Clinical Neurophysiology 129 (2018) 1291–1299

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Clinical Neurophysiology
journal homepage: www.elsevier.com/locate/clinph

Automatic ictal onset source localization in presurgical epilepsy

evaluation
Johannes Koren a, Gerhard Gritsch c, Susanne Pirker a, Johannes Herta b, Hannes Perko c, Tilmann Kluge c,
Christoph Baumgartner a,d,⇑
a
Karl Landsteiner Institute for Clinical Epilepsy Research and Cognitive Neurology, Neurological Department, General Hospital Hietzing with Neurological Center Rosenhügel,
Vienna, Austria
b
Department of Neurosurgery, Medical University of Vienna, Vienna, Austria
c
Austrian Institute of Technology GmbH (AIT), Safety & Security Department, Vienna, Austria
d
Department of Epileptology and Clinical Neurophysiology, Sigmund Freud University, Vienna, Austria

a r t i c l e i n f o h i g h l i g h t s

Article history:
 Ictal onset source localization (IOSL) showed high diagnostic accuracy during presurgical evaluation.
Accepted 24 March 2018
 IOSL contributes to a correct localization of the seizure onset zone on a sublobar level.
Available online 6 April 2018
 IOSL can be obtained within 5 minutes per seizure and used in standard epilepsy monitoring settings.

Keywords:
Ictal
Source localization a b s t r a c t
Electric source imaging
EpiSource
Objective: To test the diagnostic accuracy of a new automatic algorithm for ictal onset source localization
Epilepsy surgery (IOSL) during routine presurgical epilepsy evaluation following STARD (Standards for Reporting of
Diagnostic Accuracy) criteria.
Methods: We included 28 consecutive patients with refractory focal epilepsy (25 patients with temporal
lobe epilepsy (TLE) and 3 with extratemporal epilepsy) who underwent resective epilepsy surgery. Ictal
EEG patterns were analyzed with a novel automatic IOSL algorithm. IOSL source localizations on a sublobar
level were validated by comparison with actual resection sites and seizure free outcome 2 years after sur-
gery.
Results: Sensitivity of IOSL was 92.3% (TLE: 92.3%); specificity 60% (TLE: 50%); positive predictive value
66.7% (TLE: 66.7%); and negative predictive value 90% (TLE: 85.7%). The likelihood ratio was more than
ten times higher for concordant IOSL results as compared to discordant results (p = 0.013).
Conclusions: We demonstrated the clinical feasibility of our IOSL approach yielding reasonable high
performance measures on a sublobar level.
Significance: Our IOSL method may contribute to a correct localization of the seizure onset zone in temporal
lobe epilepsy and can readily be used in standard epilepsy monitoring settings. Further studies are needed
for validation in extratemporal epilepsy.
Ó 2018 Published by Elsevier B.V. on behalf of International Federation of Clinical Neurophysiology.

Abbreviations: amTLR, anteromesial temporal lobe resection; ESI, electrical

source imaging; IOSL, ictal onset source localization; LAURA, local autoregressive
average; LORETA, low resolution electromagnetic tomography; MRI, magnetic
resonance imaging; MUSIC, multiple signal classification; sAHE, selective
amygdala-hippocampectomy; sLORETA, standardized low resolution electromag-
netic tomography; SMAC, spherical model with anatomical constraints; SNR, signal-
to-noise ratio,; SOZ, seizure onset zone; SPECT, single-photon emission computed
tomography; TLE, temporal lobe epilepsy; mTLE, mesial temporal lobe epilepsy;
TLR, temporal lobe resection; vEEG, video electroencephalography.
⇑ Corresponding author at: Karl Landsteiner Institute for Clinical Epilepsy
Research and Cognitive Neurology, Neurological Department, General Hospital
Hietzing with Neurological Center Rosenhügel, Riedelgasse 5, 1130 Vienna, Austria.
E-mail address: christoph.baumgartner@wienkav.at (C. Baumgartner).
1. Introduction
Epilepsy surgery is a valuable treatment option for patients
with medically refractory epilepsy (Rosenow and Luders, 2001).
Successful surgical treatment depends on a thorough presurgical
evaluation localizing the epileptogenic zone and essential brain
regions in each individual patient (Rosenow and Luders, 2001).
Video-EEG monitoring is one of the cornerstones of each presur-
gical evaluation with interictal EEG providing information on the

