Look back to leap forward: The emerging new role of magnetoencephalography (MEG) in nonlesional epilepsy

Accepted Manuscript Look Back To Leap Forward: The Emerging New Role of Magnetoencephalography(MEG) In Nonlesional Epilepsy Anto Bagić PII: DOI: Reference:

S1388-2457(15)00539-8 http://dx.doi.org/10.1016/j.clinph.2015.05.009 CLINPH 2007486

To appear in:

Clinical Neurophysiology

Accepted Date:

8 May 2015

Please cite this article as: Bagić, A., Look Back To Leap Forward: The Emerging New Role of Magnetoencephalography(MEG) In Nonlesional Epilepsy, Clinical Neurophysiology (2015), doi: http://dx.doi.org/ 10.1016/j.clinph.2015.05.009

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Look Back To Leap Forward: The Emerging New Role of Magnetoencephalography (MEG) In Nonlesional Epilepsy

Anto Bagić, MD, PhD

University of Pittsburgh Comprehensive Epilepsy Center (UPCEC) UPMC MEG Epilepsy Program Department of Neurology University of Pittsburgh Medical School Suite 811, Kaufmann Medical Building 3471 Fifth Ave, Pittsburgh, PA 15213, USA Tel.: +1-412-692-4603 Fax: +1-412-692-4636 E-mail: [email protected]

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Highlights •

MEG in the form of magnetic source imaging (MSI) can increase the diagnostic yield of MRIs.

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MSI-guided re-review of supposedly negative MRIs may reveal significant pathology including focal cortical dysplasia (FCD).

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Clinical magnetoencephalographers (“MEG practitioners”) and the referring epilepsy teams (“MEG users”) should change their evaluation protocols accordingly.

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Abstract This review considers accumulating evidence for a new role of MEG/MSI in increasing the diagnostic yield of supposedly negative MRIs, and suggests changes in the use of MEG/MSI in presurgical epilepsy evaluations. Specific alterations in practice protocols for both the MEG practitioner (i.e. physician magnetoencephalographer) and MEG user (i.e. referring physician) are proposed that should further enhance the overall value of MEG/MSI. Although changes in MEG analysis methods will likely become assisted by computers, interpretive competency and prudent clinical judgment remain irreplaceable.

Keywords: Diagnostic yield; MSI-guided MRI review; focal cortical dysplasia (FCD); Magnetic Source Imaging (MSI); MEG practitioner; MEG user; negative MRI; epilepsy surgery.

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Introduction Resective epilepsy surgery (Wiebe et al, 2001; Engel et al, 2003a; Engel et al, 2012) is the best therapeutic option (and the only potential cure) for many persons with pharmacoresistant focal epilepsy (Engel, 2008; Haneef et al, 2010; Wiebe and Jetté, 2012; Englot et al, 2012). Resultant seizure freedom or even “worthwhile improvement” (Engel, 1993) leads to meaningful improvements in the quality of life (Fiest et al, 2014). However, even among the small minority of potential surgical candidates who do get referred for presurgical evaluation (Engel, 2003), up to 25% of those evaluated invasively ultimately do not have a resection (National Association of Epilepsy Centers, 2012 self-reported data). Furthermore, surgical outcomes vary considerably (Najm et al, 2013), and are least favorable in patients with nonlesional extratemporal epilepsy (NLETE) (Noe et al, 2013; Schneider et al, 2013). In fact, in this most challenging group, only 11% of those initially evaluated for surgery may have ultimately an operation with “an excellent” long-term outcome (Noe et al, 2013). More resections in all evaluated (non-invasively and invasively) and better overall outcomes require a more successful identification and accurate delineation of epileptogenic zones (Rosenow and Lueders, 2001; Najm et al, 2013). This necessitates further improvements in presurgical evaluations (So and Lee, 2014), particularly in truly MRI-negative cases, as illustrated in Figure 1. One of the more recent attempts to improve surgical outcomes in MRI-negative epilepsy includes the sophisticated diagnostics of single photon emission tomography (SPECT) (Sulc et al., 2014). However, “improved statistical parametric SPECT mapping of the ictogenic zone” was not associated with better surgical outcomes in this group (Sulc et al., 2014; Henry, 2014). Previous attempts with MR spectroscopy (Suhi et al, 2002), EEG-fMRI (Moeller et al, 2009) or even 7T MRI (Pan et al, 2013) mostly added to the understanding of the problem, but not 4

necessarily to its practical alleviation. In practice, focal cortical dysplasia (FCD) (Taylor et al, 1971; Blumcke et al, 2011) is the most frequently identified pathology (Mathern et al, 1999; Wellmer et al, 2010; Rowland et al, 2012) in operated patients from this challenging group. FCDs (Taylor et al, 1971) are very epileptogenic (Battaglia et al, 2013) abnormalities of cortical development (Hauptman and Mathern, 2012) that have been recently classified systematically (Blumcke et al., 2011). Yet, their identification on MRI remains a big challenge. Over 80% of small FCDs may be missed “at the bottom of a deep sulcus” in routine MRI review (Beson et al, 2008), and even 30% of pathologically confirmed FCDs are not identified on dedicated high resolution MRIs reviewed by experienced neuroradiologists (Wang et al, 2014). While PET and SPECT are generally useful to various degrees (So and Le, 2014), they also have considerable limitations (Hauptman and Mathern, 2012). The magnitude of the problem becomes even bigger knowing that the completeness of FCD resection is the key predictor of surgical outcome (Krsek et al, 2009; Rowland et al, 2012). Thus, a great need exists for additional, preferably noninvasive means of identifying and delineating FCD lesions and related zones of resection as a prerequisite for improving surgical outcomes in NLETE. MEG vs. Magnetic Source Imaging (MSI) MEG is a neurophysiologic technique that has been clinically established as a useful tool in localizing epileptic foci in patients with seizure disorders (Bagic et al, 2009; Knowlton et al, 2008; Stefan et al, 2011; Schneider et al, 2012, 2013) and eloquent cortex in those with nearby operable brain lesions (Papanicolaou et al, 1999; Bowyer et al, 2004; Castillo et al, 2004; Papanicolaou et al, 2014). In fact, MEG is of particular value in NLETE (Jung et al, 2013) and

