Electromagnetic source imaging in presurgical workup of patients with epilepsy

Study design and patients

From April 2011 to June 2016, we prospectively recruited consecutive patients undergoing presurgical evaluation, as part of the Danish Epilepsy Surgery Program. All patients had drug-resistant focal epilepsy, and for all patients, at least 2, appropriately chosen and taken antiepileptic drugs had failed. The intended sample size was ≥100 patients, based on previous studies.¹⁰ This number has proven to provide the reference standard in >50 patients undergoing intracranial recording (ICR) or operation.¹¹

Inclusion criteria were patients who underwent presurgical evaluation and who gave their consent. There were no exclusion criteria; data from all recruited patients were analyzed.

Standard protocol approvals, registrations, and patient consents

The study was approved by the regional ethics committee (case number 1-10-72-177-12) and patients gave their informed written consent. Patients underwent presurgical evaluation according to the investigation protocol approved by the Danish Health Authority (data available from Dryad, appendix 1, doi.org/10.5061/dryad.p4r01pq). This included detailed history, semiology, and EEG from video-EEG monitoring, MRI, and neuropsychological tests for all patients. When decisions could not be made based on these data, patients were referred to additional noninvasive investigations (PET, EMSI) and ICRs (stereo-EEG).

Presurgical patients, in whom the multidisciplinary team (MDT) reached a conclusion based on semiology, EEG, and MRI, were recruited as part of the research study (arm A). In these patients, EMSI was not part of the decision-making. Patients with normal MRI or discordant data (semiology, EEG, MRI) were referred to PET and EMSI as part of their presurgical evaluation, before ICR (arm B). In these patients, EMSI was part of the decision-making process.

For patients in arm B, the MDT had a 2-step decision process. Decision was first made blinded to EMSI, based on all other data, and it was logged into the database. Decisions were categorized as (1) stop (operation not offered), (2) implantation of intracranial electrodes (specifying their location), or (3) operation (resective surgery). Then, a second decision was made, based on new information (if any) provided by the EMSI, weighted against all other data. Possible changes in the management plan included any change from one of these categories to another and change within category 2 (i.e., change in the planned intracranial electrode positions).

Simultaneous MEG and EEG recordings

MEG-EEG was recorded at Aarhus University Hospital, using an Elekta Neuromag system (Elekta, Stockholm, Sweden).

MEG was recorded at 102 evenly distributed locations, with 3 sensors at each location (2 orthogonal planar gradiometers and a magnetometer), giving a total of 306 channels. Continuous head position indicators were used. MEG data were preprocessed offline using the spatiotemporal signal space separation method¹² to suppress the residual interference and to correct for head movements.

High-density EEG (64–80 electrodes) was recorded using a nonmagnetic cap (EASYCAP) and additional electrodes covering the inferior part of the head (cheek, inferior temporal chain, and neck) in all patients with head circumference <60 cm and who could cooperate with the procedure. In other patients, an array of 19 electrodes (10-20 system) or no EEG was recorded. In addition, electrooculogram and ECG were recorded. Electronic tracking of positions of electrodes and of the head position coils were done using a Polhemus system (Polhemus, Colchester, VT).¹³

Spontaneous activity (eyes closed, rest, supine position) was recorded for 60 to 90 minutes (sampling frequency 1 kHz; online bandpass 0.1–330 Hz) both for MEG and EEG. Data were offline bandpass filtered at 0.5 to 70 Hz.

Electromagnetic source imaging

MEG-EEG was inspected for EDs by 2 trained experts (L.D., S.B.). Signals were analyzed using 2 commercially available software packages, with European approval for medical use (CE-mark). L.D. used the CURRY 7 Neuroimaging Suite (Compumedics, Victoria, Australia). S.B. used BESA-Research 6 (BESA, Gräfelfing, Germany). Voltage maps and magnetic field maps were inspected, and EDs were grouped in different clusters when the topographic maps differed. Then, for each cluster, using the visually detected EDs as templates, automated algorithms (template matching) scanned the recordings, and detected EDs were visually checked. To improve the signal-to-noise ratio, EDs with similar topography were averaged.¹⁴