https://doi.org/10.1016/j.clinph.2018.03.020
1388-2457/Ó 2018 Published by Elsevier B.V. on behalf of International Federation of Clinical Neurophysiology.
1292 J. Koren et al. / Clinical Neurophysiology 129 (2018) 1291–1299
irritative zone and ictal EEG localizing the seizure onset zone
(SOZ). While routine clinical practice still relies on visual analy-
sis of EEG data, electrical source imaging (ESI) facilitates attribu-
tion of epileptiform EEG discharges to the three-dimensional
intracerebral location of their neuronal generators and thus sig-
nificantly increases the localizing information of EEG (Brodbeck
et al., 2011). Most studies on ESI concentrated on interictal
EEG data and thus on better delineation of the irritative zone
because spike averaging improves signal-to-noise ratio and
therefore robustness of source modeling (Bast et al., 2006;
Leijten and Huiskamp, 2008; Brodbeck et al., 2011; Scherg
et al., 2012; Megevand et al., 2014). However, accurate localiza-
tion of the SOZ by ESI of ictal EEG data (ictal onset source local-
ization – IOSL) seems even more important for surgical planning
(Merlet and Gotman, 2001). So far several studies using different
ictal source localization techniques have reported concordance
between 37.5% and 100% with the actual SOZ (Assaf and
Ebersole, 1997; Blanke et al., 2000; Lantz et al., 2001; Jung
et al., 2009; Lee et al., 2009; Stern et al., 2009; Holmes et al.,
2010; Yang et al., 2011; Lu et al., 2012; Beniczky et al., 2013;
Breedlove et al., 2014; Akdeniz 2016). Various reference stan-
dards for IOSL confirmation were used: interictal EEG (Boon
and D’Have, 1995; Koutroumanidis et al., 2004; Valentin et al.,
2014), intracranial EEG (Assaf and Ebersole, 1997; Lantz et al.,
2001; Merlet and Gotman, 2001; Koessler et al., 2010), postsur-
gical outcome (Assaf and Ebersole, 1999; Lantz et al., 1999;
Blanke et al., 2000; Jung et al., 2009; Lee et al., 2009; Lu et al.,
2012; Breedlove et al., 2014), MRI (Worrell et al., 2000), ictal
SPECT (Beniczky et al., 2006; Habib et al., 2016), decision of
the multidisciplinary epilepsy surgery team (Beniczky et al.,
2013) or a combination thereof (Boon et al., 2002; Ding et al.,
2007; Stern et al., 2009; Holmes et al., 2010; Yang et al.,
2011). Only one recent publication using a distributed source
model (LAURA) to localize ictal activity reported precise perfor-
mance measures (sensitivity of 70%, specificity of 76% and PPV
of 92%) (Beniczky et al., 2013).
Several drawbacks and difficulties regarding ictal source local-
ization analysis of scalp EEG recordings have to be considered:
possible low signal-to-noise ratio, lack of ictal EEG correlates
in scalp recordings during seizure onset, rapid propagation or
already propagated ictal patterns in scalp EEGs and artifacts
obscuring EEG seizure patterns (Pacia and Ebersole, 1997;
Alarcon et al., 2001; Foldvary et al., 2001; Rosenow and
Luders, 2001; Boon et al., 2002; Beniczky et al., 2013). Most
important no standard method of IOSL has been established so
far (dipole modeling, LORETA, sLORETA, MUSIC, LAURA, etc.)
and most methods require highly interactive analysis of ictal
EEG patterns including individual parameter adjustments which
complicates the use of IOSL in clinical practice (Koessler et al.,
2010).
We developed a new automatic algorithm which requires only
visual selection of the EEG pattern at ictal onset. The algorithm
then automatically performs source localization without further
interactions and parameter adjustments by the user, making IOSL
results easy to obtain, reproducible and objective. Solutions can
be obtained within five minutes per seizure. Therefore the algo-
rithm can be used in everyday clinical practice in the epilepsy
monitoring unit. We tested the algorithm’s diagnostic accuracy in
a standard long-term video-EEG monitoring setting following
STARD (Standards for Reporting of Diagnostic Accuracy) criteria.
Postoperative outcome two years after resective epilepsy surgery
was used as reference standard. We hypothesized that IOSL results
correctly localized the SOZ if IOSL matched the actual resection site
on a sublobar level and patients were seizure free after epilepsy
surgery.
2. Methods
2.1. Patient selection
We searched our database for patients with refractory focal epi-
lepsy who were admitted for presurgical evaluation in our center
and subsequently underwent resective epilepsy surgery. We
included all patients for whom raw EEG data was available and
identified in this way 30 consecutive operated patients. All patients
gave their informed consent prior to being admitted to long-term
video EEG (vEEG) monitoring. The local ethics committee approved
the study.
2.2. EEG data
Long-term vEEGs were recorded from 23 electrodes placed
according to the Extended International 10–20-system (including
additional ‘true’ anterior temporal electrodes FT9/FT10) and TP9/
TP10 at a 256 Hz sampling rate using a Micromed EEG recording
system (SystemPlus Evolution, Veneto, Italy). Patients’ EEG record-
ings were visually analyzed by board certified electroencephalog-
raphers (JK, SP and CB). We visually determined time, location
and frequency of the EEG pattern at onset of every seizure defined
according to criteria previously published (Foldvary et al., 2001).
We excluded seizures obscured by artifacts from further analysis.
All included seizures were anonymized and randomized. IOSL
was applied to the pattern at onset of these seizures by an inde-
pendent reviewer (GG) who was blinded to all clinical data.
2.3. Visual EEG seizure onset localization
We systematically localized seizure onset zones visually
according to criteria proposed by Foldvary et al. (2001). Specifically
we distinguished between the following seizure onset localiza-
tions: 1. Generalized seizure onset: activity involving multiple
electrodes over both hemispheres having a less than 2:1 amplitude
predominance over one hemisphere; 2. Lateralized seizure onset:
activity involving multiple electrodes over multiple lobes of a sin-
gle hemisphere having a 2:1 or greater amplitude predominance
over this hemisphere; 3. Regional or lobar seizure onset: activity
involving electrodes overlying a single lobe having a 2:1 or greater
amplitude predominance than that seen over other regions of the
same hemisphere; 4. Focal or sublobar seizure onset: activity with
a maximum at a single electrode with no more than 2 contiguous
electrodes within 80% to 100% of the maximum amplitude
(Foldvary et al., 2001). In temporal lobe seizures, we assigned a
medio-basal seizure onset localization if ictal activity fulfilled
these criteria with a maximum at electrodes FT9 or FT10, respec-
tively and a lateral temporal seizure onset localization if ictal activ-
ity fulfilled these criteria with a maximum at electrodes T7 or T8,
respectively.
2.4. Ictal onset source localization
The core idea of our ictal onset source localization (IOSL) tech-
nique was to automatically determine the most dominant rhyth-
mic EEG pattern within the earliest ictal activity, i.e. the first
change in EEG time–frequency plots. Next, we implemented a fre-
quency dependent time window which had to contain at least
eight ictal waves or discharges (e.g. 4 Hz ictal activity = time win-
dow of 2 s; 8 Hz ictal activity = time window of 1 s) to the selected
ictal activity. The spatial distribution of this rhythmic activity over
all EEG electrodes was the basis for our source localization method,
leading to an automatic localization approach. The inverse method
used in our study was a frequency domain version of the minimum
 J. Koren et al. / Clinical Neurophysiology 129 (2018) 1291–1299 1293