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various other complicated clinical scenarios (Kamimura et al, 2006; Knowlton et al, 2008; Wu et al, 2006; Mohamed et al, 2013; Schneider et al, 2013). An EEG-like display of the several hundred channels typical of MEG systems is impractical and nearly impossible to interpret. MEG is almost always analyzed in the form of MSI, where source estimates (dipoles) are co-registered with the patient’s MRI (Williamson et al, 1991). Thus, strictly speaking, MSI is a specific type of MEG application and not necessarily its synonym (Wheless et al, 2004). Irrespective of varying personal preferences, and the currently prevailing interchangeable use of these two terms, the distinction between them is likely to become the standard, particularly as other MEG applications are being investigated, such as connectivity analysis (Burgess, 2011; van Dellen et al, 2014), source volume estimation (Bouet et al, 2012), high-frequency oscillations (Jacobs et al, 2012; Wang et al, 2013b); distributed source analysis (Tanaka and Stufflebeam, 2014), and neuromagnetic coherence of epileptic activity (Wu et al, 2014), etc. MEG Practitioners vs. MEG users For the purpose of this discussion, the clinical MEG practice pertains to the ways and means used by physicians magnetoencephalographers (i.e “MEG practitioners”) to acquire, analyze and report clinical MEG epilepsy studies, and the clinical MEG use to the ways and means implemented by the ordering epilepsy teams (i.e. “MEG users”) to inform their clinical decisions based on MEG results in presurgical evaluation of patients. Exploring the Epileptogenicity of FCD and its Clinical Significance with MSI Intrinsic epileptogenicity of human dysplastic cortex was directly demonstrated by EEG and confirmed by surgical results almost 20 years ago (Palmini et al, 1995; Table 1). The first 6

MSI confirmation of FCD epileptogenicity was reported by Morioka et al (1999; Table 1), who studied 4 patients with FCD using MEG and electrocorticography (ECoG). Three of the four had a positive outcome from resective surgery. The authors confirmed that most MEG dipoles colocalized with FCD lesions, while a minority of them localized to surrounding cortex. They also confirmed the epileptogenicity of underlying white matter, where abnormal giant neurons and balloon cells were identified. Resection of this white matter was found to be important for a positive outcome. Bast et al (2004; Table 1) combined MSI and electric source imaging (ESI) of single and averaged interictal spikes to demonstrate noninvasively the intrinsic epileptogenicity of FCD in all 9 children with epilepsy that he studied. Consistent and similar co-localization of over 90% of MEG and EEG spike dipoles within the FCD lesions confirmed their epileptogenic nature. Surgery was successful only in 3 patients whose resected area included the irritative zone outlined by averaged MEG and EEG spikes, thus confirming its clinical significance. Recently, Itabashi and colleagues (Itabashi et al., 2014; Table 1) identified dipole-modelable MEG and EEG spikes in simultaneous recordings in 5 of 6 patients. These congruent findings (Bast et al., 2004; Itabashi et al., 2014) indicate that both MSI and ESI may be comparably useful for this purpose. This suggests that ESI may be a convenient alternative where MEG is not available. However, better designed and larger studies are needed to determine under what circumstances a single one modality may be sufficient, as the combination is considered to be the most informative overall (Ebersole and Ebersole, 2010). In the first study that attempted to characterize MEG spike sources in relation to CD subgroups, Widjaja et al (2008; Table 1) studied 27 children with CD and showed that MEG interictal spikes were present in almost all participants (96%; 26/27). Clustered MEG sources 7

were more prevalent in type II CD, while clustered and scattered sources were more frequently seen in other CDs. Despite differing MEG and MRI features between the two CD groups, complete removal of areas containing clustered MEG spike sources and MR lesions led to comparable surgical outcome: 71% and 73% Engel class I in other and type II CD, respectively (Widjaja et al. 2008). This association of MSI findings with surgical outcomes in patients with FCD (Morioka et al, 1999; Bast et al, 2004; Widjaja et al, 2008; Itabashi et al, 2014; Table 1) were confirmed recently in the largest (N = 34) MEG study of epilepsy patients with FCD who had surgery (Wilenius et al, 2013; Table 1). In this study, interictal MEG spikes were captured in almost all participants (33/34), and a good concordance between MEG and the invasive localizations was present in almost 70% (9/13) of those with negative MRI. Significantly more (p = 0.02) areas containing clustered MEG sources were removed in those with Engel class I or II (49%) outcomes as opposed to those with Engel class III or IV (5.5%) outcomes. This study provided increased evidence for the usefulness of MEG in disclosing possible FCDs despite a negative MRI, in planning a resection, and in even prognosticating outcomes. Exploiting the Epileptogenicity of FCD through MSI-Guided a Posteriori MRI Review The demonstrated association between MSI findings and what would ultimately be confirmed to be FCDs provided a rationale for using MSI to search for FCDs in patient with negative MRIs. The first published attempt of this type was done by Moore and colleagues (Moore et al., 2002; Table 1). In their series of 20 epilepsy patients, they demonstrated that MEG-guided a posteriori re-review of routine MR images previously deemed “negative”

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revealed abnormalities in 20% (4/20) of them. The same group (Funke et al, 2011) reported a larger series of patients with frontal lobe epilepsy where previously unidentified lesions were found on MEG-guided re-review of their MRI (7 out of 29, ~25%). Later, Itabashi and colleagues (Itabashi et al., 2014) used MSI to identify FCDs in 6 of 6 patients with homogeneous seizure semiology. While different in many respects (Table 1), all three above reports indicate that a focus of MSI abnormalities can successfully guide a re-review of MRIs thought to be normal and find new lesions in least 20% (Moore et al, 2002). Using a high-spatial-resolution MRI (Funke et al, 2011) for the restudy with appropriate interactive expert review (Itabashi et al, 2014) is likely to increase the yield further. Epilepsy protocol MRIs have advanced over the years (e.g. Craven et al., 2013; Pan et al., 2013; Wellmer et al., 2013; Winston et al., 2013) since the initial study (Moore et al, 2002). However, the problem now may often be an overabundance of detail and structural subtleties with unknown clinical significance. MSI may be one way to determine what is and is not of importance. A promising extension of this concept, combining MSI with morphometric MRI analysis, was published only recently (Wang et al, 2014). This study elegantly indicated how computational methods may increase the yield from supposedly negative MRIs. Here then is a possible new direction for a better integrated MEG/MSI. Additional promising computational approaches include high resolution magnetic resonance spectroscopic imaging (Pan et al, 2012; Pan et al, 2013) and other advanced imaging methods (Chan et al, 2014). Although the above studies vary in size, epilepsy populations and even methodology, with none being prospective, the message is clear that there is an inherent synergism between diagnostic functional measures (MEG, EEG) and structural measures (e.g. MRI) that is not 9

