The epileptogenic zone (cortical area indispensable for the generation of clinical seizures) cannot be localized by a single method (Rosenow & Lüders, 2001). Therefore the presurgical investigation relies on a multimodal approach, in which an important part is the localization of the seizure-onset zone, defined as the area of the cortex from which clinical seizures are actually generated, as demonstrated by electroencephalography (EEG) techniques (Rosenow & Lüders, 2001).
Most studies on the accuracy of EEG source localization techniques focused on the interictal epileptiform discharges (the irritative zone) (Michel et al., 2004; Leijten & Huiskamp, 2008; Plummer et al., 2008; Brodbeck et al., 2011). However, several studies suggested that the source of interictal epileptiform activity does not necessarily coincide with the seizure-onset area (So et al., 1989; Hirsch et al., 1991; Alarcon et al., 1994). Despite the high clinical relevance, there are relatively few clinical studies on the source localization of the ictal epileptiform activity. None of the previously published studies included blinded analysis and interpretation of the source localization, and only one study was prospective (Boon et al., 2002). Similarly, only one study determined the specificity (Assaf & Ebersole, 1997), whereas the majority of studies were done on relatively few (5–15) patients (Boon & D'Havé, 1995; Lantz et al., 1999; Blanke et al., 2000; Worrell et al., 2000; Lantz et al., 2001; Merlet & Gotman, 2001; Beniczky et al., 2006; Ding et al., 2007; Stern et al., 2009; Holmes et al., 2010; Koessler et al., 2010; Yang et al., 2011; Lu et al., 2012a,b). The only prospective study in the literature, which also included a larger patient population (Boon et al., 2002) addressed the clinical usefulness of EEG source localization techniques as defined by their influence on decision-making. However, the accuracy (sensitivity and specificity) of the ictal source localization was not determined in this study.
The major difficulties with analyzing the source localization of ictal EEG activity consist in artifacts often occurring during the seizures, low signal-to-noise ratio, absence of ictal EEG correlate in scalp recordings, short duration of some seizures, and the rapid propagation of ictal activity (Pacia & Ebersole, 1997; Foldvary et al., 2001; Rosenow & Lüders, 2001; Boon et al., 2002). Although a standardized algorithm for the analysis of interictal epileptiform discharges has been proposed (Leijten & Huiskamp, 2008), there is no consensus on the strategy of localizing the source of the rhythmic ictal activity (Foldvary et al., 2001).
To improve the accuracy and completeness of reporting of studies of diagnostic accuracy, and to improve the design of these studies, the STARD (Standards for Reporting of Diagnostic Accuracy) initiative was published simultaneously in six journals (Bossuyt et al., 2003).
Our objective was to assess the clinical feasibility and to estimate the accuracy of source localization of rhythmic ictal activity, using a distributed source model (local autoregressive average [LAURA]) for the ictal EEG signals selected with a standardized method. The aim of the standardized method was to shortcut the intrinsic problems of the ictal EEG signals—the low signal-to-noise ratio and the rapid propagation—using an approach that is not time-consuming and that is feasible in the clinical practice. We designed the study and we report it according to the STARD criteria. We determined the sensitivity, specificity, predictive values, and likelihood ratios of the ictal source localization.
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Ictal source localization was completed and yielded interpretable results in all included patients with visually identifiable rhythmic ictal activity (n = 42). The average time from the first clinical sign to the start of the analyzed rhythmic ictal activity was 7.7 s (range: 16 s before – 38 s after the first sign). In one case the analyzed rhythmic ictal activity started 37 s after the electrodecremental response (“flattening”); in all other cases, the analyzed rhythmic ictal activity was the first identifiable ictal EEG pattern.
Figures 4 and 5 and Data S3 and S4 show the results of the ictal source localization for patients with mesial temporal lobe epilepsy, lateral-neocortical temporal lobe epilepsy, and frontal lobe epilepsy. The results of the ictal source localization for the 42 patients are summarized in Data S1.
Figure 5. Ictal source localization in a patient with right lateral frontal focus (patient 10). The original ictal EEG is showed in Data S6.
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None of the included patients with visually identifiable rhythmic ictal activity was excluded because of artifacts. Examples of analyzed ictal recordings contaminated by artifacts are in Data S4 (page 2) and Data S7.
Using the standardized method, the analyses took <30 min for a seizure. All patients had been discussed at the meetings of the multidisciplinary epilepsy surgery team. However, consensus conclusion on the seizure-onset zone (reference standard) could not be achieved in nine cases (Fig. 1; Data S1).
Reference standard was thus available in 33 patients. The ictal source localization showed identical results with the reference standard in 23 patients. The sensitivity of the ictal source localization was 69.7% and the specificity was 75.7%. The mean measurement of agreement (kappa) was 0.61 (95% CI for k: 0.38–0.84) corresponding to substantial agreement. Of the 25 patients with potentially epileptogenic lesion on the MRI, 18 patients (72%) had ictal source localization concordant with the lesion location.