variance beamformer (MVB) based on a Spherical Model with
Anatomical Constraints (SMAC) (Spinelli et al., 2000) head model
derived from the Colin 27 Average Brain (Montreal Neurological
Institute) (Gritsch et al., 2011). The MVB tends to determine ictal
activity as a more focal solution rather than a distributed one
(Robinson et al., 1999; Gritsch et al., 2011). Finally, the spatial ori-
gin of ictal EEG activity was visualized in a graphical user interface,
presenting the corresponding neural activity as color coded overlay
in coronal, sagittal and axial slices on a standard MRI. No activity
was represented as dark blue, activities in the range of 50% of
the maximum strength were colored green and the region of max-
imum activity was visualized in red. We used a threshold of 50% for
depicting IOSL results and concentrated on the maximum activity.
With this commercially available software tool (EpiSource; www.
encevis.com) all representative seizures were blindly analyzed by
one co-author (GG). The graphical results of the calculated ictal
activity at the time of seizure onset were saved. The complete
source localization procedure took approximately five minutes
per seizure.
TN/[TN + FN]), positive likelihood ratio (LR+; sensitivity/[1–specifi
city]) and negative likelihood ratio (LR-; [1–sensitivity]/specificity)
were calculated. Performance measures for visual seizure onset
localization were calculated in the same manner as for IOSL.
2.8. Statistical analysis
We determined agreement between visual seizure onset local-
ization, IOSL and surgical resection location with weighted Cohen’s
Kappa. Values were interpreted according to the following criteria:
no agreement (k  0), slight (0.01–0.2), fair (0.21–0.4), moderate
(0.41–0.6), substantial (0.61–0.8) and almost perfect agreement
(>0.8) (Landis et al., 1977). Sensitivity and specificity of the IOSL
method was statistically tested using Chi-Square test. Yates’ cor-
rection for continuity was used if necessary. Level of significance
was set to p = 0.05 for all statistical tests. We used Microsoft Excel
2007 and IBM SPSS Statistics 19 for calculations and statistical
testing.

2.5. Agreement of visual seizure onset localization, IOSL and surgical

3. Results
resection location
We included 28 consecutive operated patients in our study
We determined the agreement between visual seizure onset
(Fig. 1). 25 subjects (89.2%) suffered from temporal lobe epilepsy
localization, IOSL and surgical resection location using the follow-
(TLE subgroup). Patients showed the following demographic
ing location categories with respect to previous studies (Beniczky
characteristics: mean age at surgical resection was 41 years (range
et al., 2013): left temporal medio-basal, right temporal medio-
15–61) and 57.1% (16) were female. Individual clinical characteris-
basal, left temporal lateral, right temporal lateral, left temporal
tics, visual seizure onset localization, IOSL localization, resection
medio-basal and lateral, right temporal medio-basal and lateral,
site and postoperative seizure outcome are shown in Table 1. We
extratemporal. We chose these categories because most subjects
excluded two patients because all their recorded seizures were
in our study suffered from temporal lobe epilepsy (TLE subgroup;
obscured by artifacts. The 28 included patients had a total of 146
25 of 28 patients, 89%).
seizures during long-term video EEG monitoring (range: 1–15
seizures per patient). We had to exclude 76 seizures from further
2.6. Postoperative outcome
analysis due to obscuration by artifacts. Thus, IOSL could be
applied in 70 seizures (range: 1–6 seizures per patient).
We determined two-years postoperative seizure outcome of all
included patients according to the ILAE classification (Wieser et al.,
2001). We divided patients into two groups based on postoperative
outcome two years after epilepsy surgery:

(1) seizure-free group: patient achieved sustained complete sei-

zure freedom (including freedom from auras) after epilepsy
surgery (ILAE Class 1a)
(2) seizure group: patient did not achieve complete seizure free-
dom after epilepsy surgery (ILAE Class 1 to 6).