currently being exploited sufficiently. Accordingly, a change in routine clinical practice seems warranted. MSI-guided re-review of MRIs will positively affect clinical outcomes, will not increase cost significantly, and will help most the challenging population of patients NLETE. Current Prevailing Clinical Practice and Use of MEG in Epilepsy The variability in routine clinical MEG practice in the USA has been reported (Bagic, 2011). Epileptologists or clinical neurophysiologists displayed the most favorable attitude towards its standardization (Bagic, 2011). Most of the routine clinical MEG reports did not include specific practical recommendations beyond rare suggestions to repeat a study with sleep deprivation and/or antiepileptic drug manipulations if it was negative. Furthermore, there were proponents of purely “technical reporting” of MSI without involvement of an appropriately trained physician magnetoencephalographer (Bagic, 2011; Bagic A, unpublished data). The fundamental initial progress on addressing this variability in clinical MEG practice was made by the publication expertly crafted by the ACMEGS (American Clinical MEG Society) clinical practice guidelines (CPG) (Bagic et al, 2011a, Burgess et al, 2011a; Bagic et al, 2011b; Bagic et al, 2011c). But, promulgation of CPGs has to be followed by their sustained implementation and validation in practice (Burgess et al, 2011b). Here, a wider international scrutiny of these American Clinical Neurophysiology Society endorsed CPGs under the flagship of the International Clinical Neurophysiology Society (ICNS) and/or other professional organizations would be greatly helpful. When it comes to clinical use of MEG/MSI in epileptology, according to an informal direct communication with the leading USA epilepsy centers, and author’s referring physicians, it is routinely taken into consideration during a multidisciplinary epilepsy patient management conference (MEPMC) in the context of patients other tests (MRI, V-EEG, PET, and SPECT). 10

Excluding a small minority of epilepsy centers that have a MEG in their institution and appropriately trained physician magnetoencephalographers within their teams, routine consideration of “dots on MRI” (as some referring physicians still call MSIs) usually involves visual attempts to assess the congruence of the “MEG cluster” with the patient’s “neurophysiology” (i.e. EEG, V-EEG) and already independently interpreted imaging (MRI, PET, SPECT). This is usually done in an analogous fashion as a “quick look” at a SPECT or PET. It is a reasonable assumption that such a consideration may be misleading as it is dominated by the impressions of “a size and tightness of cluster” (Jeong et al., 2012; Vadera et al, 2013) that are considerably influenced by the type of display used (e.g. paper printed images vs. standard computer screen display of DICOM images). Importantly, this approach does not give proper attention to a dipole orientation that contains clinically relevant information (Ebersole and Ebersole, 2010). If dipole cluster(s) is(are) perceived as co-localized with previously identified lesion(s) on MRI, and/or other “positive” findings, this is taken as a reassuring convergence of diagnostic evidence and the treatment planning process proceeds. But, these cases are not the focus of this discussion, as the biggest challenge is faced when an MRI is reported as “normal”, “unremarkable”, “showing no cause of epilepsy” or is truly negative (Figure 1). In these situations, if a neuroradiologist is present at the conference, additional attention is dedicated to “that MEG area” on a patient’s MRI. However, even some large USA centers indicated informally that the presence of a neuroradiologist at their MEPMC is “variable”, and many others emphasized that “time is limited”. Going beyond this has been mainly a clinical research exercise (e.g. Sutherling et al., 2008; Knowlton et al., 2008a, 2008b, 2009).

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The evidence is growing for changing the above suboptimal practice based on the converging results about the additional usefulness of MEG/MSI (Morioka et al, 1999; Moore et al, 2002; Widjaja et al, 2008; Funke et al, 2011; Wang et al., 2014). Changing the Current Practice and Use of MEG in Epilepsy A certain degree of variability in clinical practice is likely inevitable in technologically demanding fields such as MEG where resources and staffing differ among centers (Bagic, 2011). However, prudent clinicians should use every opportunity to improve their own practice based on the best available evidence. As discussed above, one such opportunity for improvement in clinical MEG will likely involve the evaluation of patients with NLETE (Noe et al, 2013; Jung et al, 2013; Schneider et al, 2013). I recommend that physician magnetoencephalographers begin making specific comments in their reports regarding the significance of a cluster of MEG dipoles in guiding a re-review of negative MRIs. On the user end, MSI-guided re-review of MRI (Funke et al, 2011; Wilenius et al, 2013; Itabashi et al, 2014) should become a routine part of clinical practice in epilepsy centers that use MEG in the presurgical evaluation of patients. This is particularly true in cases with clustered MSI sources (Jeong et al, 2012; Wilenius et al, 2013; Wang et al, 2014). Sufficient advanced planning should allow enough time for an additional and preferably interactive MRI review by a neuroradiologist and epileptologist and/or additional image acquisition, if warranted. These recommended changes in practice will immediately improve the care for the most challenging population of patients by better identification of surgical candidates and improved planning of optimal diagnostic and therapeutic steps.

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Conflict of Interest Statement Anto Bagić is the Immediate Past President of the American Clinical MEG Society (ACMEGS) which receives an unrestricted educational grant from Elekta Neuromag Oy (Helsinki, Finland), the member of the Magnetoencephalography International Consortium for Alzheimer’s Disease (MAGIC-AD) that was initially supported by Elekta Neuromag Oy (Helsinki, Finland), and anticipated member of Elekta Clinical Advisory Group. He received no financial compensation for nay of these activities. His other research unassociated with MEG and the subject of this manuscript includes the NIH multicenter studies (ROSE and MONEAD), one industry-sponsored multicenter study (Cyberonics) and one investigator-initiated EEG study (Persyst).