Twenty patients underwent surgery and 16 patients (80%) became seizure-free (see the flow diagram in Fig. 1). In 13 cases, the resection included the cortical area showed by the ictal source localization; 12 of them became seizure-free. The PPV of the ictal source localization was 92%. Seven patients underwent resection not including the cortical area showed by the ictal source localization; three of them did not become seizure-free. The NPV was 42.8%.
Of the 20 operated patients, 10 had selective amygdalohippocampectomy or tailored resections. Two patients with the epileptogenic zone involving both mesial and neocortical temporal structures underwent anteromedial temporal resection. Eight patients with mesial temporal focus underwent anteromedial temporal resection. Therefore, in these eight patients the resection exceeded the ictal sublobar localization. A subgroup analysis for the 12 patients in which the localization at sublobar level had therapeutic consequences, yielded results similar to the whole group of operated patients (PPV 86%; NPV 60%).
The likelihood ratio for the concordant results (ictal source localization matching the reference standard) was nine times higher than the likelihood ratio of the discordant results (mismatch between ictal source localization and the reference standard) (Table 1).
In 17 patients, the basic modalities (MRI, semiology, visually analyzed EEG) did not localize well the focus (normal MRI and/or discordant data). In these patients, additional investigations (functional neuroimaging, invasive recordings) were done. In this subgroup of patients with difficult temporal lobe epilepsy, the ictal source localization matched the reference standard in 13 cases (76%). In nine of these patients, the resection included the cortical area showed by the ictal source localization; all of them became seizure-free (PPV = 100%). Four patients in this subgroup underwent resection not including the cortical area showed by the ictal source localization; two of them did not become seizure free (NPV = 50%).
Most of the patients fulfilling the inclusion criteria turned out to have temporal lobe epilepsy (91%). Reference standard was available for three patients with extratemporal focus. The result of the ictal source analysis matched the reference standard in two of these patients. The third (no-match) patient underwent surgery in a location outside the area indicated by the ictal source localization; this patient did not become seizure-free. Two patients had several foci. The ictal source localization correctly localized them in both patients.
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Source localization of the rhythmic ictal activity, using a standardized method for selection and preparation of the ictal signals, and a distributed source model (LAURA), proved to be feasible in clinical practice: it yielded localization solutions in all patients who fulfilled inclusion criteria, and the total extra time consumption was <30 min for a patient.
Sixteen patients referred to the EMU for presurgical evaluation and who had at least one seizure, did not meet the inclusion criteria. Therefore, our method could be applied in 72% (n = 42) of the patients who had at least one epileptic seizure in the EMU (n = 58). The relatively low number of electrodes allowed only a sublobar precision level. However, this level can be helpful for making clinical decisions.
The proposed method evades the two major difficulties with source analysis of the ictal signals: low signal-to-noise ratio and propagation of the ictal activity. As suggested previously, to increase the signal-to-noise ratio we averaged the selected ictal wave-forms with similar topography (Assaf & Ebersole, 1997; Merlet & Gotman, 2001; Beniczky et al., 2006). We aimed at confining the analysis to the earliest detectable ictal signals, using two steps. First, we selected the EEG epoch with the initial frequency (Lantz et al., 1999, 2001) (Fig. 3). Then, on the ascending slope of the averaged waveform we marked the last timeframe showing the initial voltage distribution (Fig. 4).
One of the impediments of implementing source analysis of the ictal EEG signals in the clinical practice is the high extra workload imposed by time-consuming methods. Only two of the previous publications addressed this issue, and the authors reported that ictal source localization was highly time-consuming, often requiring several times the length of time compared with standard visual assessment, approximately 10 h per patient (Boon et al., 2002; Holmes et al., 2010). In stark contrast, our standardized method took <30 min per patient. Furthermore it provided localization results with high accuracy (sensitivity: 70%; specificity 76%) and high PPV (92%). Of other used neuroimaging methods, ictal SPECT also aims at localizing the seizure-onset zone (Rosenow & Lüders, 2001) but unlike our method, its logistic aspects and the timing are recognized as technically more demanding.
A previous, large-scale study (40 patients with temporal lobe epilepsy) using multiple fixed dipoles gave sensitivity between 36% and 66% and specificity between 92% and 96% (Assaf & Ebersole, 1997). Another study on a larger population (22 patients) used a distributed source model (low resolution electromagnetic tomography [LORETA]) and demonstrated preferential propagation patterns of the ictal activity originating in mesial temporal epileptic foci (Lee et al., 2009). The only prospective study published previously on the source localization of the ictal EEG activity comprised a large patient population (100 patients) (Boon et al., 2002). Due to movement or other artifacts, ictal source localization was possible in only 31 patients; in 14 patients it proved to be a key element in the surgical decision process. Sensitivity and specificity were not determined in this study as the results of the source analysis contributed to the decision process. All other studies were done on relatively few patients (5–15) and gave results with sensitivity between 40% and 100%. Finally, none of the previous studies were blinded.