2.7. Performance analysis of localization results

We defined the following reference standard for seizure onset

zone localization: seizure-freedom (including freedom from auras;
ILAE Class 1a) for at least two years after epilepsy surgery. We
compared IOSL results with our defined reference standard. If IOSL
results matched surgical resection location exactly or if resection
location was more extended but still contained the IOSL result
completely in a seizure free patient, then IOSL was classified as
true positive (TP). If a single patient got more than one seizure,
IOSL results of every single seizure had to match the surgical resec-
tion location in a seizure free patient in order to be classified as TP.
If IOSL and surgical resection location did not match in patients
with ongoing seizures, IOSL was classified as true negative (TN).
False positive (FP) localization results were defined as IOSL match-
ing the actual resection location in a patient with ongoing seizures.
False negative (FN) localization results were defined as IOSL not Fig. 1. Flowchart of the study; Concordant localization is a match between ictal
onset source localization (IOSL) and the actual epilepsy surgery resection location at
matching the actual resection location in a seizure free patient. sublobar level. Discordant localization is no match between ictal onset source
Sensitivity (TP/[TP + FN]), specificity (TN/[TN + FP]), positive pre- localization (IOSL) and the actual epilepsy surgery resection location at sublobar
dictive value (PPV; TP/[TP + FP]), negative predictive value (NPV; level.
1294 J. Koren et al. / Clinical Neurophysiology 129 (2018) 1291–1299

Table 1
Patients clinical characteristics. MRI: magnetic resonance imaging; L: left; R: right; FCD: focal cortical dysplasia; ILAE: International league against epilepsy.

Patient Age at MRI Visual seizure onset Ictal onset source Resection site Two-years
surgery localization localization postoperative
outcome
#01 37 Incidental lesion right temporal R hemispheric R medio-basal and R temporal lobe resection ILAE class 4
lateral temporal
R temporo-parietal
#02 50 L hypoplastic anterior temporal lobe R temporal R medio-basal R anteromesial temporal ILAE class 1a
temporal lobe resection
#03 28 R lateral frontal FCD R temporal R medio-basal and R lateral frontal ILAE class 5
lateral temporal lesionectomy
R insula
#04 45 Normal R hemispheric and R R medial occipital lobe R lateral temporo-occipital ILAE class 4
parietal resection
#05 53 L hippocampal sclerosis L temporal L medio-basal L anteromesial temporal ILAE class 3
temporal lobe resection
#06 15 L hippocampal sclerosis L hemispheric L medial frontal L anteromesial temporal ILAE class 1a
L insula lobe resection
#07 53 L hippocampal atrophy L temporal L medio-basal L selective ILAE class 3
temporal amygdalohippocampectomy
L lateral frontal
#08 51 L medio-basal-and-lateral temporal L temporal L medio-basal and L temporal lobe resection ILAE class 3
posthemorrhagic lesion lateral temporal
L insula
#09 28 Normal R temporal R medio-basal R anteromesial temporal ILAE class 4
temporal lobe resection
#10 37 Normal R hemispheric and R R medio-basal R anteromesial temporal ILAE class 1a
temporal temporal lobe resection
#11 37 R hippocampal atrophy R temporal L medio-basal R anteromesial temporal ILAE class 3
temporal lobe resection
#12 35 Normal L temporal L medio-basal L anteromesial temporal ILAE class 1a
temporal lobe resection
#13 50 L hippocampal atrophy L temporal L medio-basal L anteromesial temporal ILAE class 1a
temporal lobe resection
#14 29 L hippocampal atrophy L temporal L medio-basal L anteromesial temporal ILAE class 3
temporal lobe resection
#15 49 Normal L temporal L medio-basal L selective ILAE class 1a
temporal amygdalohippocampectomy
#16 29 L hippocampal sclerosis L hemispheric L medio-basal and L selective ILAE class 4
lateral temporal amygdalohippocampectomy
#17 51 L hippocampal sclerosis L hemispheric and L L medio-basal L anteromesial temporal ILAE class 1a
temporal temporal lobe resection
#18 44 L temporo-occipital cystic lesion L temporal L medio-basal L medial temporo-occipital ILAE class 3
temporal lesionectomy
#19 61 R hippocampal atrophy R hemispheric R medio-basal R anteromesial temporal ILAE class 1a
temporal lobe resection
#20 52 R hippocampal sclerosis R temporal R medio-basal and R selective ILAE class 3
lateral temporal amygdalohippocampectomy
#21 39 R hippocampal sclerosis R temporal, L R medio-basal R anteromesial temporal ILAE class 3
temporal temporal lobe resection
#22 52 L hippocampal sclerosis L hemispheric L medio-basal L selective ILAE class 1a
temporal amygdalohippocampectomy
#23 38 Normal R temporal R medio-basal R anteromesial temporal ILAE class 3
temporal lobe resection
#24 31 R hippocampal sclerosis R temporal R medio-basal R selective ILAE class 1a
temporal amygdalohippocampectomy
#25 58 Normal R temporal R medio-basal and R temporal lobe resection ILAE class 5
lateral temporal
#26 41 L medio-basal temporal ganglioglioma L temporal L medio-basal L medio-basal temporal ILAE class 1a
temporal lesionectomy
#27 31 R occipital postoperative lesion R temporal R medio-basal R selective ILAE class 1a
temporal amygdalohippocampectomy
#28 37 R hippocampal sclerosis R temporal R medio-basal R selective ILAE class 1a
temporal amygdalohippocampectomy