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References Ansari SF, Maher CO, Tubbs RS, Terry CL, Cohen-Gadol AA. Surgery for extratemporal nonlesional epilepsy in children: a meta-analysis. Childs Nerv Syst 2010a;26:945-51. Ansari SF, Tubbs RS, Terry CL, Cohen-Gadol AA. Surgery for extratemporal nonlesional epilepsy in adults: an outcome meta-analysis. Acta Neurochir (Wien) 2010b;152:1299-305. Bagic A, Funke ME, Ebersole J; ACMEGS Position Statement Committee. American Clinical MEG Society (ACMEGS) position statement: the value of magnetoencephalography (MEG)/magnetic source imaging (MSI) in noninvasive presurgical evaluation of patients with medically intractable localization-related epilepsy. J Clin Neurophysiol 2009;26:290-3. Bagić AI. Disparities in clinical magnetoencephalography practice in the United States: a surveybased appraisal. J Clin Neurophysiol 2011;28:341-7. Bagić AI, Knowlton RC, Rose DF, Ebersole JS; ACMEGS Clinical Practice Guideline (CPG) Committee. American Clinical Magnetoencephalography Society Clinical Practice Guideline 1: Recording and analysis of spontaneous cerebral activity. J Clin Neurophysiol 2011;28:348-54. Bagić AI, Knowlton RC, Rose DF, Ebersole JS; for the ACMEGS Clinical Practice Guideline (CPG) Committee. American Clinical Magnetoencephalography Society Clinical Practice Guideline 3: MEG-EEG Reporting. J Clin Neurophysiol 2011;28:362-363. Bagić AI, Barkley GL, Rose DF, Ebersole JS; for the ACMEGS Clinical Practice Guideline Committee. American Clinical Magnetoencephalography Society Clinical Practice Guideline 4: Qualifications of MEG-EEG Personnel. J Clin Neurophysiol 2011;28:364-365. Bagić A. An ignored lighthouse: is there underappreciation and underutilization of electromagnetic source imaging? Clin Neurophysiol 2014;125:2322-3. Bagić A, Ebersole JS. Does MEG/MSI Dipole Variability Mean Unreliability? Clin Neurophysiol 2015;126:209-11. Barkley GL. Controversies in neurophysiology. MEG is superior to EEG in localization of interictal epileptiform activity: Pro. Clin Neurophysiol 2004;115:1001-9. Bast T, Oezkan O, Rona S, Stippich C, Seitz A, Rupp A, et al. EEG and MEG source analysis of single and averaged interictal spikes reveals intrinsic epileptogenicity in focal cortical dysplasia. Epilepsia 2004;45:621-31. Battaglia G, Colciaghi F, Finardi A, Nobili P. Intrinsic epileptogenicity of dysplastic cortex: converging data from experimental models and human patients. Epilepsia 2013;54 Suppl 6:33-6. Baumgartner C. Controversies in clinical neurophysiology. MEG is superior to EEG in the localization of interictal epileptiform activity: Con. Clin Neurophysiol 2004;115:1010-20. 15

Baumgartner C, Pirker S. Presurgical evaluation in adults: noninvasive. Handb Clin Neurol 2012;108:841-66. Besson P, Andermann F, Dubeau F, Bernasconi A. Small focal cortical dysplasia lesions are located at the bottom of a deep sulcus. Brain 2008;131:3246-55. Bien CG, Szinay M, Wagner J, Clusmann H, Becker AJ, Urbach H. Characteristics and surgical outcomes of patients with refractory magnetic resonance imaging-negative epilepsies. Arch Neurol 2009;66:1491-9. Blenkmann A, Seifer G, Princich JP, Consalvo D, Kochen S, Muravchik C. Association between equivalent current dipole source localization and focal cortical dysplasia in epilepsy patients. Epilepsy Res 2012;98:223-31. Blumcke I, Thom M, Aronica E, Armstrong DD, Vinters HV, Palmini A, et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011;52:158–174. Bouet R, Jung J, Delpuech C, Ryvlin P, Isnard J, Guenot M, et al. Towards source volume estimation of interictal spikes in focal epilepsy using magnetoencephalography. Neuroimage 2012;59:3955-66. Bowyer SM, Moran JE, Mason KM, Constantinou JE, Smith BJ, Barkley GL, et al. MEG localization of language-specific cortex utilizing MR-FOCUSS. Neurology 2004;62:2247-55. Burgess RC, Funke ME, Bowyer SM, Lewine JD, Kirsch HE, Bagić AI; ACMEGS Clinical Practice Guideline (CPG) Committee,. American Clinical Magnetoencephalography Society Clinical Practice Guideline 2: Presurgical functional brain mapping using magnetic evoked fields. J Clin Neurophysiol 2011a;28:355-61. Burgess RC, Barkley GL, Bagić AI. Turning a new page in clinical magnetoencephalography: practicing according to the first clinical practice guidelines. J Clin Neurophysiol 2011b;28:33640. Burgess RC. Evaluation of brain connectivity: the role of magnetoencephalography. Epilepsia. 2011;52 Suppl 4:28-31. Castillo EM, Simos PG, Wheless JW, Baumgartner JE, Breier JI, Billingsley RL, et al. Integrating sensory and motor mapping in a comprehensive MEG protocol: clinical validity and replicability. Neuroimage 2004;21:973-83. Chan HW, Pressler R, Uff C, Gunny R, St Piers K, Cross H, et al. A novel technique of detecting MRI-negative lesion in focal symptomatic epilepsy: Intraoperative ShearWave Elastography. Epilepsia. 2014 Mar 1. doi: 10.1111/epi.12562. [Epub ahead of print] PubMed PMID: 24588306.