Our study was designed and reported in accordance with the STARD recommendations (Bossuyt et al., 2003). Recently, International League Against Epilepsy (ILAE) guideline criteria for imaging and neurophysiology studies in epilepsy have been published (Gaillard et al., 2011). Although these criteria were published after we started the study, application of the STARD criteria for ictal source localization resulted in a study design that fulfils the criteria suggested by the ILAE task force of the Commission for Diagnostics (Gaillard et al., 2011).
Recently published critical reviews emphasized the difficulties in the interpretation of diagnostic accuracy studies on presurgical workup for epilepsy surgery, and it was suggested to supplement the currently available imperfect reference standard (consensus decision from a combination of tests) with the outcome following surgery (Burch et al., 2012a,b). The likelihood ratios calculated from these tables reflect the clinical usefulness of the index test. In our study the likelihood ratio for the concordant results was much (nine times) higher than the likelihood ratio of the discordant results, proving the clinical value of ictal source localization.
Seizure identification, selection, and preparation of the ictal EEG signals for analysis were integrated into the clinical setting. The source analysis was done with blinding to the clinical data, and no iteration was allowed. The MRI pictures visualizing the estimated source of the ictal EEG activity are easy to understand also for those physicians who are less familiar with EEG, and thus help communicating the results at the multidisciplinary conferences. The main goal of our approach was to equip the clinical neurophysiologist with an additional reliable tool and not to advocate the replacement of the clinical expertise with an automated method.
Pacia & Ebersole (1997), using simultaneous intracranial and surface recordings, elegantly showed that ictal activity confined to the hippocampus did not result in scalp EEG rhythms. This was explained by (1) the small volume of the hippocampus; (2) its curved geometry which causes field cancellation; and (3) the usual shielding effect of the skull and scalp. Nevertheless, scalp EEG rhythms appeared when the adjacent temporal cortex became involved. On the mesial part of the temporal lobe, the cortical structures adjacent to hippocampus are the parahippocampal gyrus and the mesial part of the fusiform gyrus. The distributed source model in our study did not show ictal activity confined to hippocampus in any of the patients with hippocampal sclerosis. In these patients the ictal activation typically appeared in the adjacent temporal cortical structures: parahippocampal gyrus, fusiform gyrus, temporal pole, and inferior temporal gyrus (Fig. 4; Data S3). This pattern was consistent with the results of the studies using simultaneous scalp and intracranial recordings.
Our study focused solely on the rhythmic ictal activity and as such does not allow for the extrapolation of its results to the other ictal EEG patterns, for example, suppression, repetitive epileptiform activity, and arrhythmic activity (Foldvary et al., 2001). Further prospective studies are needed to assess the diagnostic accuracy of source localization of these patterns. Moreover, as most of the seizures (67%) with rhythmic ictal activity originate in the temporal lobe (Foldvary et al., 2001), this constituted a selection bias in our study.
Our results can apply only to the group of patients in which a reference standard could be obtained. Ictal source analysis yielded localization results in the other patients too; however, due to lack of reference standard, the accuracy of these results could not be determined.
In all operated patients, the surgical intervention was planned based on the consensus conclusion of the multidisciplinary team. Sixteen of the 20 patients became seizure free. Therefore, the multimodal, consensus conclusion gave a PPV of 80%. The index test based on a single modality (ictal source imaging) gave a PPV of 92%.
Despite the high sensitivity and PPV, the ictal source localization gave relatively low NPV (43%) in our study. This could be partially due to the relatively low number of patients who underwent resection not including the cortical area showed by the ictal source localization. The NPV of source imaging of interictal epileptiform discharges increased significantly (from 15% to 50%) when using a high-density electrode array and individual MRI (Brodbeck et al., 2011). Therefore it is reasonable to assume that long-term EEG recordings with high-density EEG array would improve the overall performance of the ictal source localization. Further prospective studies on large patient populations are needed to elucidate whether this is feasible in a clinical setting and whether it provides an added value that is cost-effective. At the time we designed this study, the high-density EEG caps were not suitable for long-term recordings. Today, however, high-density EEG nets specially designed for long-term monitoring are available.
In conclusion, our results suggest that source localization of the rhythmic ictal activity, using a standardized method for selection and preparation of the ictal EEG signals, provides reliable solutions at sublobar resolution and that as such it should be included into the key armamentarium of the clinical neurophysiologist interpreting ictal EEG recordings.