3.1. Agreement between visual seizure onset localization and surgical
resection location
Visual seizure onset localization revealed four patients with a
lateralized, right hemispheric seizure onset (14.3%; within this
group, one patient had also an additional regional, right tempo-
ral seizure onset and one patient an additional regional, right
parietal seizure onset), four patients with a lateralized, left hemi-
spheric visual seizure onset (14.3%; within this group, one
patient showed an additional regional, left temporal seizure
onset), 10 subjects with a regional, right temporal seizure onset
(35.7%), nine subjects with a regional, left temporal seizure onset
(32.1%) and one patient with separate regional, right and left
temporal seizure onset localizations (3.6%; Table 1). It needs to
 J. Koren et al. / Clinical Neurophysiology 129 (2018) 1291–1299
be stressed that a sublobar localization based on our visual EEG
analysis criteria could not be achieved in any seizure. Therefore,
we could not assess an agreement on the sublobar level.
3.2. Agreement between ictal onset source localization and surgical
resection location
Kappa values showed substantial agreement between ictal
onset source localization (IOSL) and actual resection site for all
included patients (0.618) and the TLE subgroup (0.645). IOSL
showed consistent localization results in 23 patients. 5 patients
showed multiple different ictal onset source localizations for dif-
ferent seizures (Table 1 and Fig. 2).
IOSL results were localized within the surgical resection site in
18 of 28 patients (64.3%) of the entire patient group and in 18 of 25
patients (72%) in the TLE subgroup (Fig. 1). 8 patients (28.6%)
underwent selective amygdalohippocampectomy, 13 (46.4%) had
an anteromesial temporal lobe resection, three (10.7%) had a tem-
poral lobe resection and four (14.3%) had a lesionectomy (1 tempo-
ral, 3 extratemporal).
The results of IOSL, surgical resection site and postoperative sei-
zure outcome are shown in Fig. 2. In 19 of 28 patients (67.9%) IOSL
localized the seizure onset zone exclusively to the medio-basal
temporal compartment. In five of these patients (26.3%) a selective
amygdala-hippocampectomy (sAHE) was performed, all of them
became seizure free and therefore were classified as TP. In 12
patients (63.1%) an anteromesial temporal lobe resection (amTLR)
was performed, six patients (50%) became seizure free and were
classified as TP. Five patients (41.7%) were not seizure free after
surgery and classified as FP. One patient (8.3%) was localized to
the contralateral medio-basal temporal lobe, did not become
seizure free and was classified as TN. In two patients (10.6%) a
lesionectomy was performed: one subject had a medio-basal tem-
poral ganglioglioma, was seizure free after surgery and therefore
classified as TP. The other patient had a temporo-occipital cystic
lesion, was not seizure free after surgery and therefore classified
as TN.
Three patients (10.7%) were localized to the medio-basal and
the lateral temporal compartment. Two patients (66.7%) under-
went a sAHE, did not became seizure free and thus were consid-
ered as TN. The other patient had a temporal lobe resection
(TLR), was not seizure free after surgery and therefore was classi-
fied as FP.
In one patient (3.6%) IOSL localized to a single extratemporal
compartment, namely to the medial occipital lobe. This patient
underwent a lateral temporo-occipital resection. He did not
became seizure free and was therefore classified as TN.
5 patients (17.8%) showed multiple different ictal onset source
localizations for different seizures: One patient showed a frontal
medial and insular IOSL and underwent an amTLR. He became sei-
zure free and thus considered as FN. In one patient with a medio-
basal, lateral temporal and temporo-parietal IOSL a TLR was
performed. In two patients IOSL localized to the medio-basal and
the lateral temporal compartment as well as to the insular cortex,
one patient underwent a TLR, the other one a lateral frontal
lesionectomy. The fifth patient showed a medio-basal temporal
and lateral frontal IOSL and underwent a sAHE. The latter four sub-
jects did not become seizure free and therefore were classified as
TN.
Chi-Square test after Yates correction revealed statistical signif-
icance of our IOSL results (p = 0.013). Results shifted just slightly in
the TLE subgroup but were not statistical significant anymore after
Yates correction (p = 0.056).
Fig. 3 shows an example of a concordant IOSL result: A 37-year-
old male with right mesial TLE and hippocampal sclerosis, who
underwent a selective amygdalohippocampectomy and was
1295
seizure free for at least two years after epilepsy surgery. IOSL local-
ized to the right medio-basal temporal lobe. Fig. 4 shows an exam-
ple of a discordant IOSL result: A 28-year-old female with focal
cortical dysplasia (FCD) in the right frontal lobe who underwent
a lesionectomy and was not seizure free after epilepsy surgery.
IOSL were outside the lesions in the medio-basal and the lateral
temporal compartment as well as in the insular cortex.
Seven patients were MRI negative, meaning no lesion could be
identified on preoperative MRI scans. In this specific patient sub-
group IOSL results showed concordance with the actual resection
site in six cases (85.7%).
3.3. Performance measures of visual seizure onset localization and
IOSL
For visual EEG seizure onset localization, we could not calculate
performance measures on the sublobar level. We therefore calcu-
lated performance measures on the lobar level: eight TP (28.6%),
six TN (21.4%), nine FP (32.1%) and five FN (17.9%); Sensitivity of
visual EEG analysis for the entire patient group was 61.5%, speci-
ficity was 40%, PPV was 47.1% and NPV was 54.6%.
For IOSL, we observed 12 TP (42.9%), nine TN (32.1%), six FP
(21.4%) and one FN (3.6%) on the sublobar level (Fig. 2). Perfor-
mance measures of IOSL for the entire patient group and for the
TLE subgroup were as follows:
– Sensitivity 92.3% (entire patient group); 92.3% (TLE subgroup)
– Specificity 60%; 50%
– Positive predictive value (PPV) 66.7%; 66.7%
– Negative predictive value (NPV) 90%; 85.7%
– Positive likelihood ratio (LR+) 2.31; 1.85
– Negative likelihood ratio (LR ) 0.13; 0.15
4. Discussion
We studied a novel automatic ictal onset source localization
(IOSL) method (frequency domain version of the minimum
variance beamformer) in 28 consecutive patients with refractory
focal epilepsy who underwent resective epilepsy surgery applying
STARD criteria. IOSL was performed on individual seizure data
obtained during presurgical video-EEG monitoring using a
standard head model.
Sensitivity of our IOSL method was very high (92.3%) while
specificity was moderate (60%). Assaf and Ebersole (1997) reported
low sensitivity between 36% and 66% and high specificity between
92% and 96% in 40 patients with TLE using multiple fixed dipole
modeling (Assaf and Ebersole, 1997). Other studies showed good
agreement (63–100%) of IOSL with postsurgical outcome or
intracranial EEG recordings in small patient cohorts (5–15 sub-
jects) (Blanke et al., 2000; Lantz et al., 2001; Stern et al., 2009;
Holmes et al., 2010; Yang et al., 2011; Akdeniz 2016). Boon et al.
(2002) included 100 patients but IOSL could be applied in only
31 patients due to artifacts. Ultimately IOSL played a key role in
the surgical decision process in 14 patients but performance mea-
sures were not reported. This publication is the only prospective
IOSL study to date to the best of our knowledge (Boon et al., 2002).
Only one previous blinded study reported performance mea-
sures following STARD criteria so far (Beniczky et al., 2013). In this
study a sensitivity of 70% and a specificity of 76% was reported.
Likelihood ratios were similar to our study: We found a positive
likelihood ratio (LR+) of 2.31 (corresponding to concordant IOSL
results) and a negative likelihood ratio of (LR ) of 0.13 (corre-
sponding to discordant results), while Beniczky et al. (2013)
reported a LR+ of 3 and a LR of 0.33. This significant difference
of LR+ versus LR proves the clinical value of ictal onset source
localization.
1296 J. Koren et al. / Clinical Neurophysiology 129 (2018) 1291–1299