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Craven IJ, Griffiths PD, Bhattacharyya D, Grunewald RA, Hodgson T, Connolly DJ, et al. 3.0 T MRI of 2000 consecutive patients with localisation-related epilepsy. Br J Radiol 2012;85:123642. Ebersole JS. New applications of EEG/MEG in epilepsy evaluation. Epilepsy Res Suppl 1996;11:227-37. Ebersole JS. Non-invasive pre-surgical evaluation with EEG/MEG source analysis. Electroencephalogr Clin Neurophysiol Suppl 1999;50:167-74. Ebersole JS, Ebersole SM. Combining MEG and EEG source modeling in epilepsy evaluations. J Clin Neurophysiol 2010;27:360-71. Engel J, Cascino GD, Ness PCV, Rasmussen TB, Ojemann LM. Outcome with respect to epileptic seizures. In: Engel J, editor. Surgical treatment of the epilepsies. NY: Raven Press; 1993. Engel J Jr, Wiebe S, French J, Sperling M, Williamson P, Spencer D, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Epilepsia 2003a;44:741-51. Engel J Jr, Wiebe S, French J, Sperling M, Williamson P, Spencer D, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Association of Neurological Surgeons. Neurology 2003b;60:538-47. Engel J Jr. Surgical treatment for epilepsy: too little, too late? JAMA 2008;300:2548-2550. Engel J Jr, McDermott MP, Wiebe S, Langfitt JT, Stern JM, Dewar S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA 2012;307:922-30. Englot DJ, Ouyang D, Garcia PA, Barbaro NM, Chang EF. Epilepsy surgery trends in the United States, 1990-2008. Neurology 2012;78:1200-6. Englot DJ, Breshears JD, Sun PP, Chang EF, Auguste KI. Seizure outcomes after resective surgery for extra-temporal lobe epilepsy in pediatric patients. J Neurosurg Pediatr 2013;12:12633. Erba G, Moja L, Beghi E, Messina P, Pupillo E. Barriers toward epilepsy surgery. A survey among practicing neurologists. Epilepsia 2012;53:35-43. Faught E, Duh MS, Weiner JR, Guérin A, Cunnington MC. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM Study. Neurology 2008;71:1572-8.

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Fauser S, Schulze-Bonhage A, Honegger J, Carmona H, Huppertz HJ, Pantazis G, et al. Focal cortical dysplasias: surgical outcome in 67 patients in relation to histological subtypes and dual pathology. Brain 2004;127:2406-18. Fiest KM, Sajobi TT, Wiebe S. Epilepsy surgery and meaningful improvements in quality of life: Results from a randomized controlled trial. Epilepsia 2014; 55:886-92. Frater JL, Prayson RA, Morris III HH, Bingaman WE. Surgical pathologic findings of extratemporal-based intractable epilepsy: a study of 133 consecutive resections. Arch Pathol Lab Med 2000;124:545-9. Funke ME, Moore K, Orrison WW Jr, Lewine JD. The role of magnetoencephalography in "nonlesional" epilepsy. Epilepsia 2011;52 Suppl4:10-4. Hakimi AS, Spanaki MV, Schuh LA, Smith BJ, Schultz L. A survey of neurologists' views on epilepsy surgery and medically refractory epilepsy. Epilepsy Behav 2008;13:96-101. Haneef Z, Stern J, Dewar S, Engel J Jr. Referral pattern for epilepsy surgery after evidence-based recommendations: a retrospective study. Neurology 2010;75:699-704. Hauptman JS, Mathern GW. Surgical treatment of epilepsy associated with cortical dysplasia: 2012 update. Epilepsia 2012;53 Suppl 4:98-104. Henry TR. Resecting without detecting the lesion in extratemporal lobe epilepsy? Neurology. 2014; 82:910-1. Hughes JR. A review of sudden unexpected death in epilepsy: prediction of patients at risk. Epilepsy Behav 2009;14:280-7. Huppertz HJ, Grimm C, Fauser S, et al. Enhanced visualization of blurred graywhite matter junctions in focal cortical dysplasia by voxel-based 3D MRI analysis. Epilepsy Res 2005;67:3550. Huppertz HJ, Wellmer J, Staack AM, Altenmuller DM, Urbach H, Kroll J. Voxelbased 3D MRI analysis helps to detect subtle forms of subcortical band heterotopia. Epilepsia 2008;49:772-85. Itabashi H, Jin K, Iwasaki M, Okumura E, Kanno A, Kato K, et al. Electro- and magnetoencephalographic spike source localization of small focal cortical dysplasia in the dorsal perirolandic region. Clin Neurophysiol 2014;125:2358-63. Jacobs J, Staba R, Asano E, Otsubo H, Wu JY, Zijlmans M, et al. High-frequency oscillations (HFOs) in clinical epilepsy. Prog Neurobiol 2012;98:302-15 Jayakar P, Gaillard WD, Tripathi M, Libenson MH, Mathern GW, Cross JH; et al. Diagnostic test utilization in evaluation for resective epilepsy surgery in children. Epilepsia 2014;55:507-18. 18

Jeong W, Chung CK, Kim JS. Magnetoencephalography interictal spike clustering in relation with surgical outcome of cortical dysplasia. J Korean Neurosurg Soc 2012;52:466-71. Jung J, Bouet R, Delpuech C, Ryvlin P, Isnard J, Guenot M, et al. The value of magnetoencephalography for seizure-onset zone localization in magnetic resonance imagingnegative partial epilepsy. Brain 2013;136:3176-86. Kaiboriboon K, Lüders HO, Hamaneh M, Turnbull J, Lhatoo SD. EEG source imaging in epilepsy--practicalities and pitfalls. Nat Rev Neurol 2012;8:498-507. Kamimura T, Tohyama J, Oishi M, Akasaka N, Kanazawa O, Sasagawa M, et al. Magnetoencephalography in patients with tuberous sclerosis and localization-related epilepsy. Epilepsia 2006;47:991-7. Kerr MP. The impact of epilepsy on patients' lives. Acta Neurol Scand Suppl 2012;194:1-9. Knowlton RC, Elgavish RA, Limdi N, Bartolucci A, Ojha B, Blount J, et al. Functional imaging: I. Relative predictive value of intracranial electroencephalography. Ann Neurol 2008a;64:25–34. Knowlton RC, Elgavish RA, Bartolucci A, Ojha B, Limdi N, Blount J, et al. Functional imaging: II. Prediction of epilepsy surgery outcome. Ann Neurol 2008b;64:35-41. Knowlton RC, Razdan SN, Limdi N, Elgavish RA, Killen J, Blount J, et al. Effect of epilepsy magnetic source imaging on intracranial electrode placement. Ann Neurol 2009;65:716–723. Krsek P, Maton B, Jayakar P, Dean P, Korman B, Rey G, et al. Incomplete resection of focal cortical dysplasia is the main predictor of poor postsurgical outcome. Neurology 2009;72:21723. Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med 2011;365:919-26. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Hauser AW, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:1069-77. Kwan P, Brodie MJ. Definition of refractory epilepsy: defining the indefinable? Lancet Neurol 2010;9:27-9. Lascano AM, Lemkaddem A, Granziera C, Korff CM, Boex C, Jenny B, et al. Tracking the source of cerebellar epilepsy: hemifacial seizures associated with cerebellar cortical dysplasia. Epilepsy Res 2013;105:245-9. Lerner JT, Salamon N, Hauptman JS, Velasco TR, Hemb M, Wu JY, et al. Assessment and surgical outcomes for mild type I and severe type II cortical dysplasia: a critical review and the UCLA experience. Epilepsia 2009;50:1310–1335.

