple MRI lesions and 40 without any MRI lesion did not receive any supportive information for their SLRE in 36 patients and ILRE in nine patients. Only one patient was considered for surgical treatment because of a concordance of other

neuroimaging studies using single photon emission topography (SPECT) and positron emission topography (PET). The eight patients with ILRE received alternative medications that were indicated by their MEG abnormalities. Ten patients with clustered dipoles were congruent with MRI findings and another 14 with clustered dipoles did not indicate any relationship with MRI results (Table 1). MRI did not provide any supportive information for eight SLRE patients with advantageous (5) or confirming (3) information from MEG. Eight patients were seizure free in Engel class1a. One patient was Engel class2b and the remaining one patient was Engel class3a [11]. 3.3. EEG Simultaneous EEG findings were analyzed in 70 patients and the other three patients had artifacts on their EEG that could not be adequately interpreted (Table 2). Fifty-five patients had epileptiform discharges, which consisted of 41 (56%) with focal spikes, five (7%) with unilateral spikes or spike and waves, and nine (12%) with bilateral spikes or spike and waves. Among the 46 patients with focal and unilateral epileptiform discharges, 12 of 41 SLRE patients with MEG clusters were surgically treated. None of the patients with bilateral EEG epileptiform discharges with SLRE were surgical candidates because of MEG scatters. EEG showed no spike in 15 SLRE patients. Two of the patients with MEG clusters underwent the resective surgery. The other two without supportive information by MEG scatters underwent the resective surgery by MRI lesion. 4. Discussion In previous reports, the purpose of MEG has focused on localizing the epileptogenic zone to aid with surgical treatments and seizure outcomes [4,6,12]. In this study, we reviewed the results of MEG for tertiary care management of patient diagnosis, medical treatment, and surgical workups. Our patients were diagnosed and

Table 2 MEG and EEG findings.

SLRE, symptomatic localization related epilepsy; ILRE, idiopathic localization-related epilepsy (# of patients who underwent surgery/# of patients who are candidate of surgery).

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treated by primary family physicians or in secondary local hospitals. After they became refractory to anti-epileptic medication, they were referred to the University Hospital for tertiary care. MEG and MRI have been used to make an appropriate diagnosis and for treatment selection to control their seizures. 4.1. Advantageous Information provided by MEG The patients with MEGs who showed clustered dipoles tended to receive surgical treatments as previously reported [3,6]. Eight patients with ILRE in the clustered group were seizure-free after their medications were changed as a result of the advantageous information provided by MEG. Advantageous information and confirming information were derived from all of the patients with clustered dipoles on MEG, comparing with eight out of 49 patients with scattered dipoles. MEG provided high spatial resolution for the localization of interictal spike discharges for patients with NE and especially those with an extra-temporal lobe epilepsy [1–4,13]. Therefore, presurgical evaluations should require MEG results so that intracranial EEG electrode placements and possible resection margins can be planned. A subset of patients with scattered dipoles relating to MRI lesions and seizure foci were identified who underwent surgery and were considered for surgical treatments as a result of the confirming information. The Commission on Classification and Terminology of the International League Against Epilepsy classified ILRE in 1989 [14]. BECCT is the major epileptic syndrome among ILRE patients. Because ILRE has no lesion on MRI, In fact, MRI does not produce advantageous information for ILRE because ILRE does not have a lesion identified by MRI. An exception to this observation occurs if the neocortical lesion mimics the symptoms of BECCT such as in patients with malignant Rolandic-sylvian epilepsy [6,15]. ABPE is a form of ILRE that presents with similar EEG findings and initial symptoms to BECCT. The medical management with additional ethosuximide and off carbamazepine is critical to control the multiple types of seizures that occur in these patients [7,16]. MEG provides similar locations and identical features with clustered dipoles around Rolandic-sylvian regions in patients with ABPE [8,17,18]. In addition, MEG can be employed for patients with intractable NE to determine the correct diagnosis and optimal treatment. 4.2. MRI for intractable NE MRI should be a mandatory procedure for the clinical evaluation of patients with epilepsy. Cortical dysplasia have been reported most epileptogenic lesions to delineate the subtle MRI findings using various paradigms [19]. The presence of a discrete single lesion on

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MRI with the epileptic focus is the best scenario for epilepsy surgery if the MRI studies are normal but without any supporting information. Multiple lesions are more complicated for NE than non-lesion MRI because it becomes difficult to localize the single seizure focus that relates to the SLRE. A single lesion does not often appear in the expected epileptic region. Patients with multiple lesions and an uncorrelated single lesion require the use of the MEG procedure to provide advantageous information that will identify the relationship between the MRI lesion and epileptic focus. Unless the MRI identifies the optimal epileptogenic lesion that is relevant to their SLRE then the patient’s physician will need the supplemental information provided by MEG, further investigations using a repeat MRI, or another neuroimaging studies such as SPECT and PET [20,21]. In conclusion, MEG provides fundamental information for the diagnosis of patients with intractable NE. It also provides additional information to enable the choice of appropriate therapeutic procedures and the application of surgery, especially for SLRE patients. MEG provides advantageous information in the diagnosis of epileptic syndromes and guides the appropriate therapeutic procedure at tertiary care hospitals for epilepsy patients. A future prospective multicenter collaborative study will investigate the advantageous information provided by MEG for the diagnosis and choice of therapeutic procedures in epileptic patients. Acknowledgments We thank Prof. Tadashi Ariga of the Department of Pediatrics, Hokkaido University Graduate School of Medicine, for his valuable editorial opinion. References [1] Nakasato N, Levesque MF, Barth DS, Baumgartner C, Rogers RL, Sutherling WW. Comparisons of MEG, EEG and ECoG source localization in neocortical partial epilepsy in humans. Electroencephalogr Clin Neurophysiol 1994;91:171–8. [2] Oishi M, Kameyama S, Masuda H, Tohyama J, Kanazawa O, Sasagawa M, et al. Single and multiple clusters of magnetoencephalographic dipoles in neocortical epilepsy: significance in characterizing the epileptogenic zone. Epilepsia 2006;47:355–64. [3] Shibasaki H, Ikeda A, Nagamine T. Use of magnetoencephalography in the presurgical evaluation of epilepsy patients. Clin Neurophysiol 2007;118:1438–48. [4] Shiraishi H. Source localization in magnetoencephalography to identify epileptogenic foci. Brain Dev 2011;33:276–81. [5] Carney P, Prowse MA, Scheffer IE. Epilepsy syndromes in children. Aust Fam Physician 2005;34:1009–15. [6] Otsubo H, Ochi A, Elliott I, Chuang SH, Rutka JT, Jay V, et al. MEG predicts epileptic zone in lesional extrahippocampal epilepsy: 12 pediatric surgery cases. Epilepsia 2001;42:1523–30. [7] Fujii A, Oguni H, Hirano Y, Osawa M. Atypical benign partial epilepsy: recognition can prevent pseudocatastrophe. Pediatr Neurol 2010;43:411–9.

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Advantageous information provided by magnetoencephalography for patients with neocortical epilepsy.

We evaluated whether magnetoencephalography (MEG), in addition to surgery, was valuable for the diagnosis and management of epileptic syndromes in pat...
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