Fig. 2. Flowchart of ictal onset source localization results, resection sites and postoperative seizure outcome; * = one patient was localized to the contralateral medio-basal
temporal lobe, did not became seizure free after surgery and therefore was considered as true negative; # = one patient underwent a mesial temporal lobe lesionectomy and
one patient had a medial temporo-occipital lesionectomy; à = this specific patient was localized to the medial occipital lobe and underwent a lateral temporo-occipital
resection; sAHE: selective amygdala-hippocampectomy; amTLR: anteromesial temporal lobe resection; TLR: temporal lobe resection; TP: true positive; FP: false positive; TN:
true negative; FN: false negative.

Our IOSL method showed a moderate positive predictive does not match the planned resection site in a given patient, a
value (PPV) of 66.7% and a high negative predictive value reevaluation of the current surgical hypothesis needs to be
(NPV) of 90%. We believe that the high NPV represents a main undertaken before proceeding to surgery with a high risk of sur-
finding of our study with immediate clinical implications. If IOSL gical failure.
 J. Koren et al. / Clinical Neurophysiology 129 (2018) 1291–1299 1297

Fig. 3. Example of a patient with concordant ictal onset source localization (IOSL) results: 37-year-old male with right mesial temporal lobe epilepsy (TLE) and hippocampal
sclerosis. The corresponding ictal EEG shows a high signal-to-noise ratio and high rhythmicity. The depicted IOSL images show coronal, sagittal and axial slices with highest
seizure activity. The time-frequency plot detects changes in frequency (in Hz) over time of the analyzed seizure.

