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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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).

26

27

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

28

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 (