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Luoni C, Bisulli F, Canevini MP, De Sarro G, Fattore C, Galimberti CA, et al. Determinants of health-related quality of life in pharmacoresistant epilepsy: results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments. Epilepsia 2011;52: 2181-91. Mäkelä JP, Forss N, Jääskeläinen J, Kirveskari E, Korvenoja A, Paetau R. Magnetoencephalography in neurosurgery. Neurosurgery 2006;59:493-510; discussion 510-1. Mathern GW, Giza CC, Yudovin S, Vinters HV, Peacock WJ, Shewmon DA, et al. Postoperative seizure control and antiepileptic drug use in pediatric epilepsy surgery patients: the UCLA experience, 1986-1997. Epilepsia 1999;40:1740-9. Moeller F, Tyvaert L, Nguyen DK, LeVan P, Bouthillier A, Kobayashi E, et al. EEG-fMRI: adding to standard evaluations of patients with nonlesional frontal lobe epilepsy. Neurology 2009;73:2023–2030. Mohamed IS, Gibbs SA, Robert M, Bouthillier A, Leroux JM, Khoa Nguyen D. The utility of magnetoencephalography in the presurgical evaluation of refractory insular epilepsy. Epilepsia 2013;54:1950-9. Morioka T, Nishio S, Ishibashi H, Muraishi M, Hisada K, Shigeto H, et al. Intrinsic epileptogenicity of focal cortical dysplasia as revealed by magnetoencephalography and electrocorticography. Epilepsy Res 1999; 33:177-187. Moore KR, Funke ME, Constantino T, Katzman GL, Lewine JD. Magnetoencephalographically directed review of high-spatial-resolution surface-coil MR images improves lesion detection in patients with extratemporal epilepsy. Radiology 2002;225:880-7. Najm I, Jehi L, Palmini A, Gonzalez-Martinez J, Paglioli E, Bingaman W. Temporal patterns and mechanisms of epilepsy surgery failure. Epilepsia 2013;54:772-82. Palmini, A., Gambardella, A., Andermann, F., Dubeau, F., da Costa, J.C., Olivier, A., et al., Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol 1995;37:476-487. Pan JW, Duckrow RB, Gerrard J, Ong C, Hirsch LJ, Resor SR Jr, et al. 7T MR spectroscopic imaging in the localization of surgical epilepsy. Epilepsia 2013;54:1668-78. Pan JW, Spencer DD, Kuzniecky R, Duckrow RB, Hetherington H, Spencer SS. Metabolic networks in epilepsy by MR spectroscopic imaging. Acta Neurol Scand 2012;126:411-20. Papanicolaou AC, Simos PG, Breier JI, Zouridakis G, Willmore LJ, Wheless JW, et al. Magnetoencephalographic mapping of the language-specific cortex. J Neurosurg 1999;90:85-93. 20

Papanicolaou AC, Rezaie R, Narayana S, Choudhri AF, Wheless JW, Castillo EM, et al. Is it time to replace the Wada test and put awake craniotomy to sleep? Epilepsia 2014; 55:629-32. Rowland NC, Englot DJ, Cage TA, Sughrue ME, Barbaro NM, Chang EF. A meta-analysis of predictors of seizure freedom in the surgical management of focal cortical dysplasia. J Neurosurg 2012;116:1035-41. Schmitz B, Montouris G, Schäuble B, Caleo S. Assessing the unmet treatment need in partialonset epilepsy: looking beyond seizure control. Epilepsia 2010;51:2231-40. Schneider F, Alexopoulos AV, Wang Z, Almubarak S, Kakisaka Y, Jin K, et al. Magnetic source imaging in non-lesional neocortical epilepsy: additional value and comparison with ICEEG. Epilepsy Behav 2012;24:234-40. Schneider F, Wang IZ, Alexopoulos AV, Almubarak S, Kakisaka Y, Jin K, et al. Magnetic source imaging and ictal SPECT in MRI-negative neocortical epilepsies: additional value and comparison with intracranial EEG. Epilepsia 2013;54:359-69. Sisodiya SM. Malformations of cortical development: burdens and insights from important causes of human epilepsy. Lancet Neurol 2004;3:29-38. So EL, Lee RW. Epilepsy surgery in MRI-negative epilepsies. Curr Opin Neurol 2014;27:20612. Sperling MR. The consequences of uncontrolled epilepsy. CNS Spectr 2004;9:98-101, 106-109. Stefan H, Hummel C, Scheler G, Genow A, Druschky K, Tilz C, et al. Magnetic brain source imaging of focal epileptic activity: a synopsis of 455 cases. Brain 2003;126:2396-405. Stefan H, Rampp S, Knowlton RC. Magnetoencephalography adds to the surgical evaluation process. Epilepsy Behav 2011;20:172-7. Sulc V, Stykel S, Hanson DP, Brinkmann BH, Jones DT, Holmes DR 3rd, et al. Statistical SPECT processing in MRI-negative epilepsy surgery. Neurology 2014;82:932–939. Suhy J, Laxer KD, Capizzano AA, Vermathen P, Matson GB, Barbaro, et al. 1H MRSI predicts surgical outcome in MRI-negative temporal lobe epilepsy. Neurology 2002;58:821–823. Sutherling WW, Mamelak AN, Thyerlei D, Maleeva T, Minazad Y, Philpott L, et al. Influence of magnetic source imaging for planning intracranial EEG in epilepsy. Neurology 2008;71:990– 996. Tanaka N, Stufflebeam SM. Clinical application of spatiotemporal distributed source analysis in presurgical evaluation of epilepsy. Front Hum Neurosci 2014;8:62.