Fig. 4. Example of a patient with discordant ictal onset source localization (IOSL) results: 28-year-old female with focal cortical dysplasia in the right frontal lobe. The
corresponding ictal EEG shows a low signal-to-noise ratio and rather weak rhythmicity. The depicted IOSL images show coronal, sagittal and axial slices with highest seizure
activity. The time-frequency plot detects changes in frequency (in Hz) over time of the analyzed seizure. IOSL were outside the lesions in the medio-basal and the lateral
temporal compartment as well as in the insular cortex.

Beniczky et al. (2013) reported a high PPV of 92% and very low (2013) validated IOSL results by multidisciplinary consensus of
NPV of 43%. We assume that this discrepancy can be explained by the epilepsy surgery team. On the contrary, we used resection site
the different validation method used in our study. Beniczky et al. and postoperative seizure outcome two years after surgery to
1298 J. Koren et al. / Clinical Neurophysiology 129 (2018) 1291–1299
validate the results of IOSL for the following reasons: Ictal EEG and
therefore IOSL delineate the seizure onset zone (SOZ). Because we
did not use invasive recordings and visual analysis of scalp-EEG
provides no accurate information on the location of the SOZ, we
chose the theoretical concept of the epileptogenic zone, i.e. the
area of brain which is indispensable to generate seizures, as refer-
ence standard for IOSL localizations (Rosenow and Luders, 2001).
Usually the epileptogenic zone contains the SOZ. We assumed that
the epileptogenic zone had been removed if a patient was com-
pletely seizure-free since surgery. However, it cannot be excluded,
that the resection volume actually was larger than the epilepto-
genic zone and the resection contained but was not identical to
the epileptogenic zone. We assumed that IOSL results were correct
if they were contained within the resection site and the patient
was completely seizure-free since surgery. It should be noted that
IOSL results never exactly matched the resection volume and that
our validation method therefore only represents a rough approxi-
mation for an accurate localization of the SOZ. Nevertheless, our
approach seems reasonable from a clinical standpoint because it
potentially provides additional information to guide resection in
individual patients. Furthermore, this approach was used in several
previous studies to validate electrical source imaging (ESI) (Assaf
and Ebersole, 1997; Lantz et al., 1999; Blanke et al., 2000; Boon
et al., 2002; Jung et al., 2009; Lee et al., 2009; Stern et al., 2009;
Holmes et al., 2010; Yang et al., 2011; Lu et al., 2012; Breedlove
et al., 2014).
In the study of Beniczky et al., 20 out of 42 included patients
were operated (Beniczky et al., 2013). They applied Engel’s classi-
fication and considered patients as seizure-free if they belonged
to Engel class I after one year, i.e. were free of seizures with loss
of awareness. We used the ILAE classification and classified
patients as seizure-free only if they achieved Class 1a outcome,
i.e. were completely seizure and aura free for two years. Therefore
the proportion of 46% seizure free patients in our study is consid-
erably lower compared to the 80% seizure free rate in Beniczky’s
study. However, our surgical results compare very well to the
results of de Tisi et al., who found an overall probability of 49%
for remaining completely seizure and aura free by two years
post-surgery (de Tisi et al., 2011).
One major limitation of our study is that the majority (89.2%) of
our patients suffered from temporal lobe epilepsy (TLE). Further-
more most TLE patients suffered from mesial TLE (mTLE) and thus
subsequently underwent resections limited to the mesial temporal
compartment. Overall 8 patients had a selective amygdalohip-
pocampectomy and 13 an anteromesial temporal lobe resection,
summing up to 75% of all surgical interventions in our cohort.
Furthermore mTLE patients comprise nearly all patients with sus-
tained seizure free outcome after surgery (11 out of 12 seizure free
patients; 91%). Thus, our general conclusions only apply to tempo-
ral lobe epilepsy and cannot be readily extrapolated to extratem-
poral cases. Further studies are needed to validate our method in
extratemporal epilepsy.
The four lesionectomy cases (one temporal, three extratempo-
ral) in our cohort showed the following results: one subject with
a medio-basal temporal ganglioglioma showed a concordant IOSL
results and was seizure free after surgery. The other three patients
suffering from extratemporal lesions (one frontal, two occipital)
showed discordant IOSL results, though IOSL localizations were
in close proximity to the lesion and the actual resection site. None
of these patients became seizure free after surgery, resulting in a
perfect performance of the IOSL method in these patients.
We demonstrated the added value of automatic IOSL in compar-
ison to visual EEG seizure onset localization because a sublobar
localization was only possible with IOSL and not with visual EEG
analysis. Performance measures for visual seizure onset localiza-
tion could not be calculated on the sublobar level and therefore
not directly compared to the sublobar performance measures of
IOSL. Nevertheless, performance measures on the sublobar level
of our automatic method were superior even to performance mea-
sures on the lobar level of visual analysis in our patient cohort.
Some important methodological issues of ictal source localiza-