Sequential topographic maps were inspected in the time epoch of the ascending slope of the averaged waveforms for change in topography indicating propagation. In addition, principal components analysis was used to identify propagation.¹⁵ When propagation occurred, source imaging was done first at the onset epoch, and then at the peak. When propagation was not identified, source imaging was done at the middle third of the ascending slope.¹⁰ With both software packages, 2 different inverse solutions were applied: equivalent current dipole (ECD) and a distributed source model (DSM): sLORETA,¹⁶ with an anatomically constrained linear estimation approach, assuming the sources were distributed in the cerebral cortex in CURRY, and CLARA in BESA.⁸ ESI and MSI were done with both software packages. In addition, using CURRY, source modeling of both datasets (EEG-MEG) was done (cEMSI).¹⁷

All analyses were performed using individual head models from the patients' MRIs, coregistered with the MEG-EEG recording using fiducial landmark positions, electrode positions, and head position coils, digitized before the recording. In CURRY, 3-compartment boundary element method (BEM) head model was used.¹⁸ In BESA, an individual 4-layer finite element method (FEM) head model was used.¹⁴ Figure 1 illustrates the steps of the EMSI.

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Figure 1 Methodologic flowchart of EMSI

EMSI was performed using the following 4 steps: (1) review of the magnetoencephalography and EEG recordings and visual identification and marking of EDs belonging to the same cluster. These EDs were used for template-matching. Each detected spike was visually checked and artifacts were discarded. (2) EDs within each cluster were averaged to improve signal-to-noise ratio (critical for spike onset activity relative to the background activity).²⁸ Sequential topographic plots of the ascending phase and principal components analysis was used to identify propagation. (3) Individual head model was created for each patient, and the EEG electrodes were aligned to the scalp. (4) Source modeling was performed using 2 different inverse-solution strategies: equivalent current dipole and distributed source models where yellow indicates maximum intensity. ED = epileptiform discharge; EMSI = electromagnetic source imaging; IED = interictal epileptiform discharge.

EMSI was performed prospectively, blinded to clinical information and reference standard results.

Conventional neuroimaging methods

MRI and ¹⁸F-fluorodeoxyglucose (FDG)-PET were performed as part of the presurgical evaluation. The MRI epilepsy protocol consisted until 2015 of a sagittal T1 3-dimensional (3D) magnetization-prepared rapid-acquisition gradient echo (MPRAGE) sequence, coronal and axial fluid-attenuated inversion recovery (FLAIR) sequences, and a coronal T2-weighted (W) fast spin-echo sequence. Coronal and axial FLAIR and T2W sequences were performed perpendicular to and in plane with hippocampus long-axis. Since 2015, the protocol consisted of sagittal T1 3D MPRAGE sequence, sagittal 3D FLAIR sequence, coronal and axial T2W sequences, perpendicular and horizontal to hippocampus long-axis, axial susceptibility-weighted image sequence, axial diffusion-weighted image sequence, sagittal T1 3D MPRAGE sequence, and axial T1W spin-echo sequence after IV contrast. All 3D sequences were reconstructed in coronal and axial planes perpendicular and horizontal to the hippocampus long-axis.

For PET, FDG was administered IV with the patient in supine position and equipped with eye pads and earplugs. PET scan was commenced 40 minutes after tracer injection. PET scans were coregistered and displayed superimposed on MRI sequences using a standard clinical workstation and dedicated software supplied by the camera vendor (Leonardo station using TrueD; and from 2013 syngo.via using MI Neurology, Siemens Medical Solutions, Malvern, PA) who also provided access to age-matched normal database comparison.

Sublobar brain regions

EMSI, PET, and MRI localization results were prospectively logged into the database, with localization scores at sublobar level, corresponding to 64 categories. This included the sublobar regions proposed by an international consensus paper and IFCN (International Federation of Clinical Neurophysiology) guideline.^15,19 A descriptor of the side (left/right/mesial) was added. When more than 2 independent foci were identified, and none of them had a dominant activity, the result was scored as multifocal. A focus was considered dominant if the number of EDs was more than twice the number of EDs from all other foci. The remaining categories were (1) normal and (2) not localizable. Not localizable was when the ECD confidence interval or the distributed source analysis spanned over more than one lobe.