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Tassi L, Garbelli R, Colombo N, Bramerio M, Lo Russo G, Deleo F, et al. Type I focal cortical dysplasia: surgical outcome is related to histopathology. Epileptic Disord 2010;12:181-91. Taylor DC, Falconer MA, Bruton CJ, Corsellis JA: Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 1971;34:369-387. Taylor RS, Sander JW, Taylor RJ, Baker GA. Predictors of health-related quality of life and costs in adults with epilepsy: a systematic review. Epilepsia 2011;52:2168-80. Teutonico F, Mai R, Veggiotti P, Francione S, Tassi L, Borrelli P, et al. Epilepsy surgery in children: evaluation of seizure outcome and predictive elements. Epilepsia 2013;54 Suppl 7:706. Urbach H, Scheffler B, Heinrichsmeier T, von Oertzen J, Kral T, Wellmer J, et al. Focal cortical dysplasia of Taylor's balloon cell type: a clinicopathological entity with characteristic neuroimaging and histopathological features, and favorable postsurgical outcome. Epilepsia 2002;43:33-40. Vadera S, Jehi L, Burgess RC, Shea K, Alexopoulos AV, Mosher J, Gonzalez-Martinez J, Bingaman W. Correlation between magnetoencephalography-based "clusterectomy" and postoperative seizure freedom. Neurosurg Focus 2013;34:E9. van Dellen E, Douw L, Hillebrand A, de Witt Hamer PC, Baayen JC, Heimans JJ, et al. Epilepsy surgery outcome and functional network alterations in longitudinal MEG: a minimum spanning tree analysis. Neuroimage 2014;86:354-63. Velez-Ruiz NJ, Klein JP. Neuroimaging in the evaluation of epilepsy. Semin Neurol 2012;32:361-73. Wagner J, Weber B, Urbach H, Elger C, Huppertz H. Morphometric MRI analysis improves detection of focal cortical dysplasia type II. Brain 2011;134:2844-54. Wang ZI, Jones SE, Ristic AJ, Wong C, Kakisaka Y, Jin K, et al. Voxel-based morphometric MRI post-processing in MRI-negative focal cortical dysplasia followed by simultaneously recorded MEG and stereo-EEG. Epilepsy Res 2012;100:188-93. Wang ZI, Alexopoulos AV, Jones SE, Jaisani Z, Najm IM, Prayson RA. The pathology of magnetic-resonance-imaging-negative epilepsy. Mod Pathol 2013a;26:1051-8. Wang S, Wang IZ, Bulacio JC, Mosher JC, Gonzalez-Martinez J, Alexopoulos AV, et al. Ripple classification helps to localize the seizure-onset zone in neocortical epilepsy. Epilepsia 2013b;54:370-6. Wang Z, Alexopoulos A, Jones S, Najm I, Ristic A, Wong C, et al. Linking MRI post-processing with Magnetic source imaging in MRI-negative epilepsy. Ann Neurol 2014;75:759-70.

22

Wellmer J, Parpaley Y, von Lehe M, Huppertz HJ. Integrating magnetic resonance imaging postprocessing results into neuronavigation for electrode implantation and resection of subtle focal cortical dysplasia in previously cryptogenic epilepsy. Neurosurgery 2010;66:187-94; discussion 194-5. Wellmer J, Quesada CM, Rothe L, Elger CE, Bien CG, Urbach H. Proposal for a magnetic resonance imaging protocol for the detection of epileptogenic lesions at early outpatient stages. Epilepsia 2013;54:1977-87. Wheless JW, Castillo E, Maggio V, Kim HL, Breier JI, Simos PG, et al. Magnetoencephalography (MEG) and magnetic source imaging (MSI). Neurologist. 2004;10:138-53. Wiebe S, Blume WT, Girvin JP, Eliasziw M; Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporallobe epilepsy. N Engl J Med 2001;345:311-318. Wiebe S, Jetté N. Epilepsy surgery utilization: who, when, where, and why? Curr Opin Neurol 2012;25:187-93. Widjaja E, Otsubo H, Raybaud C, Ochi A, Chan D, Rutka JT, et al. Characteristics of MEG and MRI between Taylor's focal cortical dysplasia (type II) and other cortical dysplasia: surgical outcome after complete resection of MEG spike source and MR lesion in pediatric cortical dysplasia. Epilepsy Res 2008;82:147-55. Wilenius J, Medvedovsky M, Gaily E, Metsähonkala L, Mäkelä JP, Paetau A, et al. Interictal MEG reveals focal cortical dysplasias: special focus on patients with no visible MRI lesions. Epilepsy Res 2013;105:337-48. Williamson SJ, Lü ZL, Karron D, Kaufman L. Advantages and limitations of magnetic source imaging. Brain Topogr 1991;4:169-80. Winston GP, Micallef C, Kendell BE, Bartlett PA, Williams EJ, Burdett JL, et al. The value of repeat neuroimaging for epilepsy at a tertiary referral centre: 16 years of experience. Epilepsy Res 2013;105:349-55. Wu T, Ge S, Zhang R, Liu H, Chen Q, Zhao R, et al. Neuromagnetic coherence of epileptic activity: An MEG study. Seizure 2014; 23:417-23. Wu JY, Sutherling WW, Koh S, Salamon N, Jonas R, Yudovin S, et al. Magnetic source imaging localizes epileptogenic zone in children with tuberous sclerosis complex. Neurology 2006; 66:1270-2.

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Wu XT, Rampp S, Buchfelder M, Kuwert T, Blümcke I, Dörfler A, et al. Interictal magnetoencephalography used in magnetic resonance imaging-negative patients with epilepsy. Acta Neurol Scand 2013;127:274-80. Zhang J, Liu W, Chen H, Xia H, Zhou Z, Mei S, et al. Multimodal neuroimaging in presurgical evaluation of drug-resistant epilepsy. Neuroimage Clin 2013;4:35-44.

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Figure Legend

Figure 1: An illustrative patient with a truly NLETE (i.e. no structural abnormalities on a 1.5 and 3.0 T brain MRI with epilepsy protocol, including their MSI-guided re-review), but with a positive congruent MSI and MRS. Clinical History: A 29-year-old male with a history of a fall in childhood (his only known seizure risk factor!), headaches, hypertension, depression, burns on his chest (a result of the gang violence), lumbar spine surgery (2012), prolonged PR interval and epileptic seizures since the age of 5 years. He had failed two (lamotrigine, carbamazepine) and continues to experience seizures on his current three (divalproex, levetiracetam, topiramate) antiepileptic medications. In consideration of epilepsy surgery, he underwent a standard presurgical evaluation that included a 1.5T and 3.0T brain MRI with epilepsy protocols, routine EEG, videoEEG, Neuropsychological Testing (NPT), FDG-PET and MEG-EEG. He also kindly participated in a research MRS study (PI: Julie W. Pan, MD, PhD) comparing a 3T (was able to remain still only for this part of the scanning!) and 7T magnet’s sensitivity to detect cerebral metabolic abnormalities and his MRSIs were available for a post hoc consideration at multidisciplinary epilepsy patient management conference (MEPMC). Pertinent Diagnostic Investigations: An example of a normal 3T brain MRI with epilepsy protocol (A), normal FDG-PET (B), but positive findings from an MSI (D) indicative of significant cerebral dysfunction and epileptic potential expressed through the right inferior parietal lobule and a congruent 3T MRS (C; E) indicative of significant metabolic abnormality in

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the right inferior parietal lobule. Yellow lines on the scout image of panel E and panel C outline estimated position of the central sulcus (CS). (MRS images on panels C and E were kindly provided by Julie W. Pan, MD, PhD; University of Pittsburgh Comprehensive Epilepsy Center, Pittsburgh, PA; methods used were previously published in Pan et al, 2013).

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Table 1: Published studies that address the issues relevant for establishing the foundation for and evidence of usefulness of MEG in the form of MSI for increasing the yield of seemingly or actually negative MRI in NLETE. (Studies are listed chronologically). Reference N being reviewed

Pathology

Key diagnostic findings

Relevance for the issue

Palmini et al, 74 M FCD (34) 67% (23/34) ECoG+ of intrinsic epileptogenicity of DC (1995) OL (40) 2.5% (1/40) ECoG+ more likely to be epileptogenic than OL Extent of FCD resection relevant for outcome

First direct demonstration

Morioka et al, 4A FCD epileptogenicity of DC (ECoG) (1999) FCD epileptogenicity

4/4 ECoG+

Demonstrated intrinsic

4/4 MSI+

First MSI demonstration of

1/1 IDR+

First indication that MSI

FCDs are about 27 times

findings may predict outcome Moore et al, 20 M NE 100% (20/20) MSI+ cMRI enables detection of missed ENL (2002) 8 MRI nl/MSI+ hrMRI enables detection of ENL not visible on cMRI 4 NLs on nl cMRI, 1 on hrMRI

MSI-guided review of

Bast et al,

First relevant comparison

9C FCD 9/9 MSI+ of MSI and ESI for detecting FCDs (2004) 9/9 ESI+ localized equivalently with LZ 5/5 ICM+ of FCD intrinsic epileptogenicity

MSI-guided review of

MEG and EEG spikes coConfirmed the hypothesis Indicated the importance

of resecting MSI/ESI+ areas Widjaja et al, 27 C FCD patterns of different FCDs (2008) importance of complete resections

96% (26/27) MSI+

Discerned different MSI

85% (11/13) MSI w/ clusters => EI Demonstrated the primary 88% (15/17) MRI w/ lesion => EI No significant difference in outcomes with a complete resection MRI+ or MSI+

Funke et al, 40 M NE cMRI enables finding of missed ENL (2011) MRI for finding structural lesions in NE

MSI, EEG

MSI-guided review of

7/29 8 MSI+/MRI- => 7 NL

MEG is a useful adjunct to

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Jeong et al, 25 A FCD high sensitivity for FCD (2012a) associated with better surgical outcome

100% (25/25) MSI+

Re-demonstrated MEG’s

96% (24/25) MSI clusters +

Focal MSI clustering Proposed an objective method to classify the distribution of MSIs

Wilenius et al, 34 M FCD operated epilepsy patients with FCD (2013) finding small FCDs invisible on MRI

97% (33/34) MSI+

Largest MEG study of

MSI≈ICM (9/13) in MRI-

MEG particularly useful in Complete removal of MEG clusters areas associated with positive outcome Similar outcome in MRI+ and MRI- FCD Methods for increasing the yield from falsely negative MRIs are needed

Wu et al,

18 A

MRIwith better outcome

(2013) and/or FDG-PET associated with better outcome

89% (16/18) MEG+

Monofocal MSI associated

100% (10/10) (EI or EII)

MSI-concordant SPECT

9/10 con SPECT and/or PET likelihood of surgical candidacy Itabashi et al, 6M FCD sensitivity for detecting FCD (2014) considers MSI/ESI and seizure

Positive MSI increases the

5/5 MSI+

Equivalent MSI and ESI

5/5 ESI+

Proposed that MR review

semiology to identify subtle MR imaging abnormalities _____________________________________________________________________________________________ ________________________________

Abbreviations: A = adults (> 18 years), C = children (<18 years); M = Mixed; FCD= Focal Cortical Dysplasia, OL = other lesions; + = positive (neurophysiologic or imaging) findings, I/CEDs = Ictal or Continuous Epileptogenic Discharges; IDR = Intraoperative depth recordings; cMRI = conventional MRI; hrMRI = high resolution MRI; nl = normal; ICM = Intracranial monitoring; ECoG = Electrocorticography; MSI = Magnetic Source Imaging; ESI = Electric Source Imaging; NE = neocortical epilepsy; ENL = epileptogenic neocortical lesions; DC = dysplastic cortex; LZ = lesional zone; NL = New lesions; EI = Engel class I, EII = Engel class II. con = concordant.

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