tion need to be addressed: First, low signal-to-noise ratio (SNR)
is a major drawback. Previous publications solved this issue by
averaging ictal wave-forms (Assaf and Ebersole, 1997; Merlet and
Gotman, 2001; Beniczky et al., 2006, 2013). We localized seizures
with high SNR without averaging and excluded seizures with very
low SNR in a first step. Furthermore we used frequency domain
techniques implemented in the minimum variance beamformer
allowing for a simple suppression of noise and artifacts by focusing
only on frequency parts belonging to the desired ictal signal and
thus inherently increasing SNR (Gritsch et al., 2011). Second, fast
propagation of ictal activity in scalp EEG may cause false localiza-
tion. We aimed to localize the most dominant rhythmic EEG pat-
tern within the earliest ictal activity, i.e. the first change seen in
EEG time-frequency plots, and used a frequency dependent time
window. Therefore we cannot exclude modeling both activity in
the seizure onset zone (SOZ) as well as early propagated activity.
Nevertheless we believe that this approach is adequate due to
the limited spatial resolution and the fact that only the center of
gravity of the SOZ can be localized rather than detailed routes of
early propagation on ictal scalp EEG. It should be noted that
scalp-EEG cannot detect epileptic activity restricted to mesial tem-
poral structures especially to the hippocampus (Wennberg and
Cheyne, 2014). A recent EEG-fMRI study showed that interictal
spikes visible on scalp-EEG were associated with weaker BOLD
responses in temporal neocortex ipsilateral to stronger mesial
temporal BOLD responses suggesting that scalp-recorded spikes
result from mesial temporal spikes propagating to the temporal
neocortex (Watanabe et al., 2017). Our medio-basal ictal onset
source localizations therefore should be viewed as ictal activity
propagated from the mesial to the basal temporal compartment
rather than ictal activity restricted to the mesial temporal lobe.
Third, source localization accuracy can be significantly improved
with larger number of electrodes (Brodbeck et al., 2011; Lu et al.,
2012; Beniczky et al., 2013). To date only four IOSL studies with
relatively few patients (8–15) used more than 64 electrodes
(Koessler et al., 2010; Yang et al., 2011; Lu et al., 2012; Akdeniz
2016) and only one study applied high-density EEG (256 elec-
trodes) in 10 subjects (Holmes et al., 2010). We used a standard
10–20 electrode setup with additional true anterior temporal elec-
trodes because the present study was designed to assess diagnostic
accuracy of our IOSL method on a sublobar level and test its clinical
feasibility in a standard epilepsy monitoring unit environment.
Fourth, we used the Colin 27 Average Brain as basis for our head
model. One large-scale study showed that localization accuracy is
better if individual head models are used (Brodbeck et al., 2011).
Fifth, there are several reasons for mislocalization depending on
which inverse method is used. Our IOSL method for instance could
not exploit the full ictal EEG information in order to perform a cor-
rect localization if weak ictal EEG rhythmicity or fast propagation
of seizures was present. This dependence on rhythmicity explains
the poor localization performance in patients with extratemporal
epilepsy (Foldvary et al., 2001). In TLE patients, on the contrary,
our IOSL tool showed good results because rhythmic ictal activity
is frequently present in TLE.
One advantage of our method is that it can be applied readily in
a clinical setting without interactive parameter adjustments and
that results can be provided and interpreted within a few minutes.
So far only few studies reported on the time exposure of source
localization analysis of ictal EEG data. IOSL methods were very
time consuming in two studies, taking up to several hours (Boon
et al., 2002; Holmes et al., 2010). Beniczky et al. reported an extra
 J. Koren et al. / Clinical Neurophysiology 129 (2018) 1291–1299
time consumption of less than 30 min per patient (Beniczky et al.,
2013).
In conclusion, we demonstrated clinical feasibility of our ictal
onset source localization approach yielding reasonable high perfor-
mance measures in operated patients on a sublobar level. In partic-
ular we showed a very high NPV of our IOSL method, which may
lead to further investigations in patients with discrepancies
between IOSL and the planned resection site. We therefore believe
that IOSL provide clinically relevant information in a standard epi-
lepsy monitoring setting.
Disclosures
Johannes Koren and Johannes Herta were both partially sup-
ported by The Austrian Research Promotion Agency grant
826,816 (EpiMon). Algorithm development was conducted by the
Austrian Institute of Technology including the authors Gerhard
Gritsch, Hannes Perko and Tilmann Kluge. The Austrian Institute
of Technology is the manufacturer of the EEG software package
‘‘Encevis”, which will include the EpiSource algorithms.
We confirm that we have read the Journal’s position on issues
involved in ethical publication and affirm that this report is consis-
tent with those guidelines.
Acknowledgements
We like to thank Sofija Kopitovic, Ingeborg Moser and Sandra Zeckl
for their contribution and help during EEG data acquisition and
processing.
Statistical testing
Johannes Koren had full access to all the data in the study and
takes responsibility for the integrity of the data and the accuracy
of the data analysis.
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