Reference standard

Ideal reference standard lacks for source imaging in presurgical evaluation.⁶ Accurately localizing the generator of interictal EDs (the irritative zone [IZ]) does not necessarily imply that resection of that area will render the patient seizure-free. Therefore, we used 2 different sets of reference standards: ICR and outcome after surgery (see below).

Outcome measures

First, the number of ED clusters recorded by only MEG and only EEG were compared.

Agreement between different EMSI methods was calculated. All comparisons were done at sublobar level.

Clinical utility of EMSI was defined as the proportion of patients in whom EMSI changed the decision of the MDT. A change was defined useful as follows: (1) change from stop to ICR—the ICR localized the source; (2) change in implantation strategy—the electrode(s) implanted based on the EMSI identified the source; (3) change from implantation to operation without preceding implantation—the patient became seizure-free (at 1-year postoperative follow-up).

For EMSI, PET and MRI, we calculated the following outcome measures. Agreement with ICR: concordance with IZ and concordance with the seizure onset zone (SOZ) were determined using ICR as reference standard. Proportion of patients with results concordant with the reference standard, and agreement with this reference standard were calculated.

Sensitivity, specificity, localization accuracy, positive predictive value (PPV), and negative predictive value (NPV) were determined using outcome 1 year after surgery as reference standard. Preoperative EMSI was coregistered with the postoperative MRI; the source was considered concordant with the resected site when the ECD and respectively the maximum of the DSM was within the operation cavity. All other results (localization outside the cavity, multifocal EDs, normal recoding, not-localizable results) were considered discordant. We categorized the localizations as follows: TP (true positive)—concordant with the resection and seizure-free; FP (false positive)—concordant with the resection and not seizure-free; TN (true negative)—discordant with the resection and not seizure-free; FN (false negative)—discordant with the resection and seizure-free. We used the following formula:

Surgical procedures were tailored to each patient, based on the final conclusion of the MDT.

We calculated the odds ratio (OR) of becoming seizure-free when operation was concordant vs discordant with the localization of the index test: OR = (TP/FP)/(FN/TN).

Statistics

For assessment of agreement (κ) between EMSI methods, software packages, and operators, and for assessment of agreement between EMSI and ICR, we calculated Gwet AC₁.²⁰ We used this measure of agreement because it yields more reasonable values than the Cohen κ in case of low-trait prevalences.²⁰ Interrater agreement was interpreted according to the conventional groups: poor (κ < 0), slight (κ: 0.01–0.2), fair (κ: 0.21–0.4), moderate (κ: 0.41–0.6), substantial (κ: 0.61–0.8), and almost perfect agreement (κ > 0.8).²¹

The effect measures of sensitivity, specificity, PPV, NPV, concordance with SOZ, localization accuracy, and their 95% confidence intervals were estimated using a generalized linear model (GLM).^22,23 Identity link function was used in the GLM to compare index tests by means of the differences of the effect measure. Multiple observations per patient were considered in the GLM by specifying the patient ID as a cluster. Analysis was performed in StataCorp software release 14 (StataCorp LP, College Station, TX) using the binreg function.

Classification of evidence

The study was designed to answer the following question: What is the localization accuracy and clinical utility of EMSI in presurgical evaluation of patients with drug-resistant focal epilepsy?

The study was prospective and blinded. All patients who underwent presurgical evaluation and who gave their informed consent were recruited. Data from all recruited patients were analyzed and evaluated. All patients had drug-resistant focal epilepsy.

This study provides Class IV evidence that EMSI had a concordance of 53%–89% and 35%–73% (depending on analysis) for the localization of epilepsy as compared with ICRs—IZ and SOZ, respectively.

Data sharing

Individual deidentified data, including localization results of the imaging methods, reference standard localizations, and outcome data will be shared, along with the following related documents: study protocol and statistical analysis plan. Unrestricted access to these data will be made available from the day of the online publication of the article, until 2030, using a publicly accessible repository (datadryad.org//) (Dryad doi:10.5061/dryad.p4r01pq). During the review phase, the data package is temporarily available via the following link: datadryad.org/review?doi=doi:10.5061/dryad.p4